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  • 301.
    Fahlgren, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Defence capabilities of human intestinal epithelial cells2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The epithelial cells lining the intestinal mucosa separate the underlying tissue from components of the intestinal lumen. Innate immunity mediated by intestinal epithelial cells (IECs) provides rapid protective functions against microorganisms. Innate immunity also participates in orchestrating adaptive immunity. Key components in innate defence are defensins.

    To study the production of defensins and how it is affected by intestinal inflammation IECs were isolated from the small and large intestines of patients suffering from ulcerative colitis (UC), Crohn´s disease (MbC), celiac disease (CD), and from controls, and analyzed by quantitative RT-PCR (qRT-PCR) and immunoflow cytometry. Defensin expressing cells were also studied by in situ hybridization and immunohistochemistry.

    Normally, only small intestinal Paneth cells express human α-defensin 5 (HD-5) and HD-6. In UC colon IECs, HD-5, HD-6, and lysozyme mRNAs were expressed at high levels. In Crohn´s colitis colon the levels of HD-5 and lysozyme mRNAs were also increased although not to the same extent as in UC. No increase was detected in MbC with ileal localization. Metaplastic Paneth cell differentiation in UC colon was primarily responsible for the expression of the antimicrobial components. Human β-defensin 1 (hBD-1) mRNA was more abundant in large than in small intestine of controls, and remained unchanged in UC and MbC. hBD-2 mRNA was barely detectable in normal intestine and was induced in UC IECs but not in MbC IECs. mRNAs for the recently discovered hBD-3 and hBD-4, were detected in IECs from both small and large intestine. Both hBD-3 and hBD-4 mRNA were significantly increased in IECs of UC patients but not of MbC patients. Bacteria and IL-1β induced hBD-2 but not hBD-1 mRNA in colon carcinoma cell lines. IFN-γ, but not TNF-α or IL-1β, augmented hBD-3 expression in these cells, while none of the agents induced hBD-4. High antimicrobial activity of IECs in UC may be a consequence of changes in the epithelial lining, which permit the adherence of microorganisms.

    Unexpectedly, in situ hybridization revealed expression of hBD-3 and hBD-4 mRNAs by numerous lamina propria cells in colonic tissue from UC patients. These cells were identified as plasma cells (CD138+). hBD-3 and hBD-4 mRNAs were also demonstrated in the plasmacytoma cell line U266. This is the first demonstration of defensins in plasma cells.

    The four prominent constituents of the intestinal glycocalyx, carcinoembryonic antigen (CEA), CEA cell adhesion molecule 1 (CEACAM1), CEACAM6 and CEACAM7 all seem to play a critical role in innate defence of the intestinal mucosa by trapping and expelling microorganisms at the epithelial surface. The inducibility of these molecules in colonic epithelial cell lines was analyzed by qRT-PCR, immunoflow cytometry, and immunoelectron microscopy. IFN-g but not bacteria, LPS, TNF-α, or IL-1β modified the expression of CEA, CEACAM1 and CEACAM6. None of these agents modified CEACAM7 expression. IFN-γ was shown to have two effects: a direct effect on CEACAM1 transcription, and promotion of cell differentiation resulting in increased CEA and CEACAM6 and decreased CEACAM7 expression.

    Scanning electron microscopy of jejunal biopsies from children with CD revealed the presence of rod shaped bacteria in ~40% of patients with active CD, but only in 2% of controls. 19% of treated CD patients still had adhering bacteria. Presence of bacteria is not due to lack of antimicrobial factors. In fact, HD-5, HD-6, and lysozyme mRNA levels were significantly increased in IECs of patients with active CD. hBD-1 and hBD-2 were unchanged. Lack of induction of hBD-2 may reflect disturbed signalling in IECs of CD patients. Analysis of CEA and CEACAM1 mRNA/protein expression showed no differences between CD patients and controls. Analysis of the mucins MUC2 and MUC3 revealed significantly increased MUC2 levels in active disease and unchanged MUC3. Immunohistochemistry demonstrated goblet cell metaplasia as well as staining of the apical portion of absorptive cells. Glycosylation status of proteins was studied by lectin histochemistry. Goblet cells in the mucosa of CD patients were stained by the lectin UEAI. This was not seen in controls. The lectin PNA stained the glycocalyx of controls but not that of CD patients. Thus, unique carbohydrate structures of the glycocalyx/mucous layer are likely discriminating features of CD patients and may allow bacterial binding.

    We conclude that the intestinal epithelium is heavily involved in the innate defence of the mucosa and that its reactive pattern is affected by intestinal inflammation.

    Keywords: human intestinal mucosa; epithelial cells; innate immunity; defensin; ulcerative colitis; Crohn´s disease; celiac disease; glycoαcalyx; mucin

  • 302.
    Fahlgren, Anna
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Avican, Kemal
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Westermark, Linda
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Nordfelth, Roland
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Fällman, Maria
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Colonization of cecum is important for development of persistent infection by Yersinia pseudotuberculosis2014In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 82, no 8, p. 3471-3482Article in journal (Refereed)
    Abstract [en]

    Yersiniosis is a human disease caused by the bacterium Yersinia pseudotuberculosis or Yersinia enterocolitica. The infection is usually resolved but can lead to postinfectious sequelae, including reactive arthritis and erythema nodosum. The commonly used Yersinia mouse infection model mimics acute infection in humans to some extent but leads to systemic infection and eventual death. Here, we analyzed sublethal infection doses of Y. pseudotuberculosis in mice in real time using bioluminescent imaging and found that infections using these lower doses result in extended periods of asymptomatic infections in a fraction of mice. In a search for the site for bacterial persistence, we found that the cecum was the primary colonization site and was the site where the organism resided during a 115-day infection period. Persistent infection was accompanied by sustained fecal shedding of cultivable bacteria. Cecal patches were identified as the primary site for cecal colonization during persistence. Y. pseudotuberculosis bacteria were present in inflammatory lesions, in localized foci, or as single cells and also in neutrophil exudates in the cecal lumen. The chronically colonized cecum may serve as a reservoir for dissemination of infection to extraintestinal sites, and a chronic inflammatory state may trigger the onset of postinfectious sequelae. This novel mouse model for bacterial persistence in cecum has potential as an investigative tool to unveil a deeper understanding of bacterial adaptation and host immune defense mechanisms during persistent infection.

  • 303.
    Falk, Ronny
    KTH, School of Biotechnology (BIO).
    Systems enabling antibody-mediated proteomics research2006Doctoral thesis, comprehensive summary (Other scientific)
    Abstract [en]

    As many genome sequencing efforts today are completed, we are now provided with the genetic maps for several organisms, including man. With these maps at hand, the scientific focus is now shifting towards investigations of the functionality of proteins. This task is even more challenging than the genomic field since proteins, in contrast to DNA, do not allow themselves to be specifically probed or amplified by easy and generic methods. However, to achieve knowledge regarding protein function, useful information includes where, when and how much certain proteins are expressed in an organism. Such information can be obtained if protein-specific binding molecules are available as tools. One such class of target specific binders are the antibody molecules, traditionally employed in a broad variety of biotechnical applications, including protein localization studies on both cellular and sub cellular levels.

    In a first serie of studies, new methodology for recombinant production and purification of antigens for generation of antibodies via immunization routes were investigated. Parallel affinity gene fusion-based expression systems were used for evaluation of different concepts for production of antigen and post-immunization antibody purification. Carefully designed protein antigens from different organisms were produced and used to raise antisera which were affinity purified on their respective antigens to obtain highly specific polyclonal antibodies (monospecific antibodies). One of the constructed expression systems includes an affinity handle, ZSPA-1, previously selected from a combinatorial protein library for its capacity to selectively bind protein A. This allows for convenient, non IgG-dependent, affinity purification of proteins on conventional protein A resins.

    A strategy where highly target specific antibody preparations could be affinity purified in a more streamlined setup is also presented. By this strategy it was possible to fractionate antibodies showing reactivity to different parts of the antigen into separate fractions. This resulted in affinity purified antibodies showing monospecific but still multi-epitope reactivity. Purified monospecific antibodies were used in different studies including Western blot immunofluorescence and recovery applications. For affinity purification of endogenous target from its native surrounding a selective elution strategy where the recombinant antigen was used to competitively elute the captured target was developed.

  • 304.
    Falk, Ronny
    et al.
    KTH, Superseded Departments, Biotechnology.
    Agaton, Charlotta
    KTH, Superseded Departments, Biotechnology.
    Kiesler, E.
    Jin, S.
    Wieslander, L.
    Visa, N.
    Hober, Sophia
    KTH, Superseded Departments, Biotechnology.
    Ståhl, Stefan
    KTH, Superseded Departments, Biotechnology.
    An improved dual-expression concept, generating high-quality antibodies for proteomics research2003In: Biotechnology and applied biochemistry, ISSN 0885-4513, E-ISSN 1470-8744, Vol. 38, p. 231-239Article in journal (Refereed)
    Abstract [en]

    A novel, improved dual bacterial-expression system, designed for large-scale generation of high-quality polyclonal antibody preparations intended for proteomics research, is presented. The concept involves parallel expression of cDNA-encoded proteins, as a fusion with two different tags in two separate vector systems. Both systems enable convenient blotting procedures for expression screening on crude bacterial cell cultures and single-step affinity purification under denaturing conditions. One of the fusion proteins is used to elicit antibodies, and the second fusion protein is used in an immobilized form as an affinity ligand to enrich antibodies with selective reactivity to the cDNA-encoded part, common for the two fusion proteins. To evaluate the system, four cDNA clones from putative nuclear proteins from the non-biting midge Chironomus tentans were expressed. Antibodies to these cDNA-encoded proteins were generated, enriched and used in blotting and immunofluorescence procedures to determine expression patterns for the native proteins corresponding to the cDNAs. The four antibody preparations showed specific reactivity to the corresponding recombinant cDNA-encoded proteins, and three of the four antibodies gave specific staining in Western-blot analysis of nuclear cell extracts. Furthermore, two of the antibody preparations gave specific staining in immunofluorescence analysis of C. tentans cells. We conclude that the dual-vector concept presented offers a highly stringent strategy for the generation of monospecific polyclonal antibodies, which are useful in proteomics research.

  • 305.
    Falk, Ronny
    et al.
    KTH, Superseded Departments, Biotechnology.
    Gräslund, Susanne
    KTH, Superseded Departments, Biotechnology.
    Brundell, Eva
    Höög, Christer
    Ståhl, Stefan
    KTH, Superseded Departments, Biotechnology.
    A high-stringency proteomics concept aimed for generation of antibodies specific for cDNAencoded proteins2002In: Biotechnology and applied biochemistry, ISSN 0885-4513, E-ISSN 1470-8744, Vol. 35, no 2, p. 75-82Article in journal (Refereed)
    Abstract [en]

    A novel dual bacterial expression system, designed for high-throughput generation of antibodies specific for cDNA-encoded proteins, is presented. The concept involves parallel expression of cDNA-encoded proteins, in two vector systems, as fusions with two different tags, both enabling single-step affinity purification under denaturing conditions. One of the fusion tags includes a portion with documented immunopotentiating effect to stimulate antibody production, and the generated fusion proteins are used to elicit antibodies. The second fusion protein is used in an immobilized form as an affinity ligand to enrich, from the generated antisera, antibodies with selective reactivity to the cDNA-encoded part. To evaluate the system, five cDNA clones from a mouse testis cDNA library were expressed, and antibodies to these cDNA-encoded proteins were generated, enriched and used in blotting procedures to determine expression patterns for the native proteins corresponding to the cDNAs. The five antibody preparations showed specific reactivity to the corresponding recombinant cDNA-encoded proteins, and three of the five antibodies gave specific staining in Western-blot screening of various cell types and tissue homogenates. When the same five cDNAs were processed and analysed using a single-vector method, antibodies with a more non-specific staining were generated. We thus conclude that the presented dual-vector method offers a highly stringent strategy for generation of monospecific polyclonal antibodies.

  • 306.
    Falkeborn, Tina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Nasal vaccination using novel mucosal adjuvants: with main focus on influenza A virus2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Influenza viruses have sporadically caused pandemics during the last century, with the most severe occurring in 1918 when the “Spanish flu”, an A/H1N1 influenza virus, passed around the globe killing about 20-100 million people. Today 250 000-500 000 deaths occur annually due to influenza virus or secondary infection after influenza, e.g. pneumonia. Influenza viruses cause severe infections in susceptible age groups like children and elderly and in individuals with impaired immune response due to other medical conditions. The best way to prevent an influenza epidemic is by vaccination. Since the 1950´s we have vaccines against seasonal flu, but vaccine efficacy is not 100 % and there is a need to develop better and more effective vaccines, especially for the risk groups. Since the virus enters the host through the nasal cavity, nasal vaccination is a good approach. By stimulating a mucosal immune response already in the nasal cavity, the goal with nasal vaccination is to stop the virus before it enters the host. Nasal vaccination also reduces the risk of transmission of blood-borne diseases, and is less painful and easier to administer, compared to injectable vaccines.

    In order to be able to use less immunogenic antigens, like split and subunit antigens, as nasal vaccine components, an adjuvant is needed to enhance the immune response. At the moment there is no licensed mucosal adjuvant for human use. Several studies are ongoing, but it is a complicated and long way to reach the market. In this thesis nasal vaccination with influenza antigen together with the mucosal adjuvant Endocine™ and other mucosal adjuvants has been evaluated. The Endocine™ adjuvant has been shown to be safe and well tolerated in clinical trials. Depending on the pathogen of interest, different approaches are necessary. For HIV, DNA-vaccination has been evaluated together with a plasmid encoding Salmonella typhimurium flagellin C and the mucosal adjuvant N3. The results found in paper I-IV show that by adding adjuvant to the antigen enhances the protective immune response towards the antigen. Enhanced systemic, mucosal and cell-mediated immunity were observed. Hopefully in the future these adjuvants evaluated in this thesis, will be used in vaccines for humans.

  • 307.
    Falorni, Alberto
    et al.
    Univ Perugia, Dept Med, I-06126 Perugia, Italy..
    Bini, Vittorio
    Univ Perugia, Dept Med, I-06126 Perugia, Italy..
    Betterle, Corrado
    Univ Padua, Dept Med, Endocrine Unit, Padua, Italy..
    Brozzetti, Annalisa
    Univ Perugia, Dept Med, I-06126 Perugia, Italy..
    Castano, Luis
    Univ Basque Country, Cruces Univ Hosp, Ciberdem, BioCruces, Bilbao, Spain..
    Fichna, Marta
    Poznan Univ Med Sci, Dept Endocrinol & Metab, Poznan, Poland.;Polish Acad Sci, Inst Human Genet, PL-60479 Poznan, Poland..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mellgren, Gunnar
    Haukeland Hosp, Hormone Lab, N-5021 Bergen, Norway.;Univ Bergen, Dept Clin Sci, Bergen, Norway..
    Peterson, Pärt
    Univ Tartu, Inst Biomed & Translat Med, Mol Pathol, EE-50090 Tartu, Estonia..
    Chen, Shu
    RSR Ltd, FIRS Labs, Cardiff, S Glam, Wales..
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Seissler, Jochen
    Klinikum Univ Munchen, Med Klin & Poliklin 4, Diabet Zentrum, Munich, Germany..
    Tiberti, Claudio
    Univ Roma La Sapienza, Dept Expt Med, I-00185 Rome, Italy..
    Uibo, Raivo
    Univ Tartu, Inst Biomed & Translat Med, Dept Immunol, EE-50090 Tartu, Estonia..
    Yu, Liping
    Univ Colorado Denver, Barbara Davis Ctr Diabet, Aurora, CO USA..
    Lernmark, Åke
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Malmo, Sweden..
    Husebye, Eystein
    Univ Bergen, Dept Clin Sci, Bergen, Norway.;Haukeland Hosp, Dept Med, N-5021 Bergen, Norway..
    Determination of 21-hydroxylase autoantibodies: inter-laboratory concordance in the Euradrenal International Serum Exchange Program2015In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 53, no 11, p. 1761-1770Article in journal (Refereed)
    Abstract [en]

    Background: 21-Hydroxylase autoantibodies (21OHAb) are markers of an adrenal autoimmune process that identifies individuals with autoimmune Addison's disease (AAD). Quality and inter-laboratory agreement of various 21OHAb tests are incompletely known. The objective of the study was to determine inter-laboratory concordance for 21OHAb determinations. Methods: Sixty-nine sera from 51 patients with AAD and 51 sera from 51 healthy subjects were blindly coded by a randomization center and distributed to 14 laboratories that determined 21OHAb, either by an "in-house" assay (n=9) using in vitro-translated S-35-21OH or luciferase-labeled 21OH or a commercial kit with I-125-21OH (n=5). Main outcome measures were diagnostic accuracy of each participating laboratory and inter-laboratory agreement of 21OHAb assays. Results: Intra-assay coefficient of variation ranged from 2.6% to 5.3% for laboratories using the commercial kit and from 5.1% to 23% for laboratories using "in-house" assays. Diagnostic accuracy, expressed as area under ROC curve (AUC), varied from 0.625 to 0.947 with the commercial kit and from 0.562 to 0.978 with "in-house" methods. Cohen's. of inter-rater agreement was 0.603 among all 14 laboratories, 0.691 among "in-house" laboratories, and 0.502 among commercial kit users. Optimized cutoff levels, calculated on the basis of AUCs, increased the diagnostic accuracy of every laboratory (AUC >0.9 for 11/14 laboratories) and increased the Cohen's. of inter-rater agreement. Discrepancies in quantitation of 21OHAb levels among different laboratories increased with increasing autoantibody levels. Conclusions: The quality of 21OHAb analytical procedures is mainly influenced by selection of cutoff value and correct handling of assay materials. A standardization program is needed to identify common standard sera and common measuring units.

  • 308.
    Fant, F.
    et al.
    Department of Anesthesiology and Intensive Care, University Hospital, Örebro, Sweden.
    Tina, Elisabet
    Örebro University Hospital. Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Clinical Research Centre.
    Sandblom, D.
    Department of Urology and the Health Academy, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Department of Urology and the Health Academy, Örebro University Hospital, Örebro, Sweden.
    Magnuson, A.
    Clinical Epidemiology and Biostatistical Unit, Örebro University Hospital, Örebro, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Axelsson, Kjell
    Department of Anesthesiology and Intensive Care, University Hospital, Örebro, Sweden.
    Gupta, Anil
    Department of Anesthesiology and Intensive Care, University Hospital, Örebro, Sweden.
    Thoracic epidural analgesia inhibits the neuro-hormonal but not the acute inflammatory stress response after radical retropubic prostatectomy2013In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 110, no 5, p. 747-757Article in journal (Refereed)
    Abstract [en]

    Background: Epidural anaesthesia and analgesia has been shown to suppress the neurohormonal stress response, but its role in the inflammatory response is unclear. The primary aim was to assess whether the choice of analgesic technique influences these processes in patients undergoing radical retropubic prostatectomy.

    Methods: Twenty-six patients were randomized to Group P (systemic opioid-based analgesia) or Group E (thoracic epidural-based analgesia) perioperatively. Induction and maintenance of anaesthesia followed a standardized protocol. The following measurements were made perioperatively: plasma cortisol, glucose, insulin, C-reactive proteins, leucocyte count, plasma cytokines [interleukin (IL)-6, tumour necrosis factor (TNF)-alpha], and pokeweed mitogen-stimulated cytokines [interferon (IFN)-gamma, IL-2, IL-12p70, IL-10, IL-4, and IL-17]. Other parameters recorded were pain, morphine consumption, and perioperative complications.

    Results: Plasma concentration of cortisol and glucose were significantly higher in Group P compared with Group E at the end of surgery, the mean difference was 232 nmol litre(-1) [95% confidence interval (CI) 84-381] (P=0.004) and 1.6 mmol litre(-1) (95% CI 0.6-2.5) (P=0.003), respectively. No significant differences were seen in IL-6 and TNF-alpha at 24 h (P=0.953 and 0.368, respectively) and at 72 h (P=0.931 and 0.691, respectively). IL-17 was higher in Group P compared with Group E, both at 24 h (P=0.001) and 72 h (P=0.018) after operation. Pain intensity was significantly greater in Group P compared with Group E (P<0.05) up to 24 h.

    Conclusions: In this small prospective randomized study, thoracic epidural analgesia reduced the early postoperative stress response but not the acute inflammatory response after radical retrobupic prostatectomy, suggesting that other pathways are involved during the acute phase reaction.

  • 309.
    Faresjö, Maria
    Jönköping University, School of Health and Welfare, HHJ, Dep. of Natural Science and Biomedicine. Jönköping University, School of Health and Welfare, HHJ. Biomedical Platform.
    The link between psychological stress and autoimmune response in children2015In: Critical Reviews in Immunology, ISSN 1040-8401, E-ISSN 2162-6472, Vol. 35, no 2, p. 117-134Article in journal (Refereed)
    Abstract [en]

    Stress is defined as a state of threatened homeostasis or disharmony that is counteracted by a complex repertoire of physiological and behavioral adaptive responses in order to establish homeostasis. Confronted with a stressful condition, the nervous and immune systems initiate a coping process to maintain homeostasis in the body. Psychological stress, recognized as a public health issue in children and young adults, may be one mechanism to induce and maintain autoimmunity in children. It is necessary to increase our understanding of how psychological stress can affect the immune system at a young age because autoimmune diseases, especially type 1 diabetes, are alarmingly common in children. Psychological stress may be involved in other autoimmune diseases, such as celiac disease, systemic lupus erythematosus, and juvenile idiopathic arthritis, that frequently occur in children as well. This review summarizes the studies attempting to evaluate the link between psychological stress and autoimmune response in children. A number of them have observed that the autoimmune disease itself causes psychological stress. We are far from fully understanding how long-term psychological stress is linked to autoimmune response in children with a high risk of, or already diagnosed, autoimmune disease.

  • 310.
    Farouk, Salah Eldin
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    T cell and antibody responses in Plasmodium falciparum malaria and their relation to disease susceptibility2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Malaria antigen-induced polarization of T cells into effectors Th1 and/or Th2 cells and their subsequent release of cytokines is known to affect antibody production. This thesis includes studies on early innate responses to the parasite, with a focus on γδT cells, and acquired specific responses in African sympatric ethnic tribes. In the last part of this thesis, a method for enrichment for the asexual blood stages of P. falciparum and their use in in vitro T-cell studies is presented.

    To investigate mechanisms involved in parasite growth inhibition by γδT cells, an in vitro system was set up using blood stage parasites co-cultured with differently treated γδT cells. The results showed that Vγ9/δ2+ γδT cells inhibited the in vitro growth of P. falciparum parasites whereas CD4+ and CD8+ T cells did not. This inhibition was positively correlated with the expression of cytolytic molecules in the cell lines tested. Anti-granulysin antibodies reversed γδT cell-mediated inhibition, suggesting a role for granulysin in the parasite growth inhibition. Thus, our data suggest that Vγ9/δ2+ γδT cells inhibit the parasite growth by a granulysin-exocytosis dependent cytotoxic pathway that needs perforin.

    To study the humoral responses and their relation to Th1/Th2 cytokine profiles, antibody levels, numbers of cytokine-producing cells and spleen rates were measured in two sympatric tribes living in Mali, the Fulani and the Dogon. Our results revealed significantly elevated malaria-specific IgG and IgE antibody levels and spleen rates in the Fulani compared to the Dogon. The Fulani exhibited elevated numbers of both IL-4 and IFN-γ-producing cells, a typical profile seen of CD1-restricted NKT cells. This together with the higher spleen rates and elevated anti-malarial antibodies suggests a role of CD1-restricted cells in the different responses seen between these tribes.

    To investigate whether such responses were specifically confined to malaria or a reflection of a generally activated immune system, total levels of IgG and of IgM as well as IgG antibodies to non-malarial antigens were examined in the Fulani in Burkina Faso and Mali. The results showed that the Fulani consistently mounted stronger malaria-specific IgG, IgG1, IgG3 and IgM responses. Total IgM levels were significantly higher in the Fulani than the non-Fulani, whereas total IgG did not differ between the two tribes. While IgG levels to some non-malarial antigens were significantly higher in the Fulani, no such differences were seen in the responses to several other non-malarial antigens suggesting that the Fulani are not generally hyper-reactive and that other specific factors are of importance for their higher malaria resistance.

    Finally, a new method to enrich for early and late asexual blood stages of P. falciparum parasite from a single parasite culture was developed, using a 3-step centrifugation procedure. Such enriched parasite fractions beside other malaria-parasite antigen preparations were used in an in vitro system to analyse T-cell responses in malaria-exposed and non-exposed donors. Such analysis revealed significant proliferative cell response and CD4+ T cell expansion to whole-cell parasite antigens, but not to acellular parasite fractions, in the malaria-exposed as compared to the non-exposed ones. Our data suggest that natural infection preferentially leads to formation of memory cells against certain antigen expressed in live parasites.

    Malaria antigen-induced polarization of T cells into effectors Th1 and/or Th2 cells and their subsequent release of cytokines is known to affect antibody production. This thesis includes studies on early innate responses to the parasite, with a focus on γδT cells, and acquired specific responses in African sympatric ethnic tribes. In the last part of this thesis, a method for enrichment for the asexual blood stages of P. falciparum and their use in in vitro T-cell studies is presented.

    To investigate mechanisms involved in parasite growth inhibition by γδT cells, an in vitro system was set up using blood stage parasites co-cultured with differently treated γδT cells. The results showed that Vγ9/δ2+ γδT cells inhibited the in vitro growth of P. falciparum parasites whereas CD4+ and CD8+ T cells did not. This inhibition was positively correlated with the expression of cytolytic molecules in the cell lines tested. Anti-granulysin antibodies reversed γδT cell-mediated inhibition, suggesting a role for granulysin in the parasite growth inhibition. Thus, our data suggest that Vγ9/δ2+ γδT cells inhibit the parasite growth by a granulysin-exocytosis dependent cytotoxic pathway that needs perforin.

    To study the humoral responses and their relation to Th1/Th2 cytokine profiles, antibody levels, numbers of cytokine-producing cells and spleen rates were measured in two sympatric tribes living in Mali, the Fulani and the Dogon. Our results revealed significantly elevated malaria-specific IgG and IgE antibody levels and spleen rates in the Fulani compared to the Dogon. The Fulani exhibited elevated numbers of both IL-4 and IFN-γ-producing cells, a typical profile seen of CD1-restricted NKT cells. This together with the higher spleen rates and elevated anti-malarial antibodies suggests a role of CD1-restricted cells in the different responses seen between these tribes.

    To investigate whether such responses were specifically confined to malaria or a reflection of a generally activated immune system, total levels of IgG and of IgM as well as IgG antibodies to non-malarial antigens were examined in the Fulani in Burkina Faso and Mali. The results showed that the Fulani consistently mounted stronger malaria-specific IgG, IgG1, IgG3 and IgM responses. Total IgM levels were significantly higher in the Fulani than the non-Fulani, whereas total IgG did not differ between the two tribes. While IgG levels to some non-malarial antigens were significantly higher in the Fulani, no such differences were seen in the responses to several other non-malarial antigens suggesting that the Fulani are not generally hyper-reactive and that other specific factors are of importance for their higher malaria resistance.

    Finally, a new method to enrich for early and late asexual blood stages of P. falciparum parasite from a single parasite culture was developed, using a 3-step centrifugation procedure. Such enriched parasite fractions beside other malaria-parasite antigen preparations were used in an in vitro system to analyse T-cell responses in malaria-exposed and non-exposed donors. Such analysis revealed significant proliferative cell response and CD4+ T cell expansion to whole-cell parasite antigens, but not to acellular parasite fractions, in the malaria-exposed as compared to the non-exposed ones. Our data suggest that natural infection preferentially leads to formation of memory cells against certain antigen expressed in live parasites.

    Malaria antigen-induced polarization of T cells into effectors Th1 and/or Th2 cells and their subsequent release of cytokines is known to affect antibody production. This thesis includes studies on early innate responses to the parasite, with a focus on γδT cells, and acquired specific responses in African sympatric ethnic tribes. In the last part of this thesis, a method for enrichment for the asexual blood stages of P. falciparum and their use in in vitro T-cell studies is presented.

    To investigate mechanisms involved in parasite growth inhibition by γδT cells, an in vitro system was set up using blood stage parasites co-cultured with differently treated γδT cells. The results showed that Vγ9/δ2+ γδT cells inhibited the in vitro growth of P. falciparum parasites whereas CD4+ and CD8+ T cells did not. This inhibition was positively correlated with the expression of cytolytic molecules in the cell lines tested. Anti-granulysin antibodies reversed γδT cell-mediated inhibition, suggesting a role for granulysin in the parasite growth inhibition. Thus, our data suggest that Vγ9/δ2+ γδT cells inhibit the parasite growth by a granulysin-exocytosis dependent cytotoxic pathway that needs perforin.

    To study the humoral responses and their relation to Th1/Th2 cytokine profiles, antibody levels, numbers of cytokine-producing cells and spleen rates were measured in two sympatric tribes living in Mali, the Fulani and the Dogon. Our results revealed significantly elevated malaria-specific IgG and IgE antibody levels and spleen rates in the Fulani compared to the Dogon. The Fulani exhibited elevated numbers of both IL-4 and IFN-γ-producing cells, a typical profile seen of CD1-restricted NKT cells. This together with the higher spleen rates and elevated anti-malarial antibodies suggests a role of CD1-restricted cells in the different responses seen between these tribes.

    To investigate whether such responses were specifically confined to malaria or a reflection of a generally activated immune system, total levels of IgG and of IgM as well as IgG antibodies to non-malarial antigens were examined in the Fulani in Burkina Faso and Mali. The results showed that the Fulani consistently mounted stronger malaria-specific IgG, IgG1, IgG3 and IgM responses. Total IgM levels were significantly higher in the Fulani than the non-Fulani, whereas total IgG did not differ between the two tribes. While IgG levels to some non-malarial antigens were significantly higher in the Fulani, no such differences were seen in the responses to several other non-malarial antigens suggesting that the Fulani are not generally hyper-reactive and that other specific factors are of importance for their higher malaria resistance.

    Finally, a new method to enrich for early and late asexual blood stages of P. falciparum parasite from a single parasite culture was developed, using a 3-step centrifugation procedure. Such enriched parasite fractions beside other malaria-parasite antigen preparations were used in an in vitro system to analyse T-cell responses in malaria-exposed and non-exposed donors. Such analysis revealed significant proliferative cell response and CD4+ T cell expansion to whole-cell parasite antigens, but not to acellular parasite fractions, in the malaria-exposed as compared to the non-exposed ones. Our data suggest that natural infection preferentially leads to formation of memory cells against certain antigen expressed in live parasites.

  • 311. Fearon, Elizabeth
    et al.
    Wiggins, Richard D.
    Pettifor, Audrey E.
    MacPhail, Catherine
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Medical Research Council/Wits University Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; INDEPTH Network, Accra, Ghana.
    Selin, Amanda
    Gómez-Olivé, F. Xavier
    Delany-Moretlwe, Sinéad
    Piwowar-Manning, Estelle
    Laeyendecker, Oliver
    Hargreaves, James R.
    Associations between friendship characteristics and HIV and HSV-2 status amongst young South African women in HPTN-0682017In: Journal of the International AIDS Society, ISSN 1758-2652, E-ISSN 1758-2652, Vol. 20, article id e25029Article in journal (Refereed)
    Abstract [en]

    Introduction: Prevalence of HIV among young women in South Africa remains extremely high. Adolescent peer groups have been found to be an important influence on a range of health behaviours. The characteristics of young women's friendships might influence their sexual health and HIV risk via connections to sexual partners, norms around sexual initiation and condom use, or provision of social support. We investigated associations between young women's friendships and their Herpes Simplex Virus Type 2 (HSV-2) and HIV infection status in rural South Africa. Methods: Our study is a cross-sectional, egocentric network analysis. In 2011 to 2012, we tested 13- to 20-year-old young women for HIV and HSV-2, and collected descriptions of five friendships for each. We generated summary measures describing friend socio-demographic characteristics and the number of friends perceived to have had sex. We used logistic regression to analyse associations between friend characteristics and participant HIV and HSV-2 infection, excluding likely perinatal HIV infections. Results: There were 2326 participants included in the study sample, among whom HIV and HSV-2 prevalence were 3.3% and 4.6% respectively. Adjusted for participant and friend socio-demographic characteristics, each additional friend at least one year older than the participant was associated with raised odds of HIV (odds ratio (OR)=1.37, 95% CI 1.03 to 1.82) and HSV-2 (adjusted OR=1.41, 95% CI 1.18 to 1.69). Each additional friend perceived to have ever had sex also raised the odds of HIV (OR=1.29, 95% CI 1.03 to 1.63) and HSV-2 (OR=1.18, 95% CI 1.03 to 1.35). Discussion: We found good evidence that a greater number of older friends and friends perceived to have had sex were associated with increased risk for HSV-2 and HIV infection among young women. Conclusions: The characteristics of young women's friendships could contribute to their risk of HIV infection. The extent to which policies or programmes influence age-mixing and young women's normative environments should be considered.

  • 312.
    Femel, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Therapeutic Cancer Vaccines Targeting Molecules Associated with Tumor Angiogenesis2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Induction of an endogenous antibody response by therapeutic vaccination could provide an alternative to cost-intensive monoclonal antibody-based treatments for cancer. Since the target of a cancer vaccine will most likely be a self-antigen, self-tolerance of the immune system must be circumvented. Using fusion proteins consisting of the self-antigen to be targeted and a part derived from a foreign antigen, it is possible to break tolerance against the self-antigen. Furthermore, a potent adjuvant is required to support an immune response against a self-molecule. Currently no adjuvant suitable for this purpose is approved for use in humans.

    This thesis describes the development of a therapeutic vaccine targeting the vasculature of tumors. As tumor cells have developed strategies to escape immune surveillance, targeting of molecules associated with the tumor stroma is an interesting alternative. The alternatively spliced extra domain-A and B (ED-A and ED-B) of fibronectin and the glycan-binding protein galectin-1 are selectively expressed during events of tumor angiogenesis. We have designed recombinant proteins to target ED-B, ED-A and galectin-1, containing bacterial thioredoxin (TRX) as a non-self part, resulting in TRX-EDB, TRX-EDA and TRX-Gal-1. Vaccination against ED-B induced anti-ED-B antibodies and inhibited growth of subcutaneous fibrosarcoma. Immunization against ED-A decreased tumor burden and reduced the number of lung metastases in the MMTV-PyMT model for metastatic mammary carcinoma in a therapeutic setting. Analysis of the tumor tissue from ED-B and ED-A-immunized mice indicated an attack of the tumor vasculature by the immune system. Finally, we show that galectin-1 immunization reduced tumor burden and increased leukocyte numbers in the tumor tissue. Galectin-1 is pro-angiogenic and immunosuppressive, and therefore allows simultaneous targeting of fundamental characteristics of tumorigenesis. We furthermore show that the biodegradable squalene-based Montanide ISA 720 combined with CpG oligo 1826 (M720/CpG) is at least as potent as Freund’s adjuvant with respect to breaking self-tolerance, when comparing several immunological parameters. Freund’s is a potent but toxic adjuvant used in the majority of preclinical studies.

    The work presented in this thesis shows that therapeutic cancer vaccines targeting the tumor vasculature are a feasible and promising approach for cancer therapy.

  • 313. Femel, Julia
    et al.
    Van Hooren, Luuk
    Saupe, Falk
    Huijbers, Elisabeth JM
    Verboogen, Danielle RJ
    Reichel, Matthias
    Cedervall, Jessica
    Thijssen, Victor L
    Hellman, Lars
    Griffioen, Arjan W
    Dimberg, Anna
    Olsson, Anna-Karin
    Vaccination against galectin-1 promotes cytotoxic T-cell infiltration in melanoma and reduces tumor burdenManuscript (preprint) (Other academic)
  • 314. Fergusson, J. R.
    et al.
    Huehn, M. H.
    Swadling, L.
    Walker, L. J.
    Kurioka, A.
    Llibre, A.
    Bertoletti, A.
    Hollaender, G.
    Newell, E. W.
    Davis, M. M.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Powrie, F.
    Capone, S.
    Folgori, A.
    Barnes, E.
    Willberg, C. B.
    Ussher, J. E.
    Klenerman, P.
    CD161(int)CD8+T cells: a novel population of highly functional, memory CD8+T cells enriched within the gut2016In: Mucosal Immunology, ISSN 1933-0219, E-ISSN 1935-3456, Vol. 9, no 2, p. 401-413Article in journal (Refereed)
    Abstract [en]

    The C-type lectin-like receptor CD161 is expressed by lymphocytes found in human gut and liver, as well as blood, especially natural killer (NK) cells, T helper 17 (Th17) cells, and a population of unconventional Tcells known as mucosalassociated invariant T (MAIT) cells. The association of high CD161 expression with innate T-cell populations including MAITcells is established. Here we show that CD161 is also expressed, at intermediate levels, on a prominent subset of polyclonal CD8+ T cells, including antiviral populations that display a memory phenotype. These memory CD161(int)CD8+ Tcells are enriched within the colon and express both CD103 and CD69, markers associated with tissue residence. Furthermore, this population was characterized by enhanced polyfunctionality, increased levels of cytotoxic mediators, and high expression of the transcription factors T-bet and eomesodermin (EOMES). Such populations were induced by novel vaccine strategies based on adenoviral vectors, currently in trial against hepatitis C virus. Thus, intermediate CD161 expression marks potent polyclonal, polyfunctional tissue-homing CD8+ T-cell populations in humans. As induction of such responses represents a major aim of T-cell prophylactic and therapeutic vaccines in viral disease and cancer, analysis of these populations could be of value in the future.

  • 315.
    Fernández Sjödin, Susana
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    I fotspåren av forskarnas jakt efter lösningen på gåtan: sambandet mellan narkolepsi och influensavaccinet Pandemrix2017Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 316.
    Ferraz, Natalia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Surface Biotechnology.
    Effect of Surface Nanotopography on Blood-Biomaterial Interactions2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Biologically inspired materials are being developed with the aim of improving the integration of medical implants and minimizing non-desirable host reactions. A promising strategy is the design of topographically patterned surfaces that resemble those found in the extracellular environment.

    Nanoporous alumina has been recognized as a potential biomaterial and as an important template for the fabrication of nanostructures.

    In this thesis in vitro studies were done to elucidate the role of alumina nanoporosity on the inflammatory response. Specifically, by comparing alumina membranes with two pore sizes (20 and 200 nm in diameter). Complement and platelet activation were evaluated as well as monocyte/macrophage behaviour.

    Whole blood was incubated with the alumina membranes and thereafter the biomaterial surfaces were evaluated in terms of protein and platelet adhesion as well as procoagulant properties. The fluid phase was analyzed for complement activation products and platelet activation markers. Besides, human mononuclear cells were cultured on the alumina membranes and cell adhesion, viability, morphology and release of pro-inflammatory cytokines were evaluated.

    The results indicated that nanoporous alumina with 200 nm pores promotes higher complement activation than alumina with 20 nm pores.

    In addition, platelet response to nanoporous alumina was found to be highly dependent on the material porosity, as reflected by differences in adhesion, PMP generation and procoagulant characteristics.

    A clear difference in monocyte/macrophage adhesion and activation was found between the two pore size alumina membranes. Few but highly activated cells adhered to the 200 nm membrane in contrast to many but less activated monocytes/macrophages on the 20 nm surface.

    The outcome of this work emphasizes that nanotopography plays an important role in the host response to biomaterials.

    Better understanding of molecular interactions on nano-level will undoubtedly play a significant role in biomaterial implant development and will contribute to design strategies for controlling specific biological events.

  • 317. Feyerabend, Thorsten B
    et al.
    Hausser, Heinz
    Tietz, Annette
    Blum, Carmen
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Straus, Anita H
    Takahashi, Hélio K
    Morgan, Ellen S
    Dvorak, Ann M
    Fehling, Hans Jörg
    Rodewald, Hans-Reimer
    Loss of histochemical identity in mast cells lacking carboxypeptidase A.2005In: Mol Cell Biol, ISSN 0270-7306, Vol. 25, no 14, p. 6199-210Article in journal (Refereed)
  • 318.
    Fletcher, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Antibody- and Peptide-based Immunotherapies: Proof-of-concept and safety considerations2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of cancer immunotherapy is to eradicate tumours by inducing a tumour-specific immune response. This thesis focuses on how antibodies and peptides can improve antigen presentation and the subsequent tumour-specific T cell response. Tumour recognition by the immune system can be promoted through delivery of antigen in the form of a vaccine. One example is the development of a therapeutic peptide vaccine containing both CD4+ and CD8+ T cell epitopes. So far, peptide vaccinations have shown limited success in clinical trials and further improvements are needed, such as choice of adjuvant and T cell epitopes, as well as targeted delivery of peptides and adjuvants to the same DC.

    In paper I, we describe the development of a peptide-peptide conjugate (with a tumour T cell epitope) that, via immune complex formation and FcγR binding, enhance antigen uptake and activation of DCs. The conjugate consists of three tetanus toxin-derived linear B cell epitopes (MTTE) that were identified based on specific IgG antibodies in human serum. Three MTTE peptide sequences were conjugated to a synthetic long peptide (SLP) that consists of a T cell epitope derived from the desired target tumour.

    In paper II, the conjugate was evaluated in a modified Chandler loop model containing human blood, mimicking blood in circulation. The conjugate was internalised by human monocytes in an antibody-dependent manner. A conjugate containing the model CMV-derived T cell epitope pp65NLV generated recall T cell responses dependent on MTTE-specific antibodies and the covalent conjugation of the three MTTE with the SLP.

    In paper III, a CD40-specific antibody was characterised for local treatment of solid tumours. The antibody eradicated bladder tumours in mice and induced T cell-mediated immunological memory against the tumour.

    In paper IV, we characterised the Chandler loop model (used in paper II) for its potential use in predicting cytokine release syndrome (CRS) in response to monoclonal antibodies (mAbs). Superagonistic antibodies (e.g., OKT3) induced rapid cytokine release whereas no cytokine release was induced by antibodies (e.g., cetuximab) associated with low incidence of CRS in the clinic.

    In conclusion, this thesis work demonstrates proof-of-concept of improved strategies for antibody- and peptides-based cancer immunotherapies and their potential use in multiple cancer indications.

  • 319.
    Fletcher, Erika A. K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab. Immuneed AB, Uppsala.
    Eltahir, Mohamed
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lindqvist, Frida
    Immuneed AB, Uppsala.
    Rieth, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Törnqvist, Gunilla
    Immuneed AB, Uppsala.
    Leja-Jarblad, Justyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab. Immuneed AB, Uppsala.
    Mangsbo, Sara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Immuneed AB, Uppsala.
    Extracorporeal human whole blood in motion, as a tool to predict first-infusion reactions and mechanism-of-action of immunotherapeutics2018In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 54, p. 1-11Article in journal (Refereed)
    Abstract [en]

    First infusion reactions along with severe anaphylactic responses can occur as a result of systemic administration of therapeutic antibodies. The underlying mechanisms by which monoclonal antibodies induce cytokine release syndrome (CRS) can involve direct agonistic effects via the drug target, or a combination of target-engagement along with innate receptor interactions. Despite the wide variety of pathways and cells that can play a role in CRS, many currently used assays are devoid of one or more components that must be present for these responses to occur. One assay that has not been assessed for its capacity to predict CRS is the modified Chandler loop model. Herein we evaluate a plethora of commercially available monoclonal antibodies to evaluate the modified Chandler loop model's potential in CRS prediction. We demonstrate that in a 4-hour loop assay, both the superagonistic antibodies, anti-CD3 (OKT3) and anti-CD28 (ANC28.1), display a clear cytokine response with a mixed adaptive/innate cytokine source. OKT3 induce TNFα and IFN-γ release in 20 out of 23 donors tested, whereas ANC28.1 induce TNF-α, IL-2 and IFN-γ release in all donors tested (n = 18–22). On the other hand, non-agonistic antibodies associated with no or low infusion reactions in the clinic, namely cetuximab and natalizumab, neither induce cytokine release nor cause false positive responses. A TGN1412-like antibody also display a clear cytokine release with an adaptive cytokine profile (IFN-γ and IL-2) and all donors (n = 9) induce a distinct IL-2 response. Additionally, the value of an intact complement system in the assay is highlighted by the possibility to dissect out the mechanism-of-action of alemtuzumab and rituximab. The loop assay can either complement lymph node-like assays or stand-alone to investigate drug/blood interactions during preclinical development, or for individual safety screening prior to first-in-man clinical trial.

  • 320.
    Fletcher, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala universitet.
    Eltahir, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lindqvist, Frida
    Immuneed AB.
    Rieth, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Törnqvist, Gunilla
    Immuneed AB.
    Leja-Jarblad, Justyna
    Immuneed AB.
    Mangsbo, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Extracorporeal human whole blood in motion, as a tool to predict first-infusion reactions and mechanisms-of-action of immunotherapeutics: CRS prediction in human whole bloodManuscript (preprint) (Other academic)
    Abstract [en]

    First infusion reactions along with severeanaphylactic responses can occur as a result of systemic administration oftherapeutic antibodies. The underlying mechanisms by which monoclonal antibodiesinduce cytokine release syndrome (CRS) can involve direct agonistic effects viathe drug target, or a combination of target-engagement along with innatereceptor interactions. Despite the wide variety of pathways and cells that canplay a role in CRS, many currently used assays are devoid of one or morecomponents that must be present for these responses to occur. To date, oneassay that has not been used for studying CRS is the Chandler loop model. Thismodel is commonly used to study surface/blood interface interactions and has alsobeen used to study the instant blood-mediated inflammatory reaction (IBMIR). Herein we use a modified Chandler loopmodel with a heparin conjugate lining the inner surface of the loops to studyCRS. This allows for an assay harboring immune cells, intact cascade systemsalong with endogenous antibodies. Here, we evaluated a plethora of commerciallyavailable monoclonal antibodies to assess the capacity of the Chandler loopmodel for CRS prediction. We demonstrated that in a 4-hour loop assay both thesuperagonistic antibodies, anti-CD3 (OKT3) and anti-CD28 (ANC28.1), displayed aclear cytokine response with a mixed adaptive/innate cytokine source. OKT3 induced TNFα and IFN-g release in 20 out of23 donors tested, whereas ANC28.1 induced TNF-α, IL-2 and IFN-g release in all donors tested (n=18-22). On theother hand, non-agonistic antibodies associated with no or low infusionreactions in the clinic, namely cetuximab and natalizumab, neither induced cytokinerelease nor caused false positive responses. A TGN1412-like antibody alsodisplayed a clear cytokine release with an adaptive cytokine profile (IFN-g and IL-2) and all donors (n=9) inducing adistinct IL-2 response. Additionally, the value of an intact complement systemin the assay was highlighted by the possibility to dissect out themechanism-of-action (MOA) of alemtuzumab and rituximab. The loop assay can eithercomplement lymph node-like assays or stand-alone to investigate drug/bloodinteractions during preclinical development, or for individual safety screeningprior to a first-in-man clinical trial.

  • 321.
    Fletcher, Erika
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Immuneed AB, S-75237 Uppsala, Sweden.
    van Maren, Wendy
    Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands.
    Cordfunke, Robert
    Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands.
    Dinkelaar, Jasper
    Leiden Univ, Leiden Inst Chem, Dept Bioorgan Synth, NL-2300 RA Leiden, Netherlands.
    Codee, Jeroen D. C.
    Leiden Univ, Leiden Inst Chem, Dept Bioorgan Synth, NL-2300 RA Leiden, Netherlands.
    van der Marel, Gijs
    Leiden Univ, Leiden Inst Chem, Dept Bioorgan Synth, NL-2300 RA Leiden, Netherlands.
    Melief, Cornelis J. M.
    Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands.
    Ossendorp, Ferry
    Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands.
    Drijfhout, Jan Wouter
    Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands.
    Mangsbo, Sara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Immuneed AB, S-75237 Uppsala, Sweden.
    Formation of Immune Complexes with a Tetanus-Derived B Cell Epitope Boosts Human T Cell Responses to Covalently Linked Peptides in an Ex Vivo Blood Loop System2018In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 201, no 1, p. 87-97Article in journal (Refereed)
    Abstract [en]

    Enhancing T cell responses against both viral and tumor Ags requires efficient costimulation and directed delivery of peptide Ags into APCs. Long peptide vaccines are considered favorable vaccine moieties from a clinical perspective, as they can harbor more than one immunogenic epitope enabling treatment of a broader target population. In addition, longer peptides are not extracellularly loaded on MHC class I; rather, they require intracellular processing and will thereby be presented to T cells mainly by professional APCs, thereby avoiding the risk of tolerance induction. The drawback of peptide vaccines regardless of peptide length is that naked peptides are not actively targeted to and taken up by APCs, and the standard nonconjugated adjuvant-peptide mixtures do not ensure cotargeting of the two to the same APC. We have identified a tetanus toxin-derived B cell epitope that can mediate the formation of immune complexes in the presence of circulating Abs. In this study, we show that these immune complexes improve both Ag uptake by APCs (blood monocytes and CD1c(+) dendritic cells) and consequently improve CD8(+) T cell recall responses in a human ex vivo blood loop system. The uptake of the peptide conjugate by blood monocytes is dependent on Abs and the complement component C1q. We envision that this strategy can be used to facilitate active uptake of Ags into APCs to improve T cell responses against pathogens or cancer.

  • 322.
    Folestad, Erika
    et al.
    Karolinska Inst, Sweden.
    Kunath, Anne
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    PDGF-C and PDGF-D signaling in vascular diseases and animal models2018In: Molecular Aspects of Medicine, ISSN 0098-2997, E-ISSN 1872-9452, Vol. 62Article, review/survey (Refereed)
    Abstract [en]

    Members of the platelet-derived growth factor (PDGF) family are well known to be involved in different pathological conditions. The cellular and molecular mechanisms induced by the PDGF signaling have been well studied. Nevertheless, there is much more to discover about their functions and some important questions to be answered. This review summarizes the known roles of two of the PDGFs, PDGF-C and PDGF-D, in vascular diseases. There are clear implications for these growth factors in several vascular diseases, such as atherosclerosis and stroke. The PDGF receptors are broadly expressed in the cardiovascular system in cells such as fibroblasts, smooth muscle cells and pericytes. Altered expression of the receptors and the ligands have been found in various cardiovascular diseases and current studies have shown important implications of PDGF-C and PDGF-D signaling in fibrosis, neovascularization, atherosclerosis and restenosis. (C) 2018 The Authors. Published by Elsevier Ltd.

  • 323. Forsberg, A.
    et al.
    West, Christina E.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. International Inflammation (in-FLAME) network of the World Universities Network, Umeå, Sweden.
    Prescott, S. L.
    Jenmalm, M. C.
    Pre- and probiotics for allergy prevention: time to revisit recommendations?2016In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 46, no 12, p. 1506-1521Article, review/survey (Refereed)
    Abstract [en]

    Reduced intensity and diversity of microbial exposure is considered a major factor driving abnormal postnatal immune maturation and increasing allergy prevalence, particularly in more affluent regions. Quantitatively, the largest important source of early immunemicrobial interaction, the gut microbiota, is of particular interest in this context, with variations in composition and diversity in the first months of life associated with subsequent allergy development. Attempting to restore the health consequences of the ` dysbiotic drift' in modern society, interventions modulating gut microbiota for allergy prevention have been evaluated in several randomized placebo-controlled trials. In this review, we provide an overview of these trials and discuss recommendations from international expert bodies regarding prebiotic, probiotic and synbiotic interventions. Recent guidelines from the World Allergy Organization recommend the use of probiotics for the primary prevention of eczema in pregnant and breastfeeding mothers of infants at high risk for developing allergy and in high-risk infants. It is however stressed that these recommendations are conditional, based on very low-quality evidence and great heterogeneity between studies, which also impedes specific and practical advice to consumers on the most effective regimens. We discuss how the choice of probiotic strains, timing and duration of administration can critically influence the outcome due to different effects on immune modulation and gut microbiota composition. Furthermore, we propose strategies to potentially improve allergy-preventive effects and enable future evidence-based implementation.

  • 324.
    Forsberg, Göte
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Innate and adaptive immunity in childhood celiac disease2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Celiac disease (CD) is an inflammatory small-bowel enteropathy caused by a permanent intolerance to wheat gluten and related proteins in rye and barley. Even though the disease originate from the small intestine the clinical symptoms varies in affected individuals and are often different in small children compared to adolescents and adults. Susceptibility to develop the disease is strongly associated with certain genetic factors i.e. HLADQ2/DQ8 but it is undoubtedly that additional inherited and environmental factors are involved. As specific T lymphocyte reactions are central in the pathogenesis of CD, six key cytokine messenger RNA levels in intestinal intraepithelial and lamina propria T lymphocytes (IEL, LPL), retrieved from small intestinal biopsies, were determined by using quantitative real-time reverse transcription polymerase chain reaction (RTPCR). Levels of cytokines, small secreted proteins which mediate and regulate immunity, in children with active disease were compared with that of treated children and controls. Interferon (IFN)-γ and interleukin (IL)-10 were also determined at the protein level by immunohistochemistry. Active celiac disease was characterized by distortions in cytokine expression, with highly significant increases of IFN-γ and IL-10 but no concomitant increases in tumor necrosis factor α (TNF-α), transforming growth factor β1 (TGFβ1), or IL-2 and no induction of IL-4. A marked shift of IFN-γ and IL-10 production from LPLs to IELs was characteristic of active celiac disease, and as many as one fourth of the IELs expressed IFN-γ. IELs in treated, symptom-free celiac patients still had increased IFN-γ levels compared with controls. In CD, gluten intake seems to cause an overreaction in IELs, with uncontrolled production of IFN-γ and IL-10 which may cause both recruitment of more IELs and a leaky epithelium, leading to a vicious circle with amplified immune activity and establishment of the intestinal lesion. In order to determine different IEL subsets contribution of the produced cytokines, γδIELs, CD4+αβIELs, and CD8+αβIELs as well as CD94+CD8+αβIELs and CD94CD8+αβIELs of children with active CD and children with no food-intolerance were analyzed for cytokine mRNA expression levels by RT-PCR. In active CD, CD8+αβIELs had the highest expression levels of IFN-γ- and IL-10 mRNA and constituted the cellular source for almost all IFN-γ and a large fraction of the IL-10. Expression levels of these two cytokines correlated and were higher in CD94-CD8+αβIELs than CD94+CD8+αβIELs CD4+αβIELs had the highest expression levels of TNF-α and despite the small number of this cell subset they contributed with half of the small amounts of this cytokine. Interestingly, TNF-α levels correlated with IL-10 in CD4+αβIELs. γδIELs had the lowest expression levels of IFN-γ, TNF-α, IL-10, and TGF-β1. Essentially no IL-2 mRNA was detected in the three IEL subpopulations. “Classical” CD8+CD94-αβT cells in the epithelial compartment are responsible for most of the excessive production of proinflammatory IFN-γ. The question whether an impaired extrathymic T cell maturation and/or capacity for secondary T cell receptor (TCR) gene recombination in iIELs is a contributing factor to CD was addressed. Expression levels of recombination activating gene-1 (RAG1) and the pre T α-chain (preTα) mRNAs were determined in IEL T cell lineage subsets of children with CD and controls. In controls, RAG1 was expressed in both mature (TCRγδ+ and TCRαβ+) and immature (CD2+CD7+TCR-) IELs while preTα was expressed preferentially in immature IELs. The RAG1 splice form selectively expressed outside thymus (RAG1 1A/2) as well as preTα were significantly decreased in CD patients both in active and inactive disease suggesting a deteriorated capacity of de novo TCR gene rearrangement in local T cell development and / or of secondary TCR gene rearrangement during editing or antigen-driven revision. This may lead to an imbalance between thymus- and gut derived T lymphocytes in the intestinal mucosa with consequent inefficient regulation of T cell responses against food antigens. Innate or nonspecific immunity is the first line, immediate defense against pathogens mediated by the epithelial cells in the intestine (IECs). As certain adaptive immune reaction in CD mimics that of intestinal infections, aberrant innate immune reaction could be a contributing factor to CD. Therefore jejunal biopsies were screened for bacteria and the innate immune status of the epithelium was investigated. Bacteria were freqently (40%) associated with the mucosa of children with active but also treated disease (20%) compared to controls (2%). Lack of antimicrobial factors such as mucins, proteins forming protective biofilm on the IECs, defensins and lysozym, peptides and enzymes with antibacterial effects, could not explain the presence of bacteria. If anything, mucin-2 (MUC2), α-defensins, HD-5, HD-6, and lysozyme mRNA levels were increased in epithelial cells in active CD, returning to normal levels in treated CD. Their expression levels correlated to the IFN-γ mRNA levels in IELs. Analysis of beta defensins, hBD-1 and hBD-2 as well as carcinoembryonic antigen (CEA) cell adhesion molecule 1a (CECAM1a), glycoproteins in the glycocalyx with ability to bind micro organisms, were not affected by the disease. Lectin staining by histochemistry revealed that goblet cells were stained by UEA1 in CD both active and treated but not in controls. The opposite pattern was seen for the lectin PNA where staining was seen in controls in the glycocalyx layer but not in CD. Thus altered glycocalyx/mucous layer may promote bacterial adhesion in CD.

  • 325.
    Forsberg, Ole
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Generation of Therapeutic T Cells for Prostate Cancer2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The work presented herein focuses on the activation of the adaptive immune system in order to develop T cell-based immunotherapy for viral infections and cancer. The main goal was to identify and activate viral or tumoral antigen-specific T cells by using different identification, isolation and stimulation techniques. One such approach was that we modified dendritic cells (DCs) with an adenoviral vector encoding the full length pp65 antigen from cytomegalovirus (CMV). Through strategic modification techniques we demonstrate that it is possible to obtain DCs presenting antigen-specific peptides both on major histocompatibility complex (MHC) class I and MHC class II molecules for simultaneous CD8+ and CD4+ T cell activation. We also demonstrate that it is possible to generate prostate antigen-specific CD8+ T cells from a naïve repertoire of T cells by using DCs and HLA-A2-restricted peptides derived from prostate tumor-associated antigens or by using an adenoviral vector encoding the full length prostate tumor-associated antigen STEAP. We further demonstrate that CD8+ T cells directed against several prostate-specific peptide epitopes can be found in peripheral blood and in the prostate tumor area of prostate cancer patients. Furthermore, we have characterized a number of prostate-derived cell lines in terms of HLA haplotype and tumor-association antigen expression. We concluded that our methods for generating T cells restricted to CMV antigen have the ability to be applied for adoptive T cell transfer to patients with CMV disease and that prostate antigen-specific T cells can be found within prostate cancer patients, which enables future development of immunotherapeutic strategies for prostate cancer.

  • 326.
    Forsberg, Ole
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Carlsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Strategic use of an adenoviral vector for rapid and efficient ex vivo-generation of cytomegalovirus pp65-reactive cytolytic and helper T cells2008In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 141, no 2, p. 188-199Article in journal (Refereed)
    Abstract [en]

    Cytomegalovirus (CMV) reactivation can cause severe complications for transplant patients. Such patients can be protected against CMV-associated diseases through reconstitution of donor-derived CMV-reactive cytolytic and helper T cells. We have developed a strategic protocol for efficient simultaneous generation of CMV-reactive CD8+ and CD4+ T cells ex vivo. The protocol uses peripheral blood lymphocytes (PBLs), antigen-modified mature dendritic cells (DCs) generated in only 3 days and an adenoviral vector encoding the CMV pp65 antigen (Adpp65) both as an endogenous and exogenous source of antigen. PBLs stimulated once with Adpp65-transduced DCs (endogenously expressed pp65) resulted in preferential activation and expansion of pp65-specific CD8+ T cells while PBLs stimulated with DCs pulsed with cell lysate from Adpp65-transduced autologous monocytes (exogenously expressed pp65) yielded pp65-specific CD4+ T cells. Stimulation with double-modified DCs efficiently activated and expanded cytolytic and helper T cells simultaneously. The frequency of T cells producing interferon (IFN)-γ in response to pp65 increased after one stimulation on average 9.6-fold to 4.3% for CD8+ T cells and 25.8-fold to 6.5% for CD4+ T cells. This implies that sufficient number of pp65-specific cytolytic and helper T cells for adoptive transfer may be obtained in only two weeks.

  • 327.
    Forsberg, Ole
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Hamberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Tötterman, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Identification of prostate infiltrating lymphocytes and activation of prostate antigen-specific T cells isolated from prostate cancer patientsManuscript (Other academic)
    Abstract [en]

    Although prostate antigen-specific CD8+ T lymphocytes have been found both in peripheral blood and in tumor area of prostate cancer patients there has not yet been any adequate adoptive T lymphocyte transfer trial for prostate cancer patients. Methods for efficient generation of large number of prostate antigen-specific T cells are still lacking. In the present study we isolate and expand prostate infiltrating lymphocytes (PILs) from resected prostates by fine needle aspiration of patients with localized prostate cancer. By using HLA-A*0201-restricted tetramers, specific for the prostate tumor-associated antigen epitopes TARP(P5L)4-13, STEAP262-270 and PSA53-61, we were able to identify prostate antigen-specific CD8+ PILs in 5 out of 5 patients. Most frequent were STEAP262-270-specific T cells (5/5). Furthermore, by using fast-matured dendritic cells (DCs) transduced with an adenoviral vector encoding the STEAP antigen we were able to generate CD8+ T cells from peripheral blood of prostate cancer patients, for three HLA-A*0201-restricted STEAP epitopes simultaneously by one stimulation only. If combined, an effective protocol for generation of prostate antigen-specific T cells may be developed.

  • 328.
    Forsberg-Nilsson, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dunder, U.
    Nilsson, K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Schwartz, L.
    Nilsson, G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    The fibroblast mitogenic activity resleased from human basophilic cell line KU812 is separated from tryptase and PDGF expression1996In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 44, no 3, p. 267-272Article in journal (Refereed)
    Abstract [en]

    The human leukaemia cell line KU812 has previously been used to study basophil differentiation. In this study the authors analysed the capacity of KU812 to produce the mast cell proteinase tryptase and to synthesize factor(s) mitogenic for fibroblasts. KU812 cells were treated with tetradecanoyl-phorbol-13-acetate (TPA), conditioned medium from the human T-cell line Mo (Mo-CM), or cultured under serum free conditions. After 4 days the cells were analysed for cell growth, differentiation, content of tryptase, and secretion of fibroblast mitogenic activity. Mo-CM and serum starvation increased the expression while TPA treatment down-regulated the expression of Fc epsilon RI-alpha chain. An increase in tryptase content in cell extracts was detected after 4 days of culture in serum-free medium or in the presence of Mo-CM. KU812 conditioned media was found to have a baseline expression of mitogenic activity on normal human foreskin fibroblasts that was increased after serum starvation or after treatment with TPA. Mast cell-derived tryptase has previously been reported to be mitogenic for fibroblasts, but in this study the expression of tryptase did not correlate with the expression of fibroblast mitogenic activity in KU812 cells. Furthermore, affinity-purified lung tryptase did not show any mitogenic activity. Platelet-derived growth factor was also excluded. Although the factor(s) from KU812 cells stimulating fibroblast proliferation have not been identified, our results indicate that basophils may be potential producers of growth factors inducing fibroblast proliferation.

  • 329.
    Forsell, Mattias N. E.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Kvastad, Linda
    Sedimbi, Saikiran K.
    Andersson, John
    Karlsson, Mikael C. I.
    Regulation of Subunit-Specific Germinal Center B Cell Responses to the HIV-1 Envelope Glycoproteins by Antibody-Mediated Feedback2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 738Article in journal (Refereed)
    Abstract [en]

    The regulation of germinal center (GC) B cell responses to single epitopes is well investigated. How monoclonal B cells are regulated within the polyclonal B cell response to protein antigens is less so. Here, we investigate the primary GC B cell response after injection of mice with HIV-1 envelope glycoproteins. We demonstrate that single GCs are seeded by a diverse number of B cell clones shortly after a single immunization and that the presence of Env-specific antibodies can inhibit the development of early GC B cells. Importantly, the suppression was dependent on the GC B cells and the infused antibodies to target the same subunit of the injected HIV-1 envelope glycoproteins. An affinity-dependent antibody feedback has previously been shown to regulate GC B cell development. Here, we propose that this antibody-based feedback acts on GC B cells only if they target the same or overlapping epitopes. This study provides important basic information of GC B cell regulation, and for future vaccine designs with aim to elicit neutralizing antibodies against HIV-1.

  • 330. Forsell, Mattias N E
    et al.
    Li, Yuxing
    Sundbäck, Maria
    Svehla, Krisha
    Liljeström, Peter
    Mascola, John R
    Wyatt, Richard
    Karlsson Hedestam, Gunilla B
    Biochemical and immunogenic characterization of soluble human immunodeficiency virus type 1 envelope glycoprotein trimers expressed by semliki forest virus.2005In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 79, no 17, p. 10902-14Article in journal (Refereed)
    Abstract [en]

    The current lack of envelope glycoprotein immunogens that elicit broadly neutralizing antibody responses remains a major challenge for human immunodeficiency virus type 1 (HIV-1) vaccine development. However, the recent design and construction of stable soluble gp140 trimers have shown that some neutralization breadth can be achieved by using immunogens that better mimic the functional viral spike complex. The use of genetic delivery systems to drive the in vivo expression of such immunogens for the stimulation of neutralizing antibodies against HIV-1 may offer advantages by maintaining the quaternary structure of the trimeric envelope glycoproteins. Here, we describe the biochemical and immunogenic properties of soluble HIV-1 envelope glycoprotein trimers expressed by recombinant Semliki Forest virus (rSFV). The results presented here demonstrate that rSFV supports the expression of stable soluble gp140 trimers that retain recognition by conformationally sensitive antibodies. Further, we show that rSFV particle immunizations efficiently primed immune responses as measured after a single boost with purified trimeric gp140 protein, resulting in a Th1-biased antibody response. This differed from the Th2-biased antibody response obtained after repeated immunizations with purified gp140 protein trimers. Despite this difference, both regimens stimulated neutralizing antibody responses of similar potency. This suggests that rSFV may be a useful component of a viral vector prime-protein boost regimen aimed at stimulating both cell-mediated immune responses and neutralizing antibodies against HIV-1.

  • 331.
    Fossati-Jimack, Liliane
    et al.
    University of Geneva.
    Azeredo da Silveira, Samareh
    University of Geneva.
    Moll, Thomas
    University of Geneva.
    Kina, Tatsuo
    Kyoto University.
    Kuypers, Frans A
    Children's Hospital Oakland Research Institute, Oakland, California.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Reininger, Luc
    Institut National de la Santé et de la Recherche Médicale U 399, Marseille.
    Izui, Shozo
    University of Geneva.
    Selective increase of autoimmune epitope expression on aged erythrocytes in mice: implications in anti-erythrocyte autoimmune responses2002In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 18, no 1, p. 17-25Article in journal (Refereed)
    Abstract [en]

    We investigated the impact of changes occurring during red blood cell (RBC) ageing on the RBC-binding activity of pathogenic anti-erythrocyte monoclonal antibodies derived from autoimmune-prone New Zealand black (NZB) mice. As assessed by flow cytometric analysis on in vivo biotinylated RBCs, all five NZB-derived anti-RBC mAb exhibited more efficient binding to aged RBCs than to young RBCs, and resulted in a selective elimination of more aged RBCs from the circulating blood. In addition, treatment of RBCs with proteases markedly enhanced the binding of all five anti-RBC mAb, raising the possibility that increased exposure of autoimmune epitopes on aged RBCs may be in part, a result of contacts with proteolytic enzymes during the lifetime of circulating RBCs. In marked contrast, the binding activity of mAb raised in non-autoimmune animals against antigens expressed on RBCs, such as CD44, CD47, CD147 and TER-119, was either decreased or unchanged with RBC ageing, and these epitopes, except for that recognized by anti-CD47 mAb, were highly sensitive to mild treatment with proteases. Our data unravel the unique molecular feature of RBC epitopes involved in autoimmune haemolytic anaemia, suggesting that membrane alterations in aged RBCs might play a significant role in the development of the autoantibody response to RBCs.

  • 332.
    Fotaki, Grammatiki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Allogeneic dendritic cells as adjuvants in cancer immunotherapy2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In recent years, immunotherapeutic approaches have achieved remarkable successes through checkpoint blockade antibodies, advances in the use of chimeric antigen receptor (CAR) T cells and new insights into the immunosuppressive role of the tumor microenvironment (TME). Through the advances, the role of cancer vaccines based on ex vivo manipulated autologous dendritic cells (DC) has been challenged. The main aim of DC-based vaccination is the induction of tumor-specific T-cell responses through presentation of tumor-associated antigens. However, this process has been found to be highly dependent on the ability of the injected vaccine-DCs to activate endogenous bystander DCs.

    In this work, we examined the feasibility of having an allogeneic source of vaccine-DCs (alloDCs), not for direct antigen-presentation to T cells but as an immune primer aiming to activate bystander DCs. In paper I, we treated alloDCs with a T helper cell type 1 (Th1)-promoting maturation cocktail alone or combined with a replication-deficient, infection-enhanced adenoviral vector (Ad5M) as a potential gene delivery vehicle. We found that mature pro-inflammatory alloDCs, either non-transduced or transduced, created a cytokine- and chemokine-enriched milieu in vitro, and promoted the activation of co-cultured immune cells, including cytolytic NK cells, from unrelated donors. The emerged milieu induced the maturation of bystander DCs, which cross-presented antigens from their environment to autologous antigen-specific T cells. In paper II, we found that alloDCs promoted the migration of murine immune cells both to the site of injection and to the draining lymph node. When Ad5M was used for the delivery of the melanoma-associated antigen gp100, we found that gp100-expressing alloDCs were able to control tumor growth through gp100-specific T-cell responses and alteration of the TME. In paper III, we found that co-administration of alloDCs with an adenoviral vector encoding for HPV-antigens is effective in controlling the growth of HPV-related tumors and this may depend on a cross-talk between alloDCs and NK cells which leads to further recruitment of immune cells into the TME. In paper IV, we observed that concomitant targeting of immune checkpoint receptors or co-stimulatory molecules results in synergistic therapeutic effects in a murine colorectal model.

  • 333.
    Fotaki, Grammatiki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jin, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Karlsson-Parra, Alex
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Allogeneic dendritic cells (AlloDCs) transduced with an infection enhanced adenovirus as adjuvant for cancer immunotherapy2016In: CANCER IMMUNOLOGY RESEARCH, ISSN 2326-6066, Vol. 4, no 1Article in journal (Other academic)
  • 334.
    Fotaki, Grammatiki
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jin, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kerzeli, Iliana Kyriaki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ramachandran, Mohanraj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Martikainen, Minttu-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlsson-Parra, Alex
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab. Immunicum AB, Gothenburg.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cancer vaccine based on a combination of an infection-enhanced adenoviral vector and pro-inflammatory allogeneic DCs leads to sustained antigen-specific immune responses in three melanoma models2018In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 7, no 3, article id e1397250Article in journal (Refereed)
    Abstract [en]

    Autologous patient-derived dendritic cells (DCs) modified ex vivo to present tumor-associated antigens (TAAs) are frequently used as cancer vaccines. However, apart from the stringent logistics in producing DCs on a patient basis, accumulating evidence indicate that ex vivo engineered DCs are poor in migration and in fact do not directly present TAA epitopes to naïve T cells in vivo. Instead, it is proposed that bystander host DCs take up material from vaccine-DCs, migrate and subsequently initiate antitumor T-cell responses. We used mouse models to examine the possibility of using pro-inflammatory allogeneic DCs (alloDCs) to activate host DCs and enable them to promote antigen-specific T-cell immunity. We found that alloDCs were able to initiate host DC activation and migration to draining lymph node leading to T-cell activation. The pro-inflammatory milieu created by alloDCs also led to recruitment of NK cells and neutrophils at the site of injection. Vaccination with alloDCs combined with Ad5M(gp100), an infection-enhanced adenovirus encoding the human melanoma-associated antigen gp100 resulted in generation of CD8+ T cells with a T-cell receptor (TCR) specific for the gp10025-33 epitope (gp100-TCR+). Ad5M(gp100)-alloDC vaccination in combination with transfer of gp100-specific pmel-1 T cells resulted in prolonged survival of B16-F10 melanoma-bearing mice and altered the composition of the tumor microenvironment (TME). We hereby propose that alloDCs together with TAA- or neoepitope-encoding Ad5M can become an “off-the-shelf” cancer vaccine, which can reverse the TME-induced immunosuppression and induce host cellular anti-tumor immune responses in patients without the need of a time-consuming preparation step of autologous DCs.

  • 335.
    Fotaki, Grammatiki
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jin, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ramachandran, Mohanraj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kerzeli, Iliana Kyriaki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlsson-Parra, Alex
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab. Immunicum AB, Uppsala.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pro-inflammatory allogeneic DCs promote activation of bystander immune cells and thereby license antigen-specific T-cell responses2018In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 7, no 3, article id e1395126Article in journal (Refereed)
    Abstract [en]

    Accumulating evidence support an important role for endogenous bystander dendritic cells (DCs) in the efficiency of autologous patient-derived DC-vaccines, as bystander DCs take up material from vaccine-DCs, migrate to draining lymph node and initiate antitumor T-cell responses. We examined the possibility of using allogeneic DCs as vaccine-DCs to activate bystander immune cells and promote antigen-specific T-cell responses. We demonstrate that human DCs matured with polyI:C, R848 and IFN-γ (denoted COMBIG) in combination with an infection-enhanced adenovirus vector (denoted Ad5M) exhibit a pro-inflammatory state. COMBIG/Ad5M-matured allogeneic DCs (alloDCs) efficiently activated T-cells and NK-cells in allogeneic co-culture experiments. The secretion of immunostimulatory factors during the co-culture promoted the maturation of bystander-DCs, which efficiently cross-presented a model-antigen to activate antigen-specific CD8+ T-cells in vitro. We propose that alloDCs, in combination with Ad5M as loading vehicle, may be a cost-effective and logistically simplified DC vaccination strategy to induce anti-tumor immune responses in cancer patients.

  • 336.
    Fotaki, Grammatiki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ma, Jing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jin, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlsson-Parra, Alex
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Therapeutic vaccination of HPV-associated tumors using pro-inflammatory allogeneic dendritic cells and an HPV-E6/E7-encoding vectorManuscript (preprint) (Other academic)
  • 337.
    Fotaki, Grammatiki
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlsson-Parra, Alex
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Concomitant targeting of PD-1 or CD137 enhances the effect of adjuvant pro-inflammatory allogeneic dendritic cells.Manuscript (preprint) (Other academic)
  • 338. Frankowiack, Marcel
    et al.
    Olsson, Mia
    Cluff, H. Dean
    Evans, Alina L.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Mansson, Johan
    Arnemo, Jon M.
    Hammarstrom, Lennart
    IgA deficiency in wolves from Canada and Scandinavia2015In: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 50, no 1, p. 26-28Article in journal (Refereed)
    Abstract [en]

    Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in both humans and selected breeds of domestic dogs. In both species, IgAD is associated with recurrent infections and immune mediated diseases. Previous results imply that IgAD is also common in the wild ancestor of domestic dogs, the gray wolf. Here, we report that serum IgA concentrations are significantly different in Scandinavian and Canadian wolves (p =3.252e-15) with an increased prevalence for IgAD in Scandinavian wolves (60%), which is as high as those found in high-risk dog breeds. 

  • 339. Fransen-Pettersson, Nina
    et al.
    Duarte, Nadia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. nstituto Gulbenkian de Sciencia, Oeiras, 2780–156 Oeiras, Portugal.
    Nilsson, Julia
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mayans, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Larefalk, Åsa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Hannibal, Tine D.
    Hansen, Lisbeth
    Schmidt-Christensen, Anja
    Ivars, Fredrik
    Cardell, Susanna
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rozell, Bjoern
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. EMV Immunology, BMC, Lund University, Lund, Sweden; ISIM- Immunology, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark.
    A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 7, article id e0159850Article in journal (Refereed)
    Abstract [en]

    Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders.

  • 340.
    Fransson, Moa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    CNS-Targeted Cell Therapy for Multiple Sclerosis2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS). In the current thesis, we have preformed an immunological investigation of patients with MS and developed an immunosuppressive cell therapy that could be beneficial for these patients.

    MS has been considered to be driven by T helper type1 (Th1) lymphocytes but new data indicate the involvement of Th17 responses. T cells from patients with MS that were evaluated for immunological status secreted both interferon-γ and interleukin-17 upon stimulation. However, T cells from patients with MS in remission, in contrast to relapse, had poor proliferative capacity suggesting that they are controlled and kept in anergy.

    T regulatory cells (Tregs) are important to maintain self-tolerance and the role of CD4+CD25+FoxP3+ Tregs in autoimmunity has been extensively investigated. We analyzed Tregs from patients with MS in relapse and remission by multicolor flow cytometry for the expression of CD3, CD4, IL2R (CD25), FoxP3 and the IL7R (CD127). Patients in relapse exhibited higher levels of FoxP3-positive Tregs lacking CD25 compared to healthy controls, indicating that Tregs might attempt to restrain immune activity during relapse.

    In the murine experimental autoimmune encephalomyelitis (EAE) model of MS, therapy with suppressive cells such as Tregs or mesenchymal stromal cells (MSCs) has proven beneficial. However, systemic administration of such cells may immunologically compromise the recipient and promote infections due to general immunosuppression. We hypothesized that suppressive cells can be equipped with a CNS-targeting receptor and be delivered intra-nasally to avoid systemic exposure. CD4+ T cells were modified with a lentiviral vector system to express a myelin oligodendrocyte (MOG)-targeting receptor in trans with the FoxP3 gene that drives Treg differentiation. Genetically engineered Tregs demonstrated suppressive capacity in vitro and localized to the brain and suppressed ongoing encephalomyelitis in vivo. Cured mice were rechallenged with an EAE-inducing inoculum but remained healthy.

    MSCs are a heterogeneous population of stromal cells residing in most connective tissues and have the capacity to suppress effector cells of the immune system. MSCs were engineered to express MOG-targeting receptors using lentiviral vectors. Genetically engineered MSCs retained their suppressive capacity in vitro and successfully targeted the brain upon intranasal delivery. Engineered MSCs cured mice from disease symptoms and these mice were resistant to further EAE challenge. Encephalitic T cells isolated from cured mice displayed an anergic profile while peripheral T cells were still responsive to stimuli.

    In conclusion, MS patients have peripheral CNS-reactive T cells of both Th1 and Th17 type that, while in remission, are kept in anergy. Also, MS patients in relapse exhibit increased levels of CD25 negative Tregs indicating an attempt to restrain immune activity. Finally, immunosuppressive cells can be genetically engineered to target CNS and efficiently suppress encephalomyelitis in an active EAE model upon intranasal delivery.

     

  • 341.
    Fransson, Moa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Piras, E
    Wang, H
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Duprez, I
    Harris, R
    LeBlanc, K
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Human Mesenchymal stromal cells expressing a CNS-targeting receptor can be administrated intra nasally and cure expersimental autoimmune enchphlomyelitisManuscript (preprint) (Other academic)
    Abstract [en]

    Mesenchymal stromal cells (MSCs) are a heterogeneous population of stromal cells residing in most connective tissues and have the capacity to suppress effector cells of the immune system. In experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, systemic treatments with both murine and human MSCs have proven beneficial because of their capacity to suppress overt immune reactions. However, systemic administration of such cells may cause problems with infectious disease and low numbers of cells that reach the inflamed tissue. We hypothesized that MSCs can be accumulated and retained in the CNS using gene transfer of a CNS-targeting device and intranasal cell delivery. In the current investigation, MSCs were engineered to express a myelin oligodendrocyte glycoprotein (MOG)-specific receptor using lentiviral vectors. Genetically engineered MSCs retained their suppressive capacity in vitro and successfully targeted the brain upon both intraperitoneal and intranasal delivery. Engineered MSCs cured mice from disease symptoms and these mice were resistant to further EAE challenge. Encephalitic T cells isolated from cured mice displayed an anergic profile while peripheral T cells were still responsive to stimuli. Further, MSC treatment reduced the level of inflammatory cytokines in the brain and implyed reduced damage to axons. In conclusion, MSCs can be genetically engineered to target CNS and efficiently suppress encephalomyelitis in an active EAE model upon intranasal delivery.

  • 342.
    Fransson, Moa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Piras, E
    Wang, H
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Harris, R
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Engineered T regulatory cells target CNS and suppress active EAE upon intra nasal deliveryManuscript (preprint) (Other academic)
    Abstract [en]

    Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS). In the murine experimental autoimmune encephalomyelitis (EAE) model of MS, T regulatory (Treg) cell therapy has proven beneficial. However, systemic administration of such cells may immunologically compromise the recipient and promote infections due to general immunosuppression. We hypothesized that Tregs can be equipped with a CNS-targeting receptor and be delivered intra-nasally to avoid systemic exposure. In the current investigation, CD4+ T cells were modified with a lentiviral vector system to express a myelin oligodendrocyte (MOG)-targeting receptor in trans with the FoxP3 gene that drives Treg differentiation. The genetically engineered Tregs demonstrated suppressive capacity in vitro and were then tested in the EAE model. Engineered Tregs localized to the brain and suppressed ongoing encephalomyelitis in vivo. Cured mice were rechallenged with an EAE-inducing inoculum but remained healthy. Cytokine profile of the brain reveled lower levels of effector cytokines in TregCAR treated mice and acordingly, reduced axonal damage was seen in these mice. In conclusion, CNS-specific Tregs were able to localize to the CNS and efficiently cure mice with ongoing EAE.

  • 343.
    Fretland, Asmund Avdem
    et al.
    The Intervention Centre, Oslo University Hospital, Norway.
    Sokolov, Andrey
    Oslo University Hospital, Norway.
    Postriganova, Nadya
    Intervention Centre, Oslo University Hospital, Norway.
    Kazaryan, Airazat M
    Intervention Centre, Oslo University Hospital, Norway.
    Pischke, Soren E
    Intervention Centre, Oslo University Hospital, Norway.
    Nilsson, Per H.
    Oslo University Hospital, Norway.
    Rognes, Ingrid Nygren
    Oslo University Hospital, Norway.
    Bjornbeth, Bjorn Atle
    Oslo University Hospital, Norway.
    Fagerland, Morten Wang
    Oslo University Hospital, Norway.
    Mollnes, Tom Eirik
    Oslo University Hospital, Norway.
    Edwin, Bjorn
    Intervention Centre, Oslo University Hospital, Norway.
    Inflammatory Response After Laparoscopic Versus Open Resection of Colorectal Liver Metastases: Data From the Oslo-CoMet Trial.2015In: Medicine (Baltimore, Md.), ISSN 0025-7974, E-ISSN 1536-5964, Vol. 94, no 42, p. 1-7, article id e1786Article in journal (Refereed)
    Abstract [en]

    Laparoscopic and open liver resection have not been compared in randomized trials. The aim of the current study was to compare the inflammatory response after laparoscopic and open resection of colorectal liver metastases (CLM) in a randomized controlled trial.This was a predefined exploratory substudy within the Oslo CoMet-study. Forty-five patients with CLM were randomized to laparoscopic (n = 23) or open (n = 22) resection. Ethylenediaminetetraacetic acid-plasma samples were collected preoperatively and at defined time points during and after surgery and snap frozen at -80 C. A total of 25 markers were examined using luminex and enzyme-linked immunosorbent assay techniques: high-mobility box group 1(HMGB-1), cell-free DNA (cfDNA), cytokines, and terminal C5b-9 complement complex complement activation.Eight inflammatory markers increased significantly from baseline: HMGB-1, cfDNA, interleukin (IL)-6, C-reactive protein, macrophage inflammatory protein -1β, monocyte chemotactic protein -1, IL-10, and terminal C5b-9 complement complex. Peak levels were reached at the end of or shortly after surgery. Five markers, HMGB-1, cfDNA, IL-6, C-reactive protein, and macrophage inflammatory protein -1β, showed significantly higher levels in the open surgery group compared with the laparoscopic surgery group.Laparoscopic resection of CLM reduced the inflammatory response compared with open resection. The lower level of HMGB-1 is interesting because of the known association with oncogenesis.

  • 344.
    Friberg, Andrew S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lundgren, Torbjörn
    Malm, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Felldin, M
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jenssen, T
    Kyllonen, L
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Tibell, Annika
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Transplanted functional islet mass: donor islet preparation, and recipitent factors influence early graft function in islet-after-kidney patients2012In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 93, no 6, p. 632-638Article in journal (Refereed)
    Abstract [en]

    Background.

    The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal.

    Methods.

    Analysis of 10 donor, 7 islet isolation, 3 quality control, and 6 recipient variables was undertaken in 110 islet-after-kidney transplants and correlated to the pre- to 28-day posttransplant change in C-peptide to glucose and creatinine ratio ([DELTA]CP/GCr).

    Results.

    Univariate analysis yielded islet volume transplanted (Spearman r=0.360, P<0.001) and increment of insulin secretion (r=0.377, P<0.001) as variables positively associated to [DELTA]CP/GCr. A negative association to [DELTA]CP/GCr was cold ischemia time (r=-0.330, P<0.001). A linear, backward-selection multiple regression was used to obtain a model for the transplanted functional islet mass (TFIM). The TFIM model, composed of islet volume transplanted, increment of insulin secretion, cold ischemia time, and exocrine tissue volume transplanted, accounted for 43% of the variance of the clinical outcome in the islet-after-kidney data set.

    Conclusion.

    The TFIM provides a straightforward and potent tool to guide the decision to use a specific islet preparation for clinical transplantation.

  • 345.
    Frischmeyer-Guerrerio, Pamela A.
    et al.
    NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Rasooly, Marjohn
    Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, NCI Campus, Frederick, MD USA.
    Gu, Wenjuan
    Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, NCI Campus, Frederick, MD USA.
    Levin, Samara
    NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Jhamnani, Rekha D.
    NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Milner, Joshua D.
    NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Stone, Kelly
    NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Guerrerio, Anthony L.
    Johns Hopkins Sch Med, Dept Pediat, Baltimore, MD USA.
    Jones, Joseph
    Phadia US Inc, Thermo Fisher Sci, ImmunoDiagnost Branch, Portage, MI USA.
    Borres, Magnus P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Brittain, Erica
    NIH, Biostat Res Branch, DCR, Bldg 10, Bethesda, MD 20892 USA.
    IgE testing can predict food allergy status in patients with moderate to severe atopic dermatitis2019In: Annals of Allergy, Asthma & Immunology, ISSN 1081-1206, E-ISSN 1534-4436, Vol. 122, no 4, p. 393-400Article in journal (Refereed)
    Abstract [en]

    Background: Diagnosing food allergy in patients with atopic dermatitis (AD) is complicated by their high rate of asymptomatic sensitization to foods, which can lead to misdiagnosis and unnecessary food avoidance.

    Objective: We sought to determine whether food-specific (sIgE) or component immunoglobulin (Ig) E levels could predict allergic status in patients with moderate to severe AD and elevated total IgE.

    Methods: Seventy-eight children (median age, 10.7 years) with moderate to severe AD were assessed for a history of clinical reactivity to milk, egg, peanut, wheat, and soy. The IgE levels for each food and its components were determined by ImmunoCAP. The level and pattern of IgE reactivity to each food and its components, and their ratio to total IgE, were compared between subjects who were allergic and tolerant to each food.

    Results: Ninety-one percent of subjects were sensitized, and 51% reported allergic reactivity to at least 1 of the 5 most common food allergens. Allergy to milk, egg, and peanut were most common, and IgE levels to each of these foods were significantly higher in the allergic group. Component IgEs most associated with milk, egg, and peanut allergy were Bos d8, Gal d1, and Ara h2, respectively. The ratio of sIgE to total IgE offered no advantage to sIgE alone in predicting allergy.

    Conclusion: Specific IgE levels and the pattern of IgE reactivity to food components can distinguish AD subjects allergic vs tolerant to the major food allergens and may therefore be helpful in guiding the clinical management of these patients. 

  • 346.
    Frisk, Jun Mei Hu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kjellén, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Melo, Fabio R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Öhrvik, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden.
    Mitogen-Activated Protein Kinase Signaling Regulates Proteoglycan Composition of Mast Cell Secretory Granules2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 1670Article in journal (Refereed)
    Abstract [en]

    Mast cells (MCs) are characterized by an abundance of lysosome-like secretory granules filled with immunomodulatory compounds including histamine, cytokines, lysosomal hydrolases, MC-restricted proteases, and serglycin proteoglycans. The latter are essential for promoting the storage of other granule compounds and are built up of the serglycin core protein to which highly sulfated and thereby negatively charged glycosaminoglycan (GAG) side chains of heparin or chondroitin sulfate type are attached. In the search for mechanisms operating in regulating MC granule homeostasis, we here investigated the role of mitogen-activated protein kinase (MAPK) signaling. We show that inhibition of MEK1/2 (a MAPK kinase) leads to increased metachromatic staining of MC granules, indicative of increased proteoglycan content. Indeed, MEK1/2 inhibition caused a profound increase in the expression of the gene coding for the serglycin core protein and of genes coding for various enzymes involved in the biosynthesis/sulfation of the GAGs attached to the serglycin core protein. This was accompanied by corresponding increases in the levels of the respective GAGs. Deletion of the serglycin core protein abrogated the induction of enzymes operative in proteoglycan synthesis, indicating that availability of the serglycin proteoglycan core protein has a regulatory function impacting on the expression of the various serglycin-modifying enzymes. MEK1/2 inhibition also caused a substantial increase in the expression of granule-localized, proteoglycan-binding proteases. Altogether, this study identifies a novel role for MAPK signaling in regulating the content of secretory granules in MCs.

  • 347.
    Fritsch Fredin, Maria
    et al.
    Astra-Zeneca, Mölndal.
    Hultin, Leif
    Astra-Zeneca, Mölndal.
    Hyberg, Gina
    Astra-Zeneca, Mölndal.
    Rehnström, Erika
    Astra-Zeneca, Mölndal.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences.
    Melgar, Silvia
    Astra-Zeneca, Mölndal.
    Jansson, Liselotte
    Astra-Zeneca, Mölndal.
    Predicting and monitoring colitis development in mice by micro-computed tomography2008In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 14, no 4, p. 491-499Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Computed tomography (CT) has been developed as a tool for monitoring human inflammatory bowel disease (IBD). The aim of this study was to evaluate colon wall thickness as a noninvasive marker in the dextran sodium sulfate (DSS) mouse model of colitis using micro-CT. METHODS: Mice were examined by micro-CT 1, 2, or 4 times between day 0 (d0) and d26 after induction of colitis to document the kinetics of changes in colon wall thickness and its relation to colitis development. RESULTS: DSS-treated mice displayed a significantly thicker colon wall at all timepoints (days 5, 8, 12, 19, and 26) investigated compared to healthy controls. Colon wall thickness showed a good correlation to the macroscopic grading of colitis (r = 0.81). The increase in colon wall thickness occurred mainly during the acute phase of colitis (between days 5 and 12) and did not progress much further in the chronic phase of colitis (d26). Colon wall thickness at d26 was thereby predicted by measurements at d12. All mice did not respond equally to DSS and this difference was manifest during the first 2 weeks of colitis, providing an important tool in stratifying responders from nonresponders. CONCLUSIONS: While the potential impact of handling and anesthesia should be considered on repeated micro-CT, irradiation exposure during repeated micro-CT did not affect the development of colitis. Thus, the results suggest that micro-CT can be used for monitoring and prediction of the inflammatory response in mouse colitis in future therapeutic studies.

  • 348.
    Fritz, Michael
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Klawonn, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Jaarola, Maarit
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Engblom, David
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience.
    Interferon-ɣ mediated signaling in the brain endothelium is critical for inflammation-induced aversion2018In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 67, p. 54-58Article in journal (Refereed)
    Abstract [en]

    Systemic inflammation elicits malaise and a negative affective state. The mechanism underpinning the aversive component of inflammation include cerebral prostaglandin synthesis and modulation of dopaminergic reward circuits, but the messengers that mediate the signaling between the peripheral inflammation and the brain have not been sufficiently characterized. Here we investigated the role of interferon-ɣ (IFN-ɣ) in the aversive response to systemic inflammation induced by a low dose (10μg/kg) of lipopolysaccharide (LPS) in mice. LPS induced IFN-ɣ expression in the blood and deletion of IFN-ɣ or its receptor prevented the development of conditioned place aversion to LPS. LPS induced expression of the chemokine Cxcl10 in the striatum of normal mice, but this induction was absent in mice lacking IFN-ɣ receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation-induced aversion was blocked in mice lacking Cxcl10 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-ɣ receptor in brain endothelial cells did not develop inflammation-induced aversion, demonstrating that the brain endothelium is the critical site of IFN-ɣ action. Collectively, these findings show that circulating IFN-ɣ that binds to receptors on brain endothelial cells and induces Cxcl10, is a central link in the signaling chain eliciting inflammation-induced aversion.

  • 349.
    Frodlund, M.
    et al.
    Linkoping Univ, Div Neuro & Inflammat Sci, Dept Clin & Expt Med, Linkoping, Sweden.
    Vikerfors, A.
    Swedish Med Prod Agcy, SE-75103 Uppsala, Sweden;Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Unit Rheumatol, Stockholm, Sweden.
    Grosso, G.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Unit Rheumatol, Stockholm, Sweden.
    Skogh, T.
    Linkoping Univ, Div Neuro & Inflammat Sci, Dept Clin & Expt Med, Linkoping, Sweden.
    Wetterö, J.
    Linkoping Univ, Div Neuro & Inflammat Sci, Dept Clin & Expt Med, Linkoping, Sweden.
    Elvin, K.
    Karolinska Inst, Dept Clin Immunol & Transfus Med, Unit Clin Immunol, Stockholm, Sweden.
    Gunnarsson, I.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Unit Rheumatol, Stockholm, Sweden.
    Kastbom, A.
    Linkoping Univ, Div Neuro & Inflammat Sci, Dept Clin & Expt Med, Linkoping, Sweden.
    Dahlström, Ö.
    Linkoping Univ, Swedish Inst Disabil Res, Dept Behav Sci & Learning, Linkoping, Sweden.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Svenungsson, E.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Unit Rheumatol, Stockholm, Sweden.
    Sjöwall, C.
    Linkoping Univ, Div Neuro & Inflammat Sci, Dept Clin & Expt Med, Linkoping, Sweden.
    Immunoglobulin A anti-phospholipid antibodies in Swedish cases of systemic lupus erythematosus: associations with disease phenotypes, vascular events and damage accrual2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 1, p. 27-38Article in journal (Refereed)
    Abstract [en]

    Immunoglobulin (Ig) G- and IgM-class anti-cardiolipin antibodies (aCL) and lupus anti-coagulant (LA) are included in the 1997 update of the American College of Rheumatology (ACR-97) systemic lupus erythematosus (SLE) criteria. Despite limited evidence, IgA-aCL and IgA anti-(2)-glycoprotein-I (anti-(2)GPI) were included in the 2012 Systemic Lupus International Collaborating Clinics criteria. The present study aimed to evaluate IgG-/IgA-/IgM-aCL and anti-(2)GPI occurrence in relation to disease phenotype, smoking habits, pharmacotherapy, anti-phospholipid syndrome (APS) and organ damage among 526 Swedish SLE patients meeting ACR-97. Patients with rheumatoid arthritis (n=100), primary Sjogren's syndrome (n=50) and blood donors (n=507) served as controls. Anti-phospholipid antibodies (aPL) were analysed by fluoroenzyme-immunoassays detecting aCL/anti-(2)GPI. Seventy-six (14%) SLE cases fulfilled the Sydney APS-criteria, and 1 aCL/anti-(2)GPI isotype (IgG/IgA/IgM) occurred in 138 SLE patients (26%). Forty-five (9%) of the SLE cases had IgA-aCL, 20 of whom (4%) lacked IgG-/IgM-aCL. Seventy-four (14%) tested positive for IgA anti-(2)GPI, 34 (6%) being seronegative regarding IgG/IgM anti-(2)GPI. Six (1%) had APS manifestations but were seropositive regarding IgA-aCL and/or IgA anti-(2)GPI in the absence of IgG/IgM-aPL and LA. Positive LA and IgG-aPL tests were associated with most APS-related events and organ damage. Exclusive IgA anti-(2)GPI occurrence associated inversely with Caucasian ethnicity [odds ratio (OR)=021, 95% confidence interval (CI)=006-072) and photosensitivity (OR=019, 95% CI=005-072). Nephritis, smoking, LA-positivity and statin/corticosteroid-medication associated strongly with organ damage, whereas hydroxychloroquine-medication was protective. In conclusion, IgA-aPL is not rare in SLE (16%) and IgA-aPL analysis may have additional value among SLE cases with suspected APS testing negative for other isotypes of aPL and LA.

  • 350.
    Fromell, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Dührkop, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Johansson, Ulrika
    Linnaeus Univ, Linnaeus Ctr Biomat Chem, Vaxjo, Sweden..
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, Vaxjo, Sweden..
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Forms of contact-activated C3 associated with AP convertase formation2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 141-141Article in journal (Other academic)
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