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Exploring immune cell functions and ways to make use of them
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In addition to host defense, alternative functions of immune cells are emerging. Immune cells are crucial during healing of injured tissue, in formation of new blood vessels, angiogenesis, and also in maintaining the balance in inflammation having immune regulating functions. Over the last decade a higher degree of heterogeneity and plasticity of immune cells have been reported and immune cells develop different characteristics in different situations in vivo.

This thesis investigates roles for immune cells in situations of muscle hypoxia and reduced blood perfusion, wound healing in skin and at sites of transplantation of allogeneic islets of Langerhans and on top of this, ways to steer immune cell function for future therapeutic purposes. A specific neutrophil subset (CD49d+VEGFR1+CXCR4high) was found to be recruited to VEGF-A released at hypoxia and these neutrophils were crucial for functional angiogenesis. In muscle with restricted blood flow macrophages were detected in perivascular positions and started to express aSMA and PDGFR1b and were found to directly assist in blood flow regulation by iNOS-dependent NO production. This essential function in muscle regain of function could be boosted by plasmid overexpression of CXCL12 where the effect of these macrophages chaperoning the vasculature was amplified improving limb blood flow regulation. The effect on macrophages accelerating tissue regeneration being amplified by CXCL12 was tested in a model of cutaneous wound healing where the administration of CXCL12 was optimized for high bioavailability. In the skin, CXCL12-treatment induced accumulation of TGFb-expressing macrophages close to the wound driving the healing process, and subsequently the wounds healed with an efficiency never reported before. In the last study means to circumvent systemic immune suppressive therapy required in allogeneic transplantation was investigated. Allogeneic islets of Langerhans transplanted to muscle were immediately destroyed by the host immune system. Co-transplanting islets and CCL22-encoding plasmids we could curb this fast rejection for 10 days by accumulating CD4+CD25+FoxP3+ regulatory T lymphocytes at the site for transplantation preventing islet grafts from being attacked by the host cytotoxic T lymphocytes.

In summary this thesis outlines distinct immune cell subsets being essential for regain of tissue function in hypoxia, ischemia and post injury and ways to amplify specific immune cell functions in these situations that are feasible for clinical use.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1242
Keyword [en]
leukocytes, neutrophils, macrophages, regulatory T cells, chemokines, VEGF-A, hypoxia, ischemia, muscle, Islets of Langerhans, diabetes, transplantation, wound healing
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-299683ISBN: 978-91-554-9641-8OAI: oai:DiVA.org:uu-299683DiVA: diva2:951214
Public defence
2016-09-23, A1:107a, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-09-02 Created: 2016-07-25 Last updated: 2016-09-05
List of papers
1. Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans
Open this publication in new window or tab >>Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans
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2015 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 17, 2016-2026 p.Article in journal (Refereed) Published
Abstract [en]

Vascular endothelial growth factor A (VEGF-A) is upregulated during hypoxia and is the major regulator of angiogenesis. VEGF-A expression has also been found to recruit myeloid cells to ischemic tissues where they contribute to angiogenesis. This study investigates the mechanisms underlying neutrophil recruitment to VEGF-A as well as the characteristics of these neutrophils. A previously undefined circulating subset of neutrophils shown to be CD49d(+)VEGFR1(high)CXCR4(high) was identified in mice and humans. By using chimeric mice with impaired VEGF receptor 1 (VEGFR1) or VEGFR2 signaling (Flt-1tk(-/-), tsad(-/-)), we found that parallel activation of VEGFR1 on neutrophils and VEGFR2 on endothelial cells was required for VEGF-A-induced recruitment of circulating neutrophils to tissue. Intravital microscopy of mouse microcirculation revealed that neutrophil recruitment by VEGF-A versus by the chemokine macrophage inflammatory protein 2 (MIP-2 [CXCL2]) involved the same steps of the recruitment cascade but that an additional neutrophil integrin (eg, VLA-4 [CD49d/CD29]) played a crucial role in neutrophil crawling and emigration to VEGF-A. Isolated CD49d(+) neutrophils featured increased chemokinesis but not chemotaxis compared with CD49d(-) neutrophils in the presence of VEGF-A. Finally, by targeting the integrin α4 subunit (CD49d) in a transplantation-based angiogenesis model that used avascular pancreatic islets transplanted to striated muscle, we demonstrated that inhibiting the recruitment of circulating proangiogenic neutrophils to hypoxic tissue impairs vessel neoformation. Thus, angiogenesis can be modulated by targeting cell-surface receptors specifically involved in VEGF-A-dependent recruitment of proangiogenic neutrophils without compromising recruitment of the neutrophil population involved in the immune response to pathogens.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-265201 (URN)10.1182/blood-2015-03-631572 (DOI)000366389200012 ()26286848 (PubMedID)
Funder
Swedish Research CouncilThe Royal Swedish Academy of SciencesMagnus Bergvall FoundationSwedish Diabetes AssociationÅke Wiberg FoundationRagnar Söderbergs stiftelseKnut and Alice Wallenberg Foundation
Available from: 2015-10-25 Created: 2015-10-25 Last updated: 2016-08-26Bibliographically approved
2. Uncovering a new role for immune cells: macrophages assist in regulation of blood flow in ischemic muscle
Open this publication in new window or tab >>Uncovering a new role for immune cells: macrophages assist in regulation of blood flow in ischemic muscle
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-299682 (URN)
Available from: 2016-07-25 Created: 2016-07-25 Last updated: 2016-08-26Bibliographically approved
3. Accelerated skin wound healing by CXCL12 1a delivered on site by lactic acid bacteria
Open this publication in new window or tab >>Accelerated skin wound healing by CXCL12 1a delivered on site by lactic acid bacteria
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-299681 (URN)
Available from: 2016-07-25 Created: 2016-07-25 Last updated: 2016-08-26Bibliographically approved
4. Immunological shielding by induced recruitment of regulatory T lymphocytes delays rejection of islets transplanted to muscle
Open this publication in new window or tab >>Immunological shielding by induced recruitment of regulatory T lymphocytes delays rejection of islets transplanted to muscle
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2015 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 24, no 2, 263-276 p.Article in journal (Refereed) Published
Abstract [en]

The only clinically available curative treatment of type 1 diabetes mellitus is replacement of the pancreatic islets by allogeneic transplantation, which requires immunosuppressive therapies. Regimens used today are associated with serious adverse effects and impaired islet engraftment and function. The aim of the current study was to induce local immune privilege by accumulating immune-suppressive regulatory T lymphocytes (Tregs) at the site of intramuscular islet transplantation to reduce the need of immunosuppressive therapy during engraftment. Islets were co-transplanted with a plasmid encoding the chemokine CCL22 into muscle of MHC-mismatched mice, after which pCCL22 expression and leukocyte recruitment were studied in parallel with graft functionality. Myocyte pCCL22 expression and secretion resulted in local accumulation of Tregs. When islets were co-transplanted with pCCL22, significantly fewer effector T lymphocytes wereobserved in close proximity to the islets, leading to delayed graft rejection.As a result, diabeticrecipients co-transplanted with islets and pCCL22 intramuscularly became normoglycemic for ten consecutive days, while grafts co-transplanted with control plasmid muscle were rejected immediately leaving recipients severely hyperglycemic. Here, we propose a simple method to initially shield MHC-mismatched islets by the recruitment of endogenous Tregs during engraftment in order to improve early islet survival. Using this approach, the very high doses of systemic immunosuppression used initially following transplantation can thereby be avoided.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-239507 (URN)10.3727/096368914X678535 (DOI)000351251400011 ()24480306 (PubMedID)
Available from: 2014-12-29 Created: 2014-12-29 Last updated: 2016-08-26Bibliographically approved

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