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Curing Multiple Sclerosis: How to do it and how to prove it
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.ORCID iD: 0000-0002-7045-1806
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for multiple sclerosis (MS) with now more than 600 documented cases in the medical literature. Long-term remission can be achieved with this therapy, but when is it justified to claim that a patient is cured from MS? In attempt to answer this question, the outcome of the Swedish patients is described, mechanisms behind the therapeutic effect are discussed and new tools for demonstration of absence of disease have been developed.

In Swedish patients treated with HSCT for aggressive MS, disease free survival was 68 % at five years, and no patient progressed after three years of stable disease. Presence of gadolinium enhancing lesions prior to HSCT was associated with a favorable outcome (disease free survival 79 % vs 46 %, p=0.028). There was no mortality and no patient required intensive care.

The immune system of twelve of these patients was investigated further. In most respects HSCT-treated patients were similar to healthy controls, demonstrating normalization. In the presence of a potential antigen, leukocytes from HSCT-treated patients ceased producing pro-inflammatory IL-17 and increased production of the inhibitory cytokine TGF-β1 suggesting restoration of tolerance.

Cytokine levels and biomarkers of tissue damage were investigated in cerebrospinal fluid from a cohort of MS patients. The levels were related to clinical and imaging findings. A cytokine signature of patients with relapsing-remitting MS could be identified, characterized by increased levels of CCL22, CXCL10, sCD40L, CXCL1 and CCL5 as well as down-regulation of CCL2. Further, we could demonstrate that active inflammation in relapsing-remitting MS is a tissue damaging process, with increased levels of myelin basic protein and neurofilament light. Importantly, relapsing-remitting MS patients in remission displayed no tissue damage. In secondary progressive MS, moderate tissue damage was present without signs of active inflammation.

From a clinical vantage point, it seems that we confidently can claim cure of relapsing-remitting MS patients after five years absence of disease activity. The new tools for evaluation of disease can strengthen this assertion and may enable earlier prediction of outcome.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. , 74 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1005
Keyword [en]
biomarkers, cerebrospinal fluid, cytokines, hematopoietic stem cell transplantation, immunology, magnetic resonance imaging, multiple sclerosis, neuroimmunology, neurology
National Category
Neurology Immunology in the medical area
Research subject
Neurology
Identifiers
URN: urn:nbn:se:uu:diva-221888ISBN: 978-91-554-8964-9 (print)OAI: oai:DiVA.org:uu-221888DiVA: diva2:714003
Public defence
2014-06-13, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-05-23 Created: 2014-04-07 Last updated: 2014-06-30
List of papers
1. Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience
Open this publication in new window or tab >>Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience
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2014 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 85, no 10, 1116-1121 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS.

METHODS: Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months.

RESULTS: At 5 years, relapse-free survival was 87%; MRI event-free survival 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%).

CONCLUSIONS: HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-223632 (URN)10.1136/jnnp-2013-307207 (DOI)000344456000228 ()24554104 (PubMedID)
Available from: 2014-04-23 Created: 2014-04-23 Last updated: 2017-12-05Bibliographically approved
2. T-cell responses after haematopoietic stem cell transplantation for aggressive relapsing-remitting multiple sclerosis
Open this publication in new window or tab >>T-cell responses after haematopoietic stem cell transplantation for aggressive relapsing-remitting multiple sclerosis
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2013 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 140, no 2, 211-219 p.Article in journal (Refereed) Published
Abstract [en]

Autologous haematopoietic stem cell transplantation (HSCT) for relapsing-remitting multiple sclerosis is a potentially curative treatment, which can give rise to long-term disease remission. However, the mode of action is not yet fully understood. The aim of the study was to evaluate similarities and differences of the CD4(+) T-cell populations between HSCT-treated patients (n = 12) and healthy controls (n = 9). Phenotyping of memory T cells, regulatory T (Treg) cells and T helper type 1 (Th1) and type 17 (Th17) cells was performed. Further, T-cell reactivity to a tentative antigen, myelin oligodendrocyte glycoprotein, was investigated in these patient populations. Patients treated with natalizumab (n = 15) were included as a comparative group. White blood cells were analysed with flow cytometry and T-cell culture supernatants were analysed with magnetic bead panel immunoassays. HSCT-treated patients had similar levels of Treg cells and of Th1 and Th17 cells as healthy subjects, whereas natalizumab-treated patients had lower frequencies of Treg cells, and higher frequencies of Th1 and Th17 cells. Cells from HSCT-treated patients cultured with overlapping peptides from myelin oligodendrocyte glycoprotein produced more transforming growth factor-beta(1) than natalizumab-treated patients, which suggests a suppressive response. Conversely, T cells from natalizumab-treated patients cultured with those peptides produced more interleukin-17 (IL-17), IL-1 and IL-10, indicating a Th17 response. In conclusion, we demonstrate circumstantial evidence for the removal of autoreactive T-cell clones as well as development of tolerance after HSCT. These results parallel the long-term disease remission seen after HSCT.

Keyword
haematopoietic stem cell transplantation, multiple sclerosis, natalizumab, neuroimmunology
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-211463 (URN)10.1111/imm.12129 (DOI)000324303200007 ()
Available from: 2013-11-25 Created: 2013-11-25 Last updated: 2017-12-06Bibliographically approved
3. The cerebrospinal fluid cytokine signature of multiple sclerosis: a homogenous response that does not conform to the Th1/Th2/Th17 convention
Open this publication in new window or tab >>The cerebrospinal fluid cytokine signature of multiple sclerosis: a homogenous response that does not conform to the Th1/Th2/Th17 convention
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

In this cross-sectional study, we wanted to identify key cytokines characteristic of different stages of multiple sclerosis (MS) that could be used as an outcome measure in clinical trials. To this end, cerebrospinal fluid from a cohort of patients with relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) was investigated with a multiplexed fluorescent bead-based immunoassay. In total 43 cytokines were assessed and related to clinical and imaging data. Cerebrospinal fluid from a separate confirmatory cohort was used to validate cytokines pertinent to SPMS. Increased levels of CCL22, CXCL10 and sCD40L characterized RRMS patients with presence of gadolinium-enhancing lesions; decreased CCL2 and increased CXCL1 and CCL5 were typical of RRMS patients irrespectively of presence of gadolinium-enhancing lesions. IL-15 and IL-27 were increased in SPMS patients, but non-significantly in the confirmation cohort. These homogenous patterns of cytokine activation do not conform to conventional Th1/Th2/Th17 responses.

Keyword
cerebrospinal fluid, cytokines, magnetic resonance imaging, multiple sclerosis
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-223241 (URN)
Available from: 2014-04-16 Created: 2014-04-16 Last updated: 2014-06-30
4. Assessing tissue damage in multiple sclerosis: a biomarker approach
Open this publication in new window or tab >>Assessing tissue damage in multiple sclerosis: a biomarker approach
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2014 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 130, no 2, 81-89 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES:

Magnetic resonance imaging (MRI) of the brain and spinal cord is the gold standard for assessing disease activity in multiple sclerosis (MS). MRI is an excellent instrument for determination of accumulated damage to the brain and spinal cord, but tells us little about ongoing tissue damage. In this study, biomarkers of oligodendrocyte, axonal and astrocyte injury were related to MRI and clinical findings and used to assess tissue damage in MS.

MATERIALS AND METHODS:

Cerebrospinal fluid from 44 patients with relapsing-remitting MS, 20 with secondary progressive MS and 15 controls were investigated with ELISA to determine levels of myelin basic protein (MBP), neurofilament light (NFL) and glial fibrillary acidic protein (GFAp). Patients underwent MRI of the brain and spinal cord, and gadolinium enhancing lesions, T1 lesions and T2 lesions were counted.

RESULTS:

Patients in clinical relapse and patients with nonsymptomatic gadolinium enhancing lesions had high levels of MBP and NFL, indicating ongoing damage to oligodendrocytes and axons. The level of MBP dropped quickly within a week from the onset of a relapse, whereas NFL remained elevated for several weeks and GFAp slowly rose during the course of a relapse. Relapsing-remitting MS patients without gadolinium enhancing lesions had values of MBP, NFL and GFAp similar to controls, while patients with secondary progressive disease had moderately increased values of all biomarkers.

CONCLUSIONS:

Analysis of MBP, NFL and GFAp provides direct means to measure tissue damage and is a useful addition to our methods for evaluation of MS.

National Category
Neurosciences Neurology
Research subject
Clinical Immunology
Identifiers
urn:nbn:se:uu:diva-219571 (URN)10.1111/ane.12239 (DOI)000339951900006 ()24571714 (PubMedID)
Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2017-12-05Bibliographically approved

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