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Unraveling the immune etiology of multiple sclerosis - UnmetMS

English title Unraveling the immune etiology of multiple sclerosis - UnmetMS
Applicant Engelhardt Britta
Number 154483
Funding scheme Sinergia
Research institution Theodor Kocher Institut Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.10.2014 - 28.02.2018
Approved amount 1'200'000.00
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Keywords (6)

human effector T cells; human effector B cells; blood-brain barrier; multiple sclerosis; blood-cerebrospinal fluid barrier; human immunology

Lay Summary (German)

Lead
Der Titel des Sinergia Projekts UnmetMS steht für “Unravelling the immune etiology of multiple sclerosis“.
Lay summary

 In der Schweiz leiden zur Zeit mehr als 10’000 Menschen an Multipler Sklerose (MS). Bei der MS wandern Immunzellen in das zentrale Nervensystem (ZNS) und zerstören dort die Markscheiden der Nervenfasern. Die Ursachen der MS sind nur teilweise bekannt. Heutige Medikamente verhindern Schübe oder zögern die Entwicklung von Behinderungen hinaus, in dem sie das Immunsystem der Patienten hemmen, und helfen nur einem Teil der MS Patienten. 

Unser derzeitiges Verständnis der Entstehung der MS beruht zu einem grossen Teil auf Tiermodellen, welche allerdings das heterogene Erscheinungsbild der MS nicht vollständig abbilden.

Im geplanten Sinergia Forschungsprojekt Sinergia UnmetMS möchten wir daher eine detaillierte Analyse der Eigenschaften von ganz bestimmten Immunzellpopulationen, den T Zellen und den B Zellen, welche direkt aus dem ZNS von MS Patienten gewonnen und dann im Laobr vermehrt wurden, durchführen. Die T und B Zellen stehen unter dem Verdacht, die Schädigung im ZNS von MS Patienten zu verursachen. Das Labor von Roland Martin/Mireia Sospedra Ramos in Zürich ist in der einzigartigen Lage, solche Immunzellen aus dem ZNS von Patienten zu isolieren und zu klären, welche Strukturen sie angreifen. Mit Hilfe des Labors von Federica Sallusto und Antonio Lanzavecchia in Bellinzona kann geklärt warden, welche Antikörper die B Zellen im ZNS der MS Patienten produzieren und wie sich T- und B Zellen gesunder Personen von denen, die man bei MS im ZNS findet unterscheiden. Mit Hilfe des Labors von Britta Engelhardt in Bern wird untersucht, wie diese T und B Zellen über die Blut-Hirn Schranke in das ZNS vordringen können.

Mit Sinergia UnmetMS werden wir dazu beitragen ein tieferes Verständnis zur Entstehung der MS zu gewinnen. Sinergia UnmetMS hat daher das Potenzial, völlig neue therapeutische Zielstrukturen zu definieren und diese in vorklinischen und klinischen Untersuchungen zu validieren.

 

 

Direct link to Lay Summary Last update: 11.09.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Central role of Th2/Tc2 lymphocytes in pattern II multiple sclerosis lesions.
Planas R Metz I Ortiz Y Vilarrasa N Jelčić I Salinas-Riester G Heesen C Brück W Martin R So, Central role of Th2/Tc2 lymphocytes in pattern II multiple sclerosis lesions., in Ann Clin Transl Neurol. , 875.

Collaboration

Group / person Country
Types of collaboration
James McGrath United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Universität Heidelberg/Mannheim Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Université de Lens France (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Awards

Title Year
ECTRIMs Fellowship for Dr. Hideaki Nishihara 2018

Associated projects

Number Title Start Funding scheme
149420 Identification of trafficking molecules involved in the migration of CD8 T cells across the blood-brain barrier during immunosurveillance and neuroinflammation 01.10.2013 Project funding (Div. I-III)
146945 Suche nach Kandidaten-Autoantigenen und viralen/bakteriellen Triggern der Multiplen Sklerose 01.04.2013 Project funding (Div. I-III)
170213 Studies on T cell activation, differentiation and plasticity in humans 01.10.2016 Project funding (Div. I-III)
170131 Anatomical routes and molecular mechanisms of T cell migration across the brain barriers 01.10.2016 Project funding (Div. I-III)

Abstract

Multiple sclerosis (MS) is the most common inflammatory disorder of the central nervous system (CNS) in young adults and if untreated leads to irreversible and severe disability. Although distinct subtypes of the disease exist with regard to clinical and imaging presentation as well as neuropathological appearance, there is general agreement that an autoimmune inflammatory process is the driving force behind tissue injury in MS. A large body of mechanistic insight into the autoimmune pathogenesis of MS has been derived from the CD4+ T cell-mediated animal model, experimental autoimmune encephalomyelitis (EAE). However, EAE dos not mimic the full picture of MS neuropathology as a number of anti-inflammatory treatments that were highly effective in EAE, have failed in MS trials. In addition, although immunomodulatory treatments are effective in the treatment of early stages of MS, they are no longer once patients have entered the progressive phase of disease development. These observations suggest that the autoimmune pathogenesis underlying MS is much more complex as previously thought and cannot be modeled in its entire complexity in available animal models. There is therefore an unmet need for a detailed phenotypic and functional analysis of disease-relevant adaptive immune cells and tissues directly derived from MS patients to unravel the immune etiology of MS in its entire complexity. The Sinergia UnmetMS brings together the 3 Swiss laboratories of Roland Martin/Mireia Sospedra Ramos (Zürich), Britta Engelhardt (Bern) and Federica Sallusto/Antonio Lanzavecchia (Bellinzona), which combine their unique expertises in clinical MS research, human T and B cell immunology, neuroimmunology, vascular biology and CNS immune cell invasion for the first time with the aim to develop a better understanding for the temporo-spatial contribution of specific subsets of adaptive immune cells in MS pathogenesis as a pre-requisite to further unravel the immune etiology of MS. To achieve this overall goal Sinergia UnmetMS will make use of unique samples of T and B cells isolated from brains, cerebrospinal fluid (CSF) and peripheral blood of patients with different subtypes of MS to perform a concerted in-depth analysis of the phenotype, gene expression profile, antigen specificity and functional characteristics of these patient-derived and thus disease-relevant T and B cell subsets. The ability of these T and B cell subsets to enter specific CNS compartments will be studied using novel models of the human blood-cerebrospinal fluid barrier (BCSFB) and blood-brain barrier (BBB) and to be established patient-derived in vitro BBB models by nuclear reprogramming of fibroblasts. Further, the role of citrullination of CNS proteins as adaptive immune targets will be examined in detail for the first time.Sinergia UnmetMS has a strong commitment to provide novel insights into the cellular and molecular mechanism of the immune etiology underlying the diverse subtypes of MS. Results obtained in the proposed collaborative effort will improve our knowledge on the complex etiology of MS and set the stage to explore novel therapeutic targets for developing treatments for those MS patients who have not benefited to date. Sinergia UnmetMS will therefore aim at providing major advances towards understanding the immune etiology of MS and potential novel strategies for improving this disabling disease. The overall research goal of Sinergia UnmetMS can only be achieved in the proposed combination of expertises and experimental setups available within the 3 partner laboratories and progress will be achieved in a step-by-step process, in which results obtained within one laboratory will directly influence experimentation in the others. Last-but not least with a female applicatn involved in each partner's laboratory the Sinergia UnmetMS will provide an environment for junior scientists that beyond the added value of network research provides female role models which will specifically help the advancement of women in science in Switzerland
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