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What happens upstream and downstream from T cell activation in multiple sclerosis?

English title What happens upstream and downstream from T cell activation in multiple sclerosis?
Applicant Du Pasquier Renaud
Number 159997
Funding scheme Project funding
Research institution Service de Neurologie Département des Neurosciences Cliniques CHUV
Institution of higher education University of Lausanne - LA
Main discipline Immunology, Immunopathology
Start/End 01.07.2015 - 30.06.2018
Approved amount 525'000.00
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All Disciplines (3)

Discipline
Immunology, Immunopathology
Neurology, Psychiatry
Neurophysiology and Brain Research

Keywords (6)

induced-pluripotent stem cells; multiple sclerosis; T lymphocytes; antigen-presenting cells; B lymphocytes; cytokines

Lay Summary (French)

Lead
La sclérose en plaques (SEP) est une maladie neurologique se traduisant par une démyélinisation et une perte axonale. C’est la deuxième cause d’invalidité neurologique chez les jeunes. Ces dernières années ont été marquées par de grands progrès thérapeutique, cependant une véritable cure de la SEP n’existe pas encore, ce qui témoigne de notre connaissance partielle de la complexité de cette maladie. Les lymphocytes T jouent un rôle important dans la constitution des plaques. Toutefois, on ne sait pas i) ce qui active ces lymphocytes T ii) ni quelles sont leur(s) cible(s) au niveau cérébral. Une des raisons principales expliquant ce manque de connaissance est que le cerveau est difficilement accessible. Il est donc crucial i) d’identifier les acteurs situés en amont de l’activation de ces lymphocytes T et ii) de mieux définir ce qui se passe en aval. Pour ce faire, nous voulons modéliser l’interaction entre les effecteurs (lymphocytes T) et les cibles (cellules cérébrales).
Lay summary

Contenu et objectifs du travail de recherche :

Dans des travaux préliminaires, nous avons pu montrer que les lymphocytes B jouent un rôle prédominant dans la présentation antigénique aux lymphocytes T. Ces données suggèrent que les lymphocytes B ne seraient pas cantonnés à des cellules productrices d’anticorps, mais joueraient aussi un rôle dans l’activation des lymphocytes B.

Parallèlement, nous sommes en train de développer au sein de notre laboratoire la capacité de produire des cellules cérébrales in vitro, dérivées de patients souffrant de SEP. En effet, nous avons appris la technologie des cellules souches pluripotentes induites, décrite récemment par Yanekawa. Cette technologie permet de reprogrammer des cellules somatiques (cellules mononuclées du sang ou fibroblastes) en cellules souches pluripotentes, puis à partir de celles-ci, les différencier dans des cellules à choix, en particulier des neurones, astrocytes ou encore oligodendrocytes. Cet outil permet donc d’ouvrir une fenêtre pour étudier non seulement ce qui se passe dans le sang des patients SEP (périphérie), mais aussi ce qui se passe dans le cerveau (organe cible).

Dans ce projet, nous allons donc

  1. Poursuivre l’étude du rôle des lymphocytes B en tant que cellules activatrices des lymphocytes T (amont)
  2. Caractériser les effets de différentes cytokines ou lymphocytes sur les cellules cérébrales dérivées de cellules souches induites (aval)

Contexte scientifique et social du projet de recherche :

Nous sommes convaincus que ces expériences innovantes, intégrant différents systèmes (immunologique et nerveux), permettront de décloisonner la recherche sur la SEP chez l’humain. Nous nous attendons à ce que ces expériences i) élucident certains mécanismes complexes de la SEP et ii) permettent, à terme, de tester des molécules neuro-protectrices sur ces cellules nerveuses dérivées de patients souffrant de SEP. 

Direct link to Lay Summary Last update: 16.04.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Impaired T-cell migration to the CNS under fingolimod and dimethyl fumarate
Mathias Amandine, PerriotSylvain, CanalesMathieu, BlattiClaudia, GaubicherColine, SchluepMyriam, EngelhardtBritta, Du PasquierRenaud (2017), Impaired T-cell migration to the CNS under fingolimod and dimethyl fumarate, in Neurol Neuroimmunol Neuroinflamm, 4(6), e401.
The Self-Inactivating KamiCas9 System for the Editing of CNS Disease Genes
Merienne Nicolas, Vachey Gabriel, de Longprez Lucie, Meunier Cécile, Zimmer Virginie, Perriard Guillaume, Canales Mathieu, Mathias Amandine, Herrgott Lucas, Beltraminelli Tim, Maulet Axelle, Dequesne Thomas, Pythoud Catherine, Rey Maria, Pellerin Luc, Brouillet Emmanuel, Perrier Anselme L., du Pasquier Renaud, Déglon Nicole (2017), The Self-Inactivating KamiCas9 System for the Editing of CNS Disease Genes, in Cell Reports, 20(12), 2980-2991.
Increased ex vivo antigen presentation profile of B cells in multiple sclerosis
Mathias Amandine, Perriard Guillaume, Canales Mathieu, Soneson Charlotte, Delorenzi Mauro, Schluep Myriam, Du Pasquier Renaud A (2017), Increased ex vivo antigen presentation profile of B cells in multiple sclerosis, in Multiple Sclerosis Journal, 23(6), 802-809.
EBI2 Expression and Function: Robust in Memory Lymphocytes and Increased by Natalizumab in Multiple Sclerosis
Clottu Aurélie S., Mathias Amandine, Sailer Andreas W., Schluep Myriam, Seebach Jörg D., Du Pasquier Renaud, Pot Caroline (2017), EBI2 Expression and Function: Robust in Memory Lymphocytes and Increased by Natalizumab in Multiple Sclerosis, in Cell Reports, 18(1), 213-224.
The VZV/IE63-specific T cell response prevents herpes zoster in fingolimod-treated patients
Mathias Amandine, PerriardGuillaume, CanalesMathieu, VuilleumierFanny, PerrottaGaetano, SchluepMyriam, Du PasquierRenaud (2016), The VZV/IE63-specific T cell response prevents herpes zoster in fingolimod-treated patients, in Neuro Neuroimmunol Neuroinflamm, 3(2), e209.

Collaboration

Group / person Country
Types of collaboration
Prof. Nicole Déglon Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
- Industry/business/other use-inspired collaboration
INSERM, UMR 1064 Nantes France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Theodor Kocher Institute Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Young investigator meeting in MS research Talk given at a conference Studying neuroinflammation in Multiple sclerosis using an iPSC-derived CNS model 16.06.2017 Bern, Switzerland Du Pasquier Renaud;
Swiss and French MS meeting Poster Distinct activation profiles of iPSC-derived astrocytes are triggered by different MS-linked inflammatory cytokines 09.06.2017 Paris, France Du Pasquier Renaud; Mathias Amandine;
ECTRIMS Poster Impact of fingolimod treatment on T cell migration to the CNS: a four-year observational study 16.09.2016 Londres, Great Britain and Northern Ireland Mathias Amandine; Du Pasquier Renaud;
4èmes ateliers de neuroimmunologie Talk given at a conference EBV et SEP 24.06.2016 Paris, France Du Pasquier Renaud;
Jeudis de l'Hôpital neurologique Pierre Wertheimer Individual talk Vers le développement d'un modèle humain in vitro de SEP 28.04.2016 Lyon, France Du Pasquier Renaud;
Immunité, biothérapies, sclérose en plaques Individual talk Sclérose en plaques, biothérapies et leucoencéphalopathie multifocale progressive 18.03.2016 Besançon, France Du Pasquier Renaud;
Young INvestigator meeting Talk given at a conference Impact of fingolimod treatment on T cell migration to the central nervous system 11.03.2016 Grindelwald, Switzerland Du Pasquier Renaud; Mathias Amandine;
ECTRIMS Poster Fingolimod favors the migration of T cells toward the CNS without interfering with their anti-viral properties 07.10.2015 Barcelone, Spain Du Pasquier Renaud; Mathias Amandine;


Self-organised

Title Date Place
2èmes Rencontres scientifiques franco-suisse (Nantes-Lausanne) 30.11.2017 Nantes, France
1ère Rencontres scientifiques franco-suisses (Nantes-Lausanne) 01.10.2015 Lausanne, Switzerland

Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Il y a une peur exagérée autour de la maladie de Lyme transmise par les tiques Le Matin Dimanche Western Switzerland 2017
Print (books, brochures, leaflets) Sclérose en plaques, traité de neurologie International 2017
Media relations: radio, television La myéline, le turbo du cerveau RTS 1 Western Switzerland 2016
Talks/events/exhibitions Soirée Société Suisse de la SEP, Environnement et SEP: quells liens? Western Switzerland 2016
Media relations: radio, television CQFD - du nouveau sur la sclérose en plaques RTS 1 Western Switzerland 2015

Associated projects

Number Title Start Funding scheme
179531 Autologous human induced pluripotent stem cells-derived central nervous system neurons, astrocytes and oligodendrocytes as T cells targets in multiple sclerosis 01.07.2018 Project funding
138411 Exploring the connections between the innate and adaptive immune responses at play in multiple sclerosis 01.01.2012 Project funding

Abstract

Multiple sclerosis (MS) is the most common cause of neurological disability in young adults following trauma. Several immunomodulatory drugs, possibly slowing MS progression, are now available. However, there is no cure for the disease. This situation most likely reflects the fact that one does not know precisely the cause(s) of MS. Important improvement has been obtained in the understanding of the function of individual actors of the immune response. For instance, it is well established that T cells are key features in MS pathogenesis. Yet, the mere characterization of a single cell type will not allow obtaining a comprehensive view of the complex immunopathogenesis of MS. Such integrative studies can of course be better realized in the experimental autoimmune encephalomyelitis animal model (EAE) of MS, but EAE certainly does not recapitulate all the aspects of MS. Yet, relatively little has been done, in human MS, to attempt at understanding the interaction between the different immune actors. Another major limitation when one try to understand the pathogenesis of this disease is the very limited access to the central nervous system (CNS), which is though where the disease takes place. Recently, to examine what stands upstream from T cell activation, we have studied in detail the phenotype and activation level of different antigen-presenting cells (B cells and monocytes). We found that, as compared to control subjects, the ex-vivo profile of B cells of MS patients was characterized by enhanced antigen presenting capacities and decreased basal secretion of major cytokines (IL-6, TNF-? and IL-1?). These data suggest that B cells of MS patients may significantly influence the phenotype and activation profile of T cells. In parallel, to eventually obtain a chance to look at what stands downstream from T cell activation, i.e. what happens in the CNS, we have developed the induced-pluripotent stem cells (iPSC) technology in our Lab, in collaboration with the Lab or Prof. Nicole Déglon. Such a tool opens a broad new field of investigations in human MS. Indeed, among other things, it will allow us to study the interaction of activated T cells with autologous CNS target cells or to test the effect of cytokines on CNS cells. For instance, we have gathered promising preliminary data suggesting that IL-22 may have protective function on astrocytes and look forward to assess this molecule on CNS cells derived from MS patients. Specifically, to explore what stands upstream and downstream from T cell activation, we will:AIM I. Assess the antigen-presenting role of B cells to T cells in MS: the upstream partAIM II. Study the effects of T cells and cytokines on autologous CNS cells: the downstream partWe believe that these innovative experiments, integrating different systems, will not only allow to decipher the immunopathogenesis of MS, but also have the potential to lead to the discovery of neuroprotective treatments.
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