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Autologous human induced pluripotent stem cells-derived central nervous system neurons, astrocytes and oligodendrocytes as T cells targets in multiple sclerosis

English title Autologous human induced pluripotent stem cells-derived neurons, astrocytes and oligodendrocytes as T cells targets in multiple sclerosis
Applicant Du Pasquier Renaud
Number 179531
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 01.07.2018 - 30.06.2022
Approved amount 904'000.00
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All Disciplines (3)

Discipline
Immunology, Immunopathology
Neurophysiology and Brain Research
Neurology, Psychiatry

Keywords (6)

astrocytes; induced-pluripotent stem cells; oligodendrocytes; T lymphocytes; neurons; multiple sclerosis

Lay Summary (French)

Lead
La sclérose en plaques est due à une perturbation de nombreuses composantes de la réponse immune, parmi lesquelles les lymphocytes T jouent un rôle prépondérant. On suspecte que ces derniers reconnaissent des auto-antigènes présents dans le cerveau, néanmoins, ceux-ci demeurent inconnus, possiblement car les conditions favorables à l’étude de cette auto-antigénicité n’ont jamais été réunies.
Lay summary
Contexte: 
Les lymphocytes T reconnaissent un antigène lorsque celui-ci est présenté par une molécule HLA, de classe I pour une reconnaissance par les lymphocytes T CD8+, de classe II pour les lymphocytes T CD4+. Cela signifie que pour déterminer la spécificité d’un lymphocyte T, il faut se placer dans des conditions autologues, c’est-à-dire que l’antigène en question doit être présenté par une cellule présentatrice d’antigène qui possède le même HLA que le lymphocyte T étudié. En d’autres termes, ces deux types de cellules doivent provenir du même sujet. Or, il est bien évidemment impossible d’obtenir des cellules du cerveau de patients SEP pour savoir si elles seraient reconnues par leurs lymphocytes T. Utiliser des cellules de cerveau de rat ou de souris n’est d’aucune utilité dans ce contexte. 

But de la recherche
Afin de contourner ces obstacles, nous avons donc établi, dans mon laboratoire, la technologie dite des cellules souches pluripotentes induites (CSPi), cellules que nous reprogrammons à partir d’une simple prise de sang. Nous pouvons ensuite différencier ces CSPi en cellules du cerveau, en particulier neurones et astrocytes. Pour l’instant la différenciation des CSPi en oligodendrocytes (cellules productrices de myéline, dont le rôle dans la SEP est crucial) n’est pas optimale. Ainsi, dans ce projet, nous souhaitons : 
-I. : optimaliser le protocole de production d’oligodendrocytes de haute qualité et en grande quantité.  
-II. : déterminer si les cellules T reconnaissent des antigènes présents sur les cellules nerveuses (neurones, astrocytes, oligodendrocytes) dérivées de CSPi. Enfin, une fois un/des antigène/s identifié/s, nous recourrons à l’immunopeptidomique pour déterminer la structure précise des épitopes ayant élicité une réponse lymphocytaire (collaboration avec Prof. Bassani-Sternberg). 

Portée de cette recherche
Bien qu’il s’agisse d’un projet relativement risqué, nous estimons que ces expériences utilisant des techniques innovantes représentent la meilleure chance de découvrir si les lymphocytes T de patients SEP reconnaissent des antigènes présents dans le cerveau. Une telle démonstration représenterait un pas majeur dans notre compréhension des mécanismes fondamentaux de la SEP et permettrait d’élaborer des traitements très spécifiques pour ces patients. 

Direct link to Lay Summary Last update: 19.07.2018

Responsible applicant and co-applicants

Employees

Project partner

Associated projects

Number Title Start Funding scheme
192777 Longitudinal analysis of the Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study : Step 2 01.04.2020 Project funding (special)
159997 What happens upstream and downstream from T cell activation in multiple sclerosis? 01.07.2015 Project funding

Abstract

It is commonly thought that Multiple sclerosis (MS) is triggered by environmental agents in genetically-susceptible persons. Among the environmental factors, Epstein-Barr virus (EBV) is strongly associated with MS, but if and how this virus would be instrumental in MS pathogenesis remains undemonstrated. All components of the innate and adaptive immune systems are involved in the immunopathogenesis of MS, but T cells play a predominant role in this orchestra. A large genome-wise association study (GWAS) has identified several susceptibility loci in MS patients, most of them implicating T cell differentiation and further confirmed that the HLA DRB1*1501 gene was the highest single genetic risk factor for the development of MS, pointing to the importance of CD4+ T cells in MS. But, there are also growing evidences implicating CD8+ T cells: the latter are predominant in MS lesions, there is enrichment in activated CD8+ T cells in the cerebrospinal fluid, and they exhibit an oligoclonal restriction, suggesting that they are directed towards a restricted number of antigens. T cells recognize a peptide antigen only when it is presented by a HLA molecule, class I for CD8+, and class II for CD4+ T cells. This means that to determine the specificity of a T cell, one must assess it in autologous conditions, i.e. a candidate antigen must be presented by the HLA of the given patient. Yet, in the case of MS, this has been more or less impossible. Indeed, MS brain tissue is out of reach and studies in the animal model of MS, the experimental autoimmune encephalomyelitis, is of not help to determine what would a central nervous system (CNS) antigen in MS patients. The difficulty to obtain CNS cells in human may account for the disappointing results in the quest of CNS antigens that would be targeted by T cells in MS. Thus, in order to determine what the CNS targets of activated T cells in the MS patients are, we have established the technology of human induced-pluripotent stem cells (hiPSC) in the laboratory. Human iPSC offer many advantages over other experimental approaches, such as animal models or immortalized cell lines, as they combine a high throughput, mechanistic insight and human relevance. Indeed, they keep the unique genetic signature of human samples; they are an unlimited cell resource; and they can be differentiated into virtually every cell type. From these hiPSC, we are now able to derive neurons and astrocytes with good purity, quantity and quality. However, the production of oligodendrocytes is not optimal yet and as part of this proposal we would like to improve the production of these cells that are highly relevant in MS as they are myelin-producing cells. Then, having established this human in vitro model of MS, we will be in a position to examine whether CD4+ and CD8+ T cells of MS patients do recognize antigens presented by autologous hiPSC-derived neurons, astrocytes and oligodendrocytes. Specifically, we would like:AIM I. To generate an in vitro model of human CNS cells derived from hiPSC in MS T reprogram hiPSC clones from new donors, to improve the protocol for oligodendrocyte differentiation AIM II: To examine T cell specificity in MS: from blood cells to CNS epitopes IIA. TCR-expressing hybridomas to identify new candidate auto-antigens in MS IIB. T cell libraries to examine reactivity to autologous CNS cells in MSIIC. Immunopeptidomic for epitope discovery in MS If, such as suspected for a long time, T cells recognize antigens in the CNS, then we believe that this highly original and innovative model offers the best chances to verify this hypothesis and, where applicable, to determine which these antigens are. Discovering which antigen(s) is/are recognized by T cells in MS may open promising perspectives of selective immunotherapy. These experiments will also allow to confirm or rule out the hypothesis of molecular mimicry in MS, i.e. the cross-recognition of EBV and CNS cells epitopes by identical T cells.
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