Objectives:

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Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), in which activated T cells, B cells and macrophages invade CNS tissues and cause neuronal damage and permanent neurological disability. However, the role of the immune system and the contribution of autoimmune T and B cells to the initiation and progression of disease are still unclear. While existing experimental models for MS provide compelling evidence for type I autoimmune responses involving Th1 and Th17 CD4 T cells in the pathogenesis of disease, they fail to reproduce other important MS hallmarks, such as B cell and CD8 T cell involvement, and oxidative injury that underlies neurodegeneration and possibly mediates the transition of MS from relapse-remitting to progressive forms. They also often fail to predict the efficacy and safety of novel therapeutics in humans. For this reason, there is an urgent need for better disease models that would allow direct functional assessment of patient immune cells in vivo. Such humanized models could serve as an invaluable intermediate step in the process of drug development that could increase safety while reducing overall costs of clinical trials.

 

In AKESO project, we will use immunodeficient mouse strains that have been developed recently specifically for the introduction of xenografts without triggering of mouse immune responses (B2m-NOG mice). These leukopenic mice will serve as a transplantation platform for immune system reconstitution by human cells through the engraftment of human peripheral blood monocytes (PBMC) which contain human T and B lymphocytes, myeloid-derived antigen-presenting cells, and a small percentage of CD34+ hematopoietic stem cells isolated from peripheral blood. PBMC will be isolated from healthy individuals and MS patients with active disease who are positive for the MS susceptibility gene DRB1*1501. Mice will be monitored longitudinally for spontaneous development of clinical or pathological signs related to MS and for altered susceptibility to experimental autoimmune encephalomyelitis (EAE), a well-established inducible model for MS. Focus will be given to human B cell and CD8 T cell involvement in disease, as well as oxidative injury, features of MS not represented in the existing models. Proof-of-principle that DR2.MS mice are a significantly improved model for MS over existing models will be sought using pharmacological tools, including Ocrelizumab, which depletes mature B cells and ELMog (experimental drug) which induces myelin peptide-specific tolerance and represents a promising new-generation therapeutic for MS that selectively targets the cells that are implicated in disease induction, myelin-specific autoreactive T cells.