T cells from multiple sclerosis patients have been shown to respond to a variety of CNS antigens, such as MBP, MOG and PLP. Modulation of these immune responses is a goal for therapeutic intervention in MS. The focus of our lab is to develop novel approaches for the induction of tolerance that can be applied to the prevention or reversal of undesirable immune responses, particularly in autoimmune diseases like MS. We have utilized immunoglobulin fusion proteins delivered via retroviral vectors for the induction of tolerance. This technology is based on the well-established tolerogenicity of immunoglobulin carriers, onto which we engineer multiple epitope-containing polypeptides in frame with this lgG scaffold. In this system, the transfected autologous donor cells presenting this fusion protein select the relevant epitopes for the respective MHC haplotypes. Our hypothesis is that the multiple epitopes so expressed via B-cell antigen presentation lead to immunologic tolerance via a FasL-dependent mechanism. Data in several experimental autoimmune models (uveitis, diabetes, EAE with MBP for multiple sclerosis) are promising in that significant clinical efficacy has been achieved. Since numerous antigens have been identified as potential targets in multiple sclerosis, it is important to extend our model system to these additional antigens in models of MS, and to understand the mechanisms of gene therapy for tolerance in order to achieve improved efficacy. Our goal is to induce tolerance to additional encephalitogenic antigens, such as MOG and PLP, in both unprimed and primed T cells. Moreover, we wish to apply this system in a model of relapsing MS, using PLP peptides. To establish the nature of the APC, we will track the transduced B-cell APC, using GFP constructs and PKH26 dye labeling, as well as modification of tolerance by CpG-containing oligonucleotides. Finally, we will use T cells from TCR transgenic mice to establish the mechanisms involved, including the migration and fate of specific cells, role of FasL and involvement of suppression in this gene therapeutic approach for tolerance.
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