The ultimate goal of these studies is to establish an animal model for the treatment of all forms of Experimental Autoimmune Encephalomyelitis (EAE) that can serve as a paradigm for the treatment of human MS. EAE is an inflammatory, CD4+ T cell-mediated, autoimmune disease of the central nervous system characterized by perivascular demyelination typically presented as white matter plaques. EAE closely resembles the clinical histology and disease progression of human multiple sclerosis (MS). We have shown that expression of the myelin proteolipid protein (PLP) and myelin basic protein (MBP) encephalitogenic determinants in autologous B cells can effectively protect naive recipients from induction of disease. Furthermore, transfer of cells during the first remission period completely protected animals from developing relapses and completely protected PLP-specific TCR transgenic mice from developing EAE. This model could provide the foundation for a potential application of this therapeutic approach to human MS. This proposal will focus on the following issues: 1) defining the mechanism(s), the kinetics and the optimal dose of cells required for induction of T cell unresponsiveness by genetically modified B cells. 2) treatment of chronic, non-relapsing EAE. 3) expanding the model to other encephalitogenic determinants. The PLP-EAE model will be used to study the mechanisms and the kinetics of this treatment and to define the optimal cell numbers required for induction of long-lasting state of unresponsiveness. PLP-specific TCR transgenic, B cell-deficient, T cell-deficient and normal genetically susceptible mice will be employed. TCR transgenic animals offer the benefit of providing a source for large numbers of encephalitogenic T cells which can be easily traced upon adoptive transfer into a secondary host or in the transgenic animal itself following a treatment course. T and B cell-deficient mice provide a proper environment for studying dose-dependent cell interactions and the kinetics of the induction of T cell unresponsiveness. The efficacy of this treatment on the chronic form of EAE will be studied in PLP-specific TCR transgenic animals and in EAE induced by the adoptive transfer of MBP-specific T cells where high percentage of mice develop the chronic form of EAE. ? ?
