A growing body of experimental evidence indicates that the process of central nervous system (CNS) remyelination by cells of the oligodendrocyte lineage occurs concomitantly with ongoing autoimmune- mediated demyelinating disease. However, the attempt to remyelinate is incomplete. Recent studies have shown that specific growth factors developmentally regulate proliferation, differentiation, and regeneration of oligodendrocytes. We propose that delivery of remyelination growth factors in the autoimmune inflammatory milieu may stimulate the remyelination process and therapeutically modulate autoimmune-mediated demyelination. We have recently shown that autoreactive T cells can be stably transfected so that therapeutic transgene products, such as interleukin- 10 (IL-10), are secreted inducibly only upon activation of the T cell with self-antigen. We have also shown that IL-10 transfected T cell clones are effective in preventing and treating experimental autoimmune encephalomyelitis (EAE), an animal model widely used in multiple sclerosis (MS) research. Our preliminary data in the present proposal show that genetically modified autoreactive T cell clones can secrete transgene remyelination growth factors in a non-constitutive antigen- inducible manner. We hypothesize that the antigen-specificity and migratory properties of memory T cells provide a model endogenous vector system for site- specific delivery of therapeutic transgene remyelination growth factors to autoimmune inflammatory lesions. We propose to use genetically- modified autoreactive memory T cells to mediate CNS remyelination during the development of EAE.
Our specific aims i n the present study are: 1) to generate a series of transgene constructs designed to provide expression of various remyelination growth factors upon T cell engagement with self-antigen; 2) to isolate and characterize transfected autoreactive T cell clones expressing transgene remyelination growth factors; 3) to determine the biologic activity of transgene remyelination growth factors produced by transfected autoreactive T cells; and 4) to determine the ability of autoreactive T cells transfected with remyelination growth factors to regenerate CNS tissue during EAE. Our proposed experiments will directly determine appropriate choices of remyelination growth factors for use in vivo to the treatment of MS, and in broader sense will provide a rational basis for the development of a novel gene therapy approach for genetically modulation autoimmune disease in general.
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