(from the application): This proposal addresses the objective of RFA AR-97-001: Design of therapies to prevent abnormal response to self by affecting antigen processing. The challenge in designing strategies for prevention of autoimmune disease is to manipulate the immune response such that the autoimmune response is curtailed specifically without interruption of the normal immune response or elicitation of compensatory mechanisms, which could bypass the therapeutic strategy and result in adverse side-effects. In most cases, this must be accomplished in the absence of clear knowledge of the antigen(s) responsible for the pathogenesis. The overall goal of this proposal is to develop a therapeutic strategy in which antigen presenting cells, which are modified such that they express Fas ligand, are used to eliminate autoreactive T cells specifically. The feasibility of using this strategy for the prevention and treatment of autoimmune disease will be tested in three animal models of human autoimmune disease - the gld mouse model of lymphoproliterative disease; the Lewis rat experimental allergic encephalitis (EAE) model of organ-specific autoimmune disease and multiple sclerosis (MS); and the NZB/NZW F1 mouse model of systemic autoimmune disease and human systemic lupus erythematosus (SLE). The central hypothesis is that antigens-specific T cell tolerance can be induced by APCs that express Fas ligand, and that autoreactive T cells can be specifically eliminated by syngeneic Fas ligand expressing APCs that present autoantigen to the T cells. This hypothesis is strongly supported by recent findings that indicate that APCs that express Fas ligand can induce allogeneic T-cell tolerance and that induction of this T-cell tolerance is mediated by depletion of antigens-specific T cells. A unique recombinant adenovirus system, which has been developed for the expression of high levels of Fas ligand in primary culture cells, will be used to manipulate Fas ligand expression in various APCs. The therapeutic effect of Fas ligand expressing APCs will be evaluated in three different systems using Fas ligand expression on syngeneic macrophages for the treatment of Fas ligand-deficient gld/gld mice; syngeneic glial cells that express Fas ligand and present MBP autoantigen for the treatment of EAE in Lewis rats; and Fas ligand syngeneic macrophages for the treatment of NZB/W mice. Treatment will be initiated prior to or after manifestation of autoimmunity and immunologic and clinical parameters of autoimmunity will be assessed over time. This novel approach combines gene therapy with cellular therapy to target autoreactive T cells. Accomplishment of this study will lay the basis for a therapeutic approach that may prevent, delay, or reverse the chronic, debilitating, and life-threatening symptoms of human autoimmune diseases, including MS and SLE.
