MOLECULAR MECHANISMS OF AUTOIMMUNE DISEASE IN MAN AND ANIMAL MODELS

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Based on our work on the mechanism of T lymphocyte or programmed cell death or apoptosis, we have studied autoimmune diseases in two areas: 1) pathogenesis and 2) treatment. We have determined the molecular pathogenesis of one form of autoimmunity by studying a group of children that had been followed by Drs. Stephen Straus and Warren Strober in the LCI, NIAID. These children exhibit an autoimmune/lymphoproliferative syndrome (ALPS) consisting of massive nonmalignant lymphadenopathy, autoimmune phenomena and expanded populations of CD3+, CD4-, CD8- lymphocytes together with antibody-mediated autoimmune disorders. We found that several ALPS children have deleterious mutations in the apoptosis-inducing molecule Fas that lead to defective Fas-mediated T lymphocyte apoptosis. Family studies showed that the mutations were inherited and thus defined the molecular basis of a genetic autoimmune disorder. One family reveals the co-occurrence of ALPS, Hodgkin's lymphoma, and a Fas mutation. We have also detected three families that have defective apoptosis with normal Fas indicating that ALPs may involves mutations in other genes in the apoptosis pathway. In attempting to use T cell apoptosis to treat autoimmune diseases, we are testing tolerance due to antigen-induced apoptosis as a new modality of immune therapy. A CRADA has been established to test whether T cell apoptosis can be predictably induced by antigen in various animal models of autoimmune disease and graft rejection. The ultimate purpose of these investigations is to advance apoptosis therapy for T cell-mediated diseases to a clinical trial. A primary goal of the CRADA at present is to establish whether the administration of myelin antigens as an antigen-specific therapy can alleviate multiple sclerosis (MS). In preparation for a clinical trial, we have accomplished several things: 1) building and testing recombinant versions of myelin protein antigens; 2) establishing a non-human primate model of experimental allergic encephalomyelitis (EAE). This model has proven to very faithfully reproduce the clinical phenotype as well as central nervous system pathology characteristic of MS. This large animal model also allows magnetic resonance imaging which is not possible for rodent EAE.; 3) refining means to test for the elimination of myelin-reactive T cells in peripheral blood. In addition to MS, we have begun work on transgenic mouse models for myasthenia gravis and autoimmune uveitis.