Autoimmune diseases are attributed to activation of self-reactive T cells specific for a restricted epitope on a self antigen. To date, treatments of autoimmune diseases have focused predominantly on nonspecific immunosuppressive approaches rather than on the specific autoreactive T cell populations. In these diseases, it would be useful to be able to induce tolerance in T cells of a known antigen specificity, thereby reducing the risk to the patient that generalized immunosuppression presents. There exists a set of nonclassical antigens called superantigens that, upon encounter in the peripheral immune system, are capable of inducing long term tolerance in T cells expressing the appropriate T cell receptors. Experiments have been initiated to construct a peptide/superantigen hybrid capable of inducing tolerance in specific sets of T cells, thus ultimately allowing tolerization of the self-reactive T cells involved in autoimmune diseases. Interest in the ability to turn off autoreactive T cells with recombinant molecules for treatment of autoimmune disease is exemplified by the number of current and pending IND's in this area. There is a great need for the development of reliable preclinical models to test the safety and efficacy of tolerogenic molecules. Investigational protocols testing tolerance-inducing recombinant products often raise safety concerns because it is difficult to predict whether the products will promote tolerance (desirable) or immunity (undesirable). Generation of this hybrid superantigen to induce tolerance in antigen-specific T cells is designed to develop the tools necessary for reliable inactivation of immune responses to certain antigens in a novel experimental system. This system will allow the generation of preclinical mouse models with which to test tolerance-inducing therapeutic interventions, thus expediting product development. This project directly relates to active IND's addressing antigen-specific tolerance induction that are currently regulated by the DHP.
