This proposal is based on a new strategy to vaccinate against self- reactive T cells responsible for the appearance of autoimmune disease. The goal is to induce active anti-T cell receptor (TcR) immunity using antigenized antibodies (AgAbs), that is antibodies engineered to express in discrete loops of their molecule antigenic determinants of the TcR variable (V) region structural gene products. Reagents and methods will be developed to explore the possibility to prevent and/or reverse experimentally-induced autoimmune diseases by targeting two types of T cells: 1) autoimmune effector T cells; and 2) T cells that participate in the disease process by helping B cells in the production of pathogenetic autoantibodies. Specifically, we propose to construct AgAbs expressing TcR sequences of the Vbeta8.2 and Jalpha gene products found in the TcR of effector (disease-inducing) T cells in a rat model of experimental allergic encephalomyelitis, and TcR sequences of the Vbeta6 gene product of T cells involved in the production of pathogenetic autoantibodies to the acetylcholine receptor in a murine model of autoimmune myasthenia gravis. We will study the ability of vaccination by AgAbsTcR to induce specific humoral and cellular T cell responses, and the efficacy of this approach in protecting rats and mice from autoimmune disease induction. The levels of humoral and cellular immunity obtained will be correlated with the scores of clinical signs of disease and histopathological lesions. Finally, experiments will be done with AgAbsTcR encapsulated in biodegradable beads of hyaluronic acid ester, liposomes and lipophilic immune stimulating complexes (ISCOMS), as a practical way to induce T cell memory and cytotoxic T cells, respectively.
