This Program Project will investigate the in vivo regulation of the immune response including peripheral T cell tolerance and immune memory, and strategies for the control of autoimmune diseases by induction of anti-TcR immunity. Project 1 """"""""Mechanisms of Peripheral Tolerance and Resistance to Toxic Shock"""""""" studies the in vivo response to bacterial superantigen in mice transgenic for a single TcR to elucidate clonal deletion and anergy with respect to: 1) susceptibility of T cell subsets, 2) antigen presenting requirements, and 3) lymphokines involved. The investigations will include experiments on a fatal bacterial superantigen-induced toxic shock syndrome. Project 2 """"""""Immunoregulation at the Maternal-fetal Interface"""""""" analyzes pregnancy in transgenic mice engineered to express class I MHC antigens on the trophoblast as a model to investigate tolerance and autoimmunity and their regulation in peripheral organs. Project 3 """"""""Immunomodulation in alphaB Transgenic Chimeric Mice"""""""" examines the immune response of mice transgenic for a single TcR before and after vaccination with T cells clones or oligopeptides matched to sequences found in various portions of the alpha- and B- chain of the transgenic receptor. The overall goal is to understand how active anti-TcR vaccination works. Project 4 """"""""Vaccination to TcR structures and autoimmune diseases"""""""" proposes a new strategy, antigenized antibodies (AgAbs), to induce active anti-TcR immunity in the prevention and/or treatment of two autoimmune diseases, experimental allergic encephalomyelitis and myasthenia gravis. The levels of specific humoral and cellular immunity will be correlated with the in vivo effects of anti-TcR vaccination by AgAbs. Project 5 """"""""Strategies for Inducing Helper T Cell Memory"""""""" studies regulation of immunologic memory, the rapid induction of a quantitatively effective immune response following reexposure to antigen. In vivo and in vitro models will be used to study the development, recirculation, and function of memory TH cells. The goal is to elucidate the requirements for the activation of memory versus naive TH cells, and to devise a methodology for inducing and manipulating T cell memory for the purpose of vaccination.
