The central thrust of this program is definition of genetic, cellular and humoral factors leading to immunologic autoreactivity. Six approaches to this objective are proposed. First, the molecular and cellular aspects of induced immunologic tolerance will be studied using antigen specific T-H clones the helper function of which can be turned off to induce tolerance. The stability of such tolerance, the metabolic characteristics of the cells involved and the possible role of T suppressor factors will be analyzed. Second, we will look for possible T cell structural or functional abnormalities, particularly associated with the antigen specific receptor, which might be casually related to murine SLE. The T cell receptor genes will be cloned and their products characterized and compared in SLE and appropriate normal mice. Structural and functional characteristics of the receptor molecules will be assessed using as probes antibodies raised against synthetic peptides derived from the sequence of T cell receptor polypeptides. Third, an analysis of rheumatoid factor (RF) by serologic and structural studies at the clonal level will be undertaken in an effort to define the role of this class of autoantibodies in health and disease. RF spontaneous, induced and hybridoma derived from experimental animals and man will be used to determine precise domain and epitopic specificities, to define their genetic elements (V-D-J) and to characterize extent of repertoire in order to permit correlation with manifestations of disease. Fourth, a molecular analysis of virus-lymphocyte interactions is proposed in order to understand the pathogenetic bases of virus induced disordered lymphocyte function and to apply these data to autoimmune or immunodeficiency diseases of man. Fifth, an analysis of the complex events leading to glomerular injury will be undertaken in an isolated perfused kidney experimental system. Three processes - the deposition, rearrangement and dissociation of immune complexes, the effects of intraglomerular exposure to a variety of phlogogenic mediators and the pathophysiologic consequences of mesangial cell injury - will be evaluated. Finally, the potential of immunologic autoreactivity in the form of hybrid antibodies as a therapeutic modality for the in vivo targeting of cytotoxic T cells on tumors or virus-infected cells will be explored. Heteroconjugates of two monoclonal antibodies, one reactive with the T cell receptor and one with the desired target cell will be used in attempts to eradicate tumors or to control viral infection by eliminating infected cells.
