REGULATORY T AND B CELL CIRCUITS IN TRANSPLANTATION

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We plan to utilize the canine transplantation model to investigate the role of nominal, organ specific (kidney and pancreas), and MHC antigens in allograft rejection and autoimmunity. The specific aims are to: 1) generate monoclonal antibodies (mAbs) specific for various dog lymphoid and non-bone marrow derived cells; 2) to study phenotypic and functional characterization of T cell lines and clones derived from rejecting renal and pancreatic allografts with regard to tissue and allospecific reactivity. 3) To study the process of induced expression of MHC molecules in situ and on isolated kidney (and pancreatic islet) cells by in vivo and in vitro manipulations; 4) a. to study the characteristics and effects of purified canine gamma interferon (IFN-gamma) in its ability to modulate MHC and other cell surface epitope expression in vitro and in vivo; b. to assess the in vitro and in vivo effects of mAbs generated against IFN-gamma. 5) To therapeutically use several selected mAbs to both facilitate graft acceptance and modulate autoimmunity, or evoke rejection and induce autoimmunity. The dog has been recently found to have preformed naturally occurring antibodies to mouse IgG, a finding similar to isolated observations in the humans. We eventually plan to apply immunoregulatory network type protocols designed to limit the humoral response in the dog to the mAb to be used therapeutically, i.e. to prevent the production of dog anti-mouse Ig antibodies, and modulate the presence of preformed antibodies so that the immunologic consequences of mAb treatment can be enhanced. The experiments detailed in this grant, however, are in vitro assessments of such immunoregulatory anti- immunoglobulins, such as their T cell and B cell surface target epitopes (preliminary data show that both cell types bind these anti-Ig molecules). Inhibition (mAb effect) and breakthrough (anti-mAb effect) experiments of in vitro lymphoproliferative reactions also are proposed. The biological and clinical relevance of this proposal is in expanding our understanding to the point of applying practical methods of therapeutic immunoregulation in organ transplantation and the treatment of autoimmune diseases leading to end-stage organ failure. The spin off in immunobiology may clarify our understanding of network feedback as well as the role of performed anti-immunoglobulin antibodies in immunoregulation.