REGULATORY T AND B CELL CIRCUITS IN TRANSPLANTATION

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Base on several observations we have made in canines and humans we intend to clarify how human B and T cell networks can act by autoregulatory reactions to produce a prolonged immunosuppressed state after being perturbed by therapy with murine anti-CD3 (OKT3) monoclonal antibody (Ab) or with MAbs against other T Cell epitopes or lymphokines. We plan to amplify and isolate this self-perpetuating auto-immunosuppressive reactivity against the same (self) markers on T cells which were the ligands(s) of the murine MAb. We have also accumulated evidence that common epitopes exist on T cells, a common feature of both immune reactivity to organ transplants and that auto-reactivity against T cells, a common feature of both CMV infections and viral induced lymphoproliferative disorders in transplant recipients, is a function this crossreactivity or antigenic mimicry, many times involving network reactions perturbed by monoclonal anti-network influences on the human allograft response just described. Therefore, experiments will continue in the canine model of in vitro T cell lymphoproliferative reactions to purified suspensions of kidney tubular cells and cells from Islets of Langerhans, the latter complementing our clinical trial recently reinstituted of islet transplantation in type I diabetes. Recombinant DNA and immunochemical techniques will utilized to define the nominal antigens of these reactions (the peptides unique to tissues inducing the cellular responses to kidney tubular and islet cells that are inserted in the cleft of the class II MHC molecules). Recombinant techniques will also be used to generate the upregulating cytokine of class II MHC expression, canine interferon-gamma (IFN-gamma). Anti-canine cytokine MAbs will continue to be engendered in order to test them in these ex vivo essays. Therapy with these MAbs will continue to be engendered in our islet and renal transplantation model to include the use of a newly generated anti-canine IFN-gamma MAb and the plan to generate anti-canine tumor necrosis factor-alpha MAb to be delivered locally (intraportally in the case of islets or directly via the artery into the renal allograft in renal transplantation) vs systemically, in an effort to extend such therapy to clinical islet and renal transplantation. This latter study will include the question whether anti-cytokine MAbs genera network responses that cause activation or inactivation of the cytokine effects by triggering or blocking the cell surface receptor by anti-idiotype Abs, the putative internal images of the original cytokine ligand. The overall experimental plan will entail: a) studies of B and T cell mechanisms in vitro and in vitro:b) recombinant DNA/RNA technique to determine the commonality of immunoglobulin gene expression, as well as to define common code material for the peptide ligands, their transfer into ordinarily non-expression procaryotic and eucaryotic host cell lines and their participation in specific molecular rand cellular immune hinging and functional assays.