This proposal represents the first renewal application of our program project in transplantation immunology. The original focus of this program was on (a) antigen presentation and (b) cytokine regulation of immune cell function: two specific issues of paramount importance to transplant biologists. The current proposal continues this overall focus but now concentrates on the topic of cytokine immunobiology with particular emphasis on TNF and IL-1. Project 2 follows up an observation made by Robert Schreiber, Kathleen Sheehan and Paul Lacy that TNF and IL-1 can profoundly suppress T cell activation and graft rejection responses in normal mice. Schreiber and Sheehan now propose to study the cellular and molecular basis of this immunosuppressive process by examining the effects of these cytokines on antigen presenting cell function and T cell development in vivo and in vitro. Since IL-1 holds such a prominent position in this program project, the third project will characterize the physiologic mechanism by which IL-1beta is activated. Herein, David Chaplin will perform a detailed molecular analysis on a newly defined enzyme that appears to be uniquely required for proteolytically activating murine (and human) IL-1beta. Project 3 will directly apply the principles of cytokine biology which have been and continue to be obtained from our basic research studies to models of xenograft and allograft rejection. Drs. Paul Lacy and David Scharp will expand their studies on the use of TNF, IL-1 and the combination of TGFbeta and anti-IFNgamma to suppress the rejection of pancreatic islet grafts. This project is likely to provide direct benefits to transplantation biologists by better defining the basic mechanisms involved in the induction of immunologic tolerance and by helping to develop novel and safer immunosuppressive therapeutic agents. Thus, the overall benefit of this particular program project continues to be the efficient application of basic immunologic concepts to the field of transplantation biology.
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