COSTIMULATORY MOLECULES IN TRANSPLANTATION TOLERANCE

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It is now recognized that T cells required 2 signals for induction of immune responses. Interruption of costimulatory signals by blocking CD28 or its two ligands B7-1 and B7-2 can induce transplantation tolerance and prevent or reverse autoimmunity in animal models. Similar data exists for blocking the CD40-ligand:CD40 interaction, a potential additional costimulatory pathway. The overall goal of this project is to understand the role of costimulation in graft rejection and determine the strategies and mechanisms by which blockade of costimulatory signals induces transplantation tolerance. Our studies of induction of transplant tolerance through blocking CD28 or CD40L have shown a complex series of relationships between their ligand, B7- 1, B7-2 and CD40 (all expressed on antigen-presenting cells), and the induction of rejection or tolerance. Specific aim #1 will focus on these questions, using selective blocking reagents and knockout animals in a murine cardiac allograft model to: examine the separate roles of B7-1 and B7-2, test the hypothesis (based on preliminary data) that B7-1 can, in select circumstances, promote tolerance interactions with CTLA4, and examine the cellular and molecular regulation B7-1 through CD40. Our data also show that delivery of additional donor antigen, in the form of splenocytes, at the time of transplantation, is required to synergize with costimulatory blockade to induce tolerance. In the absence of donor antigen, animals are transiently immunosuppressed but undergo chronic rejection. Specific aim #2 will identify the cell and MHC type which is required in the donor- transfusion to induce tolerance. We will then test the hypothesis that immunogenic allopeptides can substitute for intact cells to induce tolerance. Lastly, using the allopeptides, we will test the postulate that chronic rejection is linked to failure to tolerize to indirect allorecognition. Finally, based on data that costimulation through CD28 induces the cell survival gene bcl-x which is required for lymphocyte survival, in specific aim #3 we will use bcl-x transgenic mice to test the hypothesis that immunosuppression through CD28- blockade operates by induction of cell death and that bcl-x transgenic mice will be resistant to tolerance induction through this maneuver. These studies will have important implications for the development of implementation of therapies for transplantation and autoimmunity.