Allogeneic bone marrow transplantation (BMT) is a highly successful treatment modality for most hematologic malignancies, bone marrow failure syndromes, and a number of inherited disorders of the immune system and metabolism. The major obstacle to more widespread allogeneic BMT is the frequent occurrence of graft vs host disease (GVHD) and its attendant complications. The overall goal of this Program Project is to demonstrate that inhibition of T cell costimulatory pathways results in the induction of host alloantigen-specific tolerance, and therefore, reduces the incidence and severity of GVHD without significantly disrupting normal T cell immunity to viruses and potentially to tumor cells. We and others have compelling preliminary evidence in in vitro murine and humans systems and in vivo murine models that inhibition of the B7:CD28/CTLA-4 costimulatory pathway results in the induction of antigen specific tolerance. We propose to undertake three projects which form a tightly interactive and synergistic effort which will hopefully bridge the gap between the laboratory and clinical investigation. Project 1 will examine murine models of allogeneic bone marrow transplantation to evaluate the potential importance of blocking T cell costimulatory pathways on the incidence and severity of GVHD using established murine bone marrow transplant models and, in addition, mice which are deficient in genes encoding costimulatory molecules. Project 2 plans to determine which, known and yet to be identified, cell surface molecules expressed on antigen presenting cells are capable of providing costimulatory signals and, more importantly, which are capable of preventing the generation of alloantigen specific tolerance. Finally, Project 3 plans to use both the reagents and systems generated in Projects 1 and 2 to develop in vitro systems to induce host alloantigen-specific tolerance and then undertake clinical studies of in vitro and/or in vivo blockade of T cell costimulation with the objective of reducing the incidence and severity of GVHD. The strength of this Program Project resides in: 1) the use of established in vitro and in vivo model systems to evaluate tolerance and GVHD; 2) the availability of unique reagents to inhibit costimulation and our ability to generate new reagents as necessary; and 3) our ability to rapidly and successfully translate basic research to the clinic. Since these approaches may lead to specific tolerance, they may eliminate or sharply curtail the need for non-specific immunosuppression to prevent or treat GVHD. Moreover, these studies may extend our ability to safely undertake allogeneic BMT in histoincompatible individuals including matched unrelated, haplomismatched, and in some situations even fully mismatched donors.
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