(Applicant's Description) The overall goal of this program project grant is to understand the mechanisms of the major BMT toxicities, in particular graft versus host disease (GVHD), in order to develop novel approaches to their prevention while enhancing the therapeutic aspects of this treatment modality. In order to achieve our goal we have assembled experts in the areas of cellular, biochemical and molecular immunology and cutaneous biology from the research community at Harvard Medical School. The research focus of this grant renewal has been enhanced by increasing its emphasis on a traditional strength of the program in BMT models. Preliminary data in these models demonstrate that the severity and tempo of acute GVHD is determined by the intensity of the BMT condition regimen that regulates the magnitude of the immune response by donor T-cells to host tissues by cytokines. This strategy to separate the toxicities of GVHD from GVL through the control of the cytokine cascade emerges as a central theme of this proposal. There are four projects proposed in this program renewal together with two core sections (administrative (A) and mouse BMT (B)). The four projects are: 1)The roles of BMT conditioning and cytokines in GVHD and GVL. 2)The effects of GVHD on thymocyte development. 3)Tumor vaccines and BMT. 4)T-cell homing and GVHD.
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