The full potential of hematopoietic stem cell transplantation (HSCT) has not been realized because of transplant related complications. Prominent among these complications is acute graft-v-host disease (GVHD). While the graft may include important anti-tumor effects, the direct organ toxicity and delay of immunologic reconstitution results in substantial morbidity and mortality. The overall goal of this project is to acquire new insights into the pathophysiology of GVHD and to foster the development of new therapies to control GVHD while maintaining graft-v-leukemia (GVL). While it is accepted that the trafficking, adhesion, and migration of lymphocytes is critical for the development of GVHD and GVL, this area has received little attention in clinical transplantation. The project is intended to provide a platform for the testing of new prophylactic strategies to prevent GVHD, while providing a stringently defined cohort of patients with and without GVHD. This will allow accurate correlation of laboratory data on immune reconstitution, chimerism, lymphocyte adhesion/migration, and minor histocompatibility antigens (mHA) recognition with patient outcomes. Specifically, the project will study: 1) strategies to prevent acute GVHD in allogeneic HSCT from related and unrelated donors. Studies of the synergistic combination of sirolimus and tacrolimus in URD transplantation, and the evaluation of CD8 T cell depletion will provide the clinical platform for the project. 2) The role of chemokines in the initiation and maintenance of the GVH reaction. Chemokines are critical mediators of organ specific leukocyte migration and trafficking, but almost nothing is known about these important molecules in HSCT. Understanding their role may allow the development of specific chemokine inhibitors with clinical value. 3) Strategies to identify novel mHA pertinent to the development of GVHD. In histocompatible transplantation GVHD is directed against mHA, but few of these antigens have been identified. The development of a serologic method to identify mHA promises to allow more precise donor selection, prediction of GVHD risk, and potentially the identification of specific targets for GVL. It is anticipated that the synergistic relationship between the clinical project and the laboratory investigations will provide insights that can be evaluated for clinical testing and the development of new approaches to GVHD control.
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