This Program Project Grant Application seeks continued support for experimental and clinical studies aimed at enhancing our understanding of the basic cell biology underlying hematopoietic cell transplantation and improving outcomes for patients with leukemia, myelodysplastic syndromes, myeloproliferative disorders, Hodgkin's disease, non- Hodgkin's lymphoma and multiple myeloma. The major problems to be addressed include stem cell engraftment, immune reconstitution, graft-vs-tumor responses, graft-vs-host disease and infectious complications. Hematopoietic cell transplantation represents the clearest example of cellular therapy currently practiced in medicine. Enhancing our understanding of the cell populations involved will have significant implications for developing strategies for improving outcomes. The 11 clinical trials in the clinical Projects explore a number of important issues including the use of novel strategies to prepare the recipient with radiation-based regimens including total body irradiation, total lymphoid irradiation, targeted radioimmune therapy and chemotherapy; the use of purified hematopoietic stem cells for allogeneic transplantation and strategies to reduce the risk of relapse with monoclonal antibody, cellular or vaccination-based therapies. The experimental Projects address critical basic biologic and translational topics including improving donor leukocyte infusions with cytokine-induced killer cells, the mechanism of GVHD reduction following preparation of the recipient with total lymphoid irradiation- based regimens, the barriers to hematopoietic stem cell engraftment, the development of idiotype-based vaccination strategies, the reconstitution of the natural killer cell repertoire following transplantation, and the recovery of immunity to VZV and CMV following autologous and allogeneic transplantation. The nine integrated and synergistic Projects are supported by three Cores: One for administration and research coordination, one for biostatistics and data management, and one for cellular imaging and molecular pathology which utilizes state-of-the-art molecular biological and in vivo imaging technology. As a whole, this integrated effort focuses basic and physician-scientists on critical issues in cellular therapy and hematopoietic cell transplantation.
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