This program project grant application seeks support for experimental and clinical studies concerning the major obstacles to successful allogeneic and autologous bone marrow or peripheral blood progenitor cell transplantation (BMT) for the hematologic malignancies: leukemia, Hodgkin's disease, non-Hodgkin's lymphoma and multiple myeloma. The relevant problems after BMT include recurrence of the underlying disease, graft-versus-host disease (GVHD) and opportunistic infections with fungi, cytomegalovirus (CMV) and/or varicella zoster virus (VZV). The program consists of nine research projects and three supporting cores. The clinical projects deal with attempts to eradicate the underlying malignancies and to explore new drugs or drug combinations intended to prevent transplant-related complications such as acute or chronic GVHD, fungal infections and clinical VZV disease. Novel hematopoietic progenitor cell preparations (allogeneic and autologous) will be explored for their capacity to successfully restore hematopoiesis and lymphopoiesis in patients with hematologic malignancies. Dendritic cells will be employed to enhance the immunological anti-tumor effect of idiotype vaccination. The clinical projects will also serve as a resource for the experimental projects of the program. The experimental projects address the following biologically important transplant-related problems and topics: development of cytokine- induced killer cells for the prevention and therapy of post-transplant relapse; identification and enrichment of T-lymphocytes from murine marrow or peripheral blood with the intent to reduce GVHD and to preserve graft-versus-leukemia activity; definition of barriers to allogeneic hematopoietic stem cell grafting; prevention of experimental GVHD; protection of immunity to VZV after allogeneic and autologous BMT; conditions for latency and reactivation of CMV. The nine interrelated projects of this application are supported by three cores, one for administration and research coordination, one providing biostatistical and data management expertise, and one for molecular and cytogenetic evaluations of transplant patients before and after BMT.
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