This Program Project application seeks support for clinical and laboratory studies concerning the major obstacles to successful allogeneic bone marrow transplantation for patients with leukemia. These problems include recurrent malignancy, viral infections and graft versus-host disease. The program consists of one clinical and five experimental projects. These six interrelated projects in the application are supported by two cores, one providing statistical expertise and one for administration and coordination of research. The clinical project deals with novel approaches to eradicate leukemia and to prospectively evaluate drug or drug combinations intended to prevent serious transplant related complications such as graft versus host disease (acute and chronic) and human cytomegalovirus associated interstitial pneumonia. These clinical studies are interrelated with the five experimental projects that will extend our understanding of the problems associated with therapeutic bone marrow allografting. The laboratory projects address biologically important transplant related problems and topics. Studies will be performed the define the antigen specific immune response to HCMV and identify immunodominant antigens. It is also our goal to develop a subunit vaccine that would allow the efficient transfer of HCMV specific T cell immunity from donor to recipient in order to alter the natural history of HCMV infection after BMT. Further characterization of HCMV infection after BMT will be accomplished utilizing molecular biologic methods to characterize the structural components of HCMV matrix proteins and to define their virologic and biologic function. Studies will also be performed to define the role of cytokines in the tissue injury of the lungs of mice and humans with CMV infection. Molecular studies will address genetic aspects of bone marrow transplantation including the cloning and characterization of a DQ-beta gene associated with the development of graft versus host disease. Finally, based on new findings that document the detection of herpes simplex virus in hematopoietic cells of mice and humans, molecular biologic studies will be performed to investigate the nature of this infection and to determine the biological significance of infection of these cell types.
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