This program project grant application seeks support for clinical and laboratory studies concerning the major obstacles to successful allogeneic bone marrow transplantation for hematologic malignancies. These include recurrent malignancy, interstitial pneumonia associated with human cytomegalovirus (HCMV) and graft-versus-host disease. In a clinical project new therapeutic regimens are being investigated to decrease the incidence of recurrent leukemia and lymphoma. In addition, studies are being conducted to further decrease the incidence of graft-vs-host disease and to prevent interstitial pneumonitis utilizing pharmacologic prophylaxis. These clinical studies are interrelated with four experimental projects that will extend our understanding of the problems associated with therapeutic bone marrow allografting. Studies will be conducted concerning the transfer of augmented immunity from donor to recipient utilizing cloned immunologically active proteins of HCMV. Further characterization of HCMV infection after BMT will be accomplished utilizing molecular biological methods for detection of HCMV in clinical specimens including broncho-alveolar lavage. Antisense technology utilizing oligonucleotide probes will be studied as a tool for analysis of HCMV infection and as a potential therapy for this disorder. Immunologic studies will also be performed to determine the role of HCMV in causing host cell abnormalities that lead to immunopathologic reactions by the graft. Finally, molecular studies will address two genetic aspects of marrow transplantation, namely the incidence and degree of mixed hematopoietic chimerism utilizing available and newly developed DNA probes to polymorphic loci and to utilize newly developed DNA probes for class II antigens to determine the degree of molecular HLA identify between bone marrow donor and recipient.
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