Current data indicate that 20-30% of all marrow transplant recipients will experience poor marrow function or frank marrow failure. With the exception of graft rejection, the mechanisms responsible for these complications have not been defined. The purpose of this project is to test the hypothesis that cytomegalovirus (CMV) and graft-versus-host reactions (GVHR) cause poor marrow function or graft failure by compromising the marrow microenvironment. This hypothesis is supported by clinical analyses associating neutropenia with both CMV and GVHR, and in vitro data indicating both can inhibit stromal function in long-term marrow cultures. The extent to which CMV and GVHR influence marrow function in outpatient population, the mechanisms involved, and why only a proportion of patients with CMV and GVHR are so affected, remains unknown. To address these issues, a prospective study will be conducted in Aim 1 to determine the frequency at which CMV can be detected in patient marrow, its association with GVHR and with marrow function. Since preliminary data suggest that CMV pathogenicity may be associated with genetic differences in CMV envelope glycoproteins, the virus detected in patient marrow will also be genotyped.
In Aims 2 and 3, different in vitro models will be used to define how specific strains of CMV, acting alone or in the presence of GVHR, influence stromal function. One model will utilize primary long-term marrow cultures from CMV seropositive normal donors to identify sites of viral latency and mechanisms of viral activation. The second model will use recently developed stromal cell lines to de fine the consequences of CMV infection in specific cell types, before and after exposure to CMV specific HLA restricted T cell clones. The information provided by these studies should increase our understanding of hematopoiesis in general, and improve our ability to accurately diagnose and treat poor marrow function in transplant recipients and other immune compromised patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Fred Hutchinson Cancer Research Center
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