Pathobiology of SAIDS-Associated Lymphomas

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DESCRIPTION (provided by applicant): Non-Hodgkin's lymphoma (NHL) is the second most frequent cancer associated with AIDS. Simian AIDS (SAIDS) in the rhesus macaque offers a useful and informative animal model for this disease. SAIDS-associated lymphoma occurs in the macaque with an incidence and other features comparable to human AIDS-NHL. A major obstacle to the effective use of the SAIDS-lymphoma model for in vivo studies is the low incidence (approximately 4%). During the previous funding period, an initial statistical model was developed that identified a set of clinical and laboratory factors with the potential to predict lymphoma in SIV-infected animals. Those factors include absolute and relative B- and T-cell counts, their rates of change, evidence and persistence of marked peripheral lymph node enlargement, SIV antigenemia and its rate of change. Other variables may also be linked, including age at inoculation or co-infections with other viruses including rhesus lymphocryptovirus (RhLCV) or rhesus rhadinovirus (RRV). Proposed in Aim 1 is a rigorous and systematic test of the utility of those predictors. Animals at high risk for lymphoma will be identified based on adherence to the risk criteria. Those animals and matched controls will be monitored for clinical, immunologic and virologic parameters as well as for disease outcome. The identification of predictive factors is exciting because it indicates the potential to forecast which SIV-infected animals are likely to develop lymphoma, and may be translatable to AIDS-NHL. A long-term objective of the work is to use the animal model for development of novel therapeutic approaches, especially those based on physiologic mechanisms that regulate the growth of lymphoma cells. Preliminary studies focused on specific cytokine interactions indicated that (i) tumor cells remain sensitive to TGF-131- mediated growth inhibition, (ii) IL-6 treatment stimulates growth of lymphoma cells, and (iii) IL-6 treatment rescues lymphoma cells from TGF-131-mediated inhibition. Proposed in Aim 2 are studies to detail the mechanisms by which TGF-131and IL-6 exert independent and interacting influences on lymphoma-derived cell lines. A clear understanding of the mechanisms by which these cytokines effect positive and negative growth regulation of 1) lymphoma cells could contribute to the development of therapeutic agents that modulate their action.