Immunologic Studies of Endemic Burkitt's Lymphoma

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DESCRIPTION (provided by applicant): The long-term goal of this research is to advance knowledge of the mechanism by which malaria interacts with the host immune system and Epstein-Barr virus (EBV) to promote the development of endemic Burkitt?s lymphoma (eBL). An association between holoendemic malaria, EBV infection and eBL during childhood is well established in Africa. EBV -specific HLA class I-restricted CD8+ cytotoxic T lymphocyte responses limit proliferation of B cells infected with EBV. These and other findings suggest that malaria suppresses EBV- specific immunity and thereby promotes the emergence of eBL. The mechanisms by which malaria alters immunity to EBV and its role in the pathogenesis of eBL are poorly understood. This mentored-training award builds upon collaborations between Case Western Reserve University and the Kenya Medical Research Institute. The proposal will test the hypothesize that EBV -specific T cell immunity is not altered by malaria exposure per se but that viral immunity is transiently and profoundly suppressed during episodes of acute malaria morbidity, thereby providing the opportunity for latently infected B cells to undergo malignant transformation. Thus, in children presenting with eBL, EBV -specific T cell immunity will be intact since suppression of such preceded development of eBL. The specific aims will test the following hypotheses: Aim 1: EBV-specific T cell IFN-y and IL-I0 responses are stable over time and not influenced by the pattern of malaria transmission in a population of healthy children. Aim 2: EBV-specific IFN-y T cell responses are transiently suppressed while IL-I0 T cell responses are induced during an attack of malaria morbidity. Aim 3: EBV-specific T cell IFN-y and IL-I0 responses in children with eBL are qualitatively and quantitatively similar to that of age-matched controls. Characterization of EBV-driven T cell responses associated with malaria will have implications for EBV vaccine trials to be conducted in populations where this lymphoma has a high prevalence.