SUPPRESSION OF B-LYMPHOMAS VIA INDUCTION OF INTERFERONS

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DESCRIPTION (provided by applicant): The ability of various infections to suppress neoplastic growth is well-documented. We have previously demonstrated that tumor suppression during acute toxoplasmosis does not involve cytotoxic functions of the immune system and readily occurs in immunocompromised mice. Instead, it relies on systemic inhibition of angiogenesis by circulating factors, most likely interferons. To determine whether AIDS-related Burkitt lymphoma would succumb to infection-mediated suppression, we have established a new mouse model for this disease. It is based on overexpression of the c-Myc oncoprotein in p53-null bone marrow progenitors. Using this model, we have found that growth of B-lymphomas during acute toxoplasmosis was completely abolished. In this proposal, we will study mechanisms whereby type I and II interferons suppress lymphomagenesis. We will use STATI-null mice in which both type I and type II interferon pathways are inactivated, and determine whether in these animals angiogenesis during infection is restored. We will also determine whether growth of neoplastic B-cells is directly inhibited by interferons. To this end, we will cross STATI- and p53-null mice and generate B-lymphomas that are deficient in STATI expression. They will be implanted into Toxoplasma gondii-infected STATl -null mice. Since in this system both host and tumor cells are refractory to interferons, we expect that B-lymphomagenesis would be completely restored. This would suggest that interferons play a dual role in lymphoma surveillance during infection: direct and aniogenesis-mediated. We will then determine whether exposure to T.gondii antigens (STAg) would lead to the induction of interferons and suppression of angiogenesis and lymphomagenesis. We will also perform tumor load studies in STAg-treated scid-beige mice, to demonstrate that anti-neoplastic properties of STAg do not rely on cell-mediated cytotoxic immunity. This anticipated result will establish that STAg or similar protozoan or bacterial antigens could be developed into new therapeutic modalities for AIDS-related Burkitt lymphoma.