SUPPRESSION OF B-LYMPHOMAS VIA INDUCTION OF INTERFERONS

描述(由申请人提供)：各种感染抑制肿瘤生长的能力是有充分证据的。我们以前已经证明，在急性弓形虫病期间，肿瘤抑制不涉及免疫系统的细胞毒性功能，很容易在免疫低下的小鼠中发生。相反，它依赖于循环因子(最有可能是干扰素)对血管生成的全身性抑制。为了确定艾滋病相关的Burkitt淋巴瘤是否会屈服于感染介导的抑制，我们为这种疾病建立了一个新的小鼠模型。它的基础是c-Myc癌蛋白在p53缺失的骨髓祖细胞中的过度表达。使用这个模型，我们发现在急性弓形虫病期间B淋巴瘤的生长完全被消除。在这项提案中，我们将研究I型和II型干扰素抑制淋巴肿大的机制。我们将使用STATI缺失的小鼠，在这些小鼠中，I型和II型干扰素通路都被灭活，并确定在这些动物中，感染期间的血管生成是否恢复。我们还将确定干扰素是否直接抑制了肿瘤B细胞的生长。为此，我们将杂交STATI和P53缺失的小鼠，并产生STATI表达缺陷的B淋巴瘤。它们将被植入感染弓形虫的STATL缺失小鼠体内。由于在这个系统中，宿主细胞和肿瘤细胞对干扰素都是耐药的，我们预计B淋巴瘤的生成将完全恢复。这表明干扰素在感染期间的淋巴瘤监测中起着双重作用：直接作用和无细胞作用。然后，我们将确定暴露于弓形虫抗原(STAg)是否会导致干扰素的诱导以及血管生成和淋巴肿大的抑制。我们还将在STAg治疗的SCID-Beige小鼠中进行肿瘤负荷研究，以证明STAg的抗肿瘤特性不依赖于细胞介导的细胞毒免疫。这一预期结果将确立，STAG或类似的原生动物或细菌抗原可能被开发成艾滋病相关Burkitt淋巴瘤的新治疗方式。

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.