SUPPRESSION OF B-LYMPHOMAS VIA INDUCTION OF INTERFERONS

通过干扰素诱导抑制 B 淋巴瘤

• 批准号: 6553976
• 负责人: Andrei Thomas-Tikhonenko
• 金额: $ 23.78万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6553976
• 关键词: AIDS related neoplasm /cancer; B cell lymphoma; Burkitt's lymphoma; Toxoplasma gondii; angiogenesis; apoptosis; cell mediated cytotoxicity; cell proliferation; cellular immunity; disease /disorder model; gene targeting; genetically modified animals; interferons; laboratory mouse; neoplastic growth

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.

描述（由申请人提供）：有据可查的各种感染抑制肿瘤生长的能力。我们先前已经证明，急性弓形虫病期间的肿瘤抑制不涉及免疫系统的细胞毒性功能，并且很容易发生在免疫功能低下的小鼠中。取而代之的是，它依赖于循环因子对血管生成的系统性抑制，这很可能是干扰素。为了确定与艾滋病相关的伯基特淋巴瘤是否会屈服于感染介导的抑制作用，我们为该疾病建立了一种新的小鼠模型。它基于p53无骨骨髓祖细胞中c-myc癌蛋白的过表达。使用该模型，我们发现急性弓形虫病期间B淋巴瘤的生长被完全消除了。在此提案中，我们将研究I型和II型干扰素抑制淋巴作用的机制。我们将使用I型和II型干扰素途径被灭活的Stati-null小鼠，并确定在这些动物中，感染过程中是否恢复了血管生成。我们还将确定肿瘤B细胞的生长是否被干扰素直接抑制。为此，我们将跨越统计和p53-null小鼠，并生成缺乏Stati表达的B淋巴瘤。它们将植入弓形虫贡迪感染的Statl -null小鼠中。由于在该系统中，宿主和肿瘤细胞对干扰素都是难治性的，因此我们希望B淋巴作用将完全恢复。这表明干扰素在感染期间在淋巴瘤监测中起双重作用：直接和厌氧介导的。然后，我们将确定暴露于T.gondii抗原（雄鹿）是否会导致干扰素诱导和抑制血管生成和淋巴细胞的作用。我们还将在经过雄鹿处理的SCID米色小鼠中进行肿瘤负荷研究，以证明雄鹿的抗塑性特性不依赖于细胞介导的细胞毒性免疫。这一预期的结果将确定可以将雄鹿或类似的原生动物或细菌抗原发展为与艾滋病相关的伯基特淋巴瘤的新治疗方式。