THYMUS INFECTION AND IMMUNITY IN VIRAL LEUKEMOGENESIS

小鼠白血病病毒（MLV）感染后淋巴瘤的形成依赖于MLV的持续存在和免疫清除的避免。具有免疫能力的成年小鼠通常对淋巴瘤的发展具有抗性。相反，新生动物和免疫抑制的成年动物对MLV依赖性白血病高度易感。我们最近发现，当胸腺内注射格罗斯鼠白血病病毒（G-MLV）时，可诱导成人白血病。我们认为，胸腺感染是废除病毒免疫和长期暴露于未成熟胸腺细胞，转化的敏感目标的一个重要组成部分。我们的研究利用了G-MLV的良好表征的分子克隆GD-17。GD-17的向胸腺性由长末端白血病发生中的独特序列通过基于G-MLV的载体的创建和体内表达来控制。在白血病前期，主要在成年胸腺髓质成年小鼠中检测到整合的病毒和病毒蛋白表达，这与抗G-MLV免疫的抑制一致相关。拟定研究阐明了以下假设：mTEC中MLV的复制是免疫耐受、持续性病毒感染和白血病发生的重要组成部分。目标1：确定上皮细胞嗜性在抑制MLV免疫应答中的作用目的2：确定嗜胸腺MLV诱导耐受的机制目的3：确定胸腺G-MLV感染对免疫耐受和白血病发生的要求

The formation of lymphomas in response to murine leukemia virus (MLV) infection is dependent on MLV persistence and avoidance of immune clearance. Immuno-competent adult mice are typically resistant to the development of lymphoma. In contrast, neonatal animals and immuno-suppressed adults are highly susceptible to MLV-dependent leukemogenesis. We recently determined that Gross murine leukemia virus )G-MLV) induced leukemia in adult when injected intra-thymically. We propose that thymic infection is an essential component of both the abrogation of virus immunity and prolonged exposure to immature thymocytes, the susceptible targets of transformation. Our studies utilize the well characterized molecular clone of G-MLV, GD-17. The thymo- tropism of GD-17 is controlled by unique sequences within the long- terminal leukemogenesis through the creation and in vivo expression of G-MLV based vectors. During the pre-leukemic phase, integrated virus and virus protein expression is detected predominantly in adult medullary thymic adult mice is uniformly linked to inhibition of anti-G-MLV immunity. The proposed studies address the hypothesis that replication of MLV in mTEC is an essential component of immune tolerance, persistent virus infection, and leukemogenesis. AIM 1: TO DETERMINE THE ROLE OF EPITHELIAL CELL TROPISM IN THE INHIBITION OF IMMUNE RESPONSES TO MLV AIM 2: TO DETERMINE THE MECHANISM OF TOLERANCE INDUCTION BY THYMO-TROPIC MLV AIM 3: TO DETERMINE THE REQUIREMENTS OF THYMIC G- MLV INFECTION ON IMMUNE TOLERANCE AND LEUKOMOGENESIS