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的持久性和免疫清除的避免。免疫能力强的成年小鼠通常对淋巴瘤的发展具有抵抗力。相比之下，新生动物和免疫抑制的成年人非常容易发生MLV依赖的白血病。我们最近发现，粗大鼠白血病病毒(G-MLV)胸腺内注射可诱发成人白血病。我们认为，胸腺感染是病毒免疫丧失和长期暴露于未成熟胸腺细胞的重要组成部分，而未成熟胸腺细胞是转化的敏感目标。我们的研究利用了特性良好的G-MLV分子克隆GD-17。GD-17的胸腺趋向性是通过G-MLV载体的创建和体内表达，在长末端白血病发生过程中由独特的序列控制的。在白血病前期，主要在成年小鼠骨髓中检测到整合病毒和病毒蛋白的表达，成年小鼠的胸腺与抗G-MLV免疫抑制一致相关。这些研究提出的假设是，MLV在mTEC中的复制是免疫耐受、持续病毒感染和白血病发生的重要组成部分。目的1：探讨上皮细胞亲和性在MLV免疫应答抑制中的作用。目的2：探讨THYMO-Trotic MLV诱导免疫耐受的机制。目的3：探讨胸腺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