Langerhans cell-mediated immune modulation of HPV8 expression and tumorgenesis

描述（由申请方提供）：致癌型人乳头瘤病毒（HPV）感染易发生肿瘤。某些致癌HPV，包括HPV 8，与人类皮肤癌有关。赫伯特菲斯特使用K14-HPV 8转基因小鼠模型实验证明了HPV 8诱导皮肤癌的能力。皮肤癌是器官移植的主要并发症。它在艾滋病患者中也异常常见，强烈表明感染性病因。由于美国有10万人接受器官移植，100万人患有艾滋病，皮肤癌是一个重大的医学问题。与艾滋病有关的癌症在全世界的重要性怎么强调都不过分。该建议的假设是郎格罕细胞（LC）控制HPV持续存在和相关的恶性进展。直到最近，LC主要被认为是适应性免疫的刺激物。最近耶鲁大学的丹尼尔·卡普兰（Daniel Kaplan）对这一观点提出了挑战，他发现LC缺陷型转基因小鼠产生了过度的接触性超敏反应（CHS），令人惊讶地证明LC下调了CHS反应。最近的研究表明，LC缺陷型小鼠意外地被保护免于化学诱导的肿瘤的发展（参见初步研究）。因此，在化学致癌以及CHS，LC下调适应性免疫。我们建议使用LC缺陷型转基因小鼠、K14-HPV 8转基因小鼠和一种新的HPV 8转基因小鼠模型来严格测试LC在HPV 8相关皮肤恶性肿瘤发展中的作用，该模型旨在对转基因表达提供严格的时间、空间和动态控制。特定目的将测试LC是否抑制或增强HPV转基因皮肤移植物（作为亚临床感染模型）和/或HPV 8相关肿瘤发生的排斥/维持。如果结果表明LC增强了HPV 8介导的致瘤性，则意味着我们对这种肿瘤类型的理解发生了重大转变。最终，这些信息将为高危人群中HPV相关癌症的预防和治疗提供新的方法。公共卫生相关性：人乳头瘤病毒（HPV）感染可导致鳞状细胞癌的发展，尽管癌是感染的罕见结果。我们假设朗格汉斯细胞，一种免疫细胞，通过下调有益免疫反应的发展促进HPV的持续存在和恶性进展。如果这项研究的结果证实了我们的假设，它们将为HPV发病机制的调节提供新的见解，并为开发基于免疫的策略提供新的靶点，这些策略对HPV相关癌症高危患者具有直接的临床益处。

DESCRIPTION (provided by applicant): Infection with oncogenic types of human papillomavirus (HPV) predisposes to neoplasia. Certain oncogenic HPVs, including HPV8, are associated with human skin cancer. The ability of HPV8 to induce skin cancer was demonstrated experimentally by Herbert Pfister using a K14-HPV8 transgenic mouse model. Skin cancer is the major complication of organ transplantation. It also is unusually common among AIDS patients, strongly indicating an infectious etiology. As 100,000 people in the U.S. are living with organ transplants and 1,000,000 with AIDS, skin cancer is a significant medical problem. The importance of AIDS-related cancers worldwide cannot be overstated. The hypothesis of this proposal is that Langerhans cells (LCs) govern HPV persistence and associated malignant progression. Until lately LCs have mainly been regarded as stimulators of adaptive immunity. This notion has been recently been challenged by Daniel Kaplan at Yale who showed that LC-deficient transgenic mice developed exaggerated contact hypersensitivity responses (CHS), demonstrating surprisingly that LCs downregulated CHS responses. Very recent studies demonstrated that the LC- deficient mice were unexpectedly protected against the development of chemically induced tumors (see Preliminary Studies). Thus during chemical carcinogenesis as well as CHS, LCs downregulated adaptive immunity. We propose to rigorously test the role of LCs in the development of HPV8-associated cutaneous malignancy using LC-deficient transgenic mice, K14-HPV8 transgenic mice and a novel HPV8 transgenic mouse model designed to provide tight temporal, spatial and dynamic control over transgene expression. The Specific Aims will test whether LCs inhibit or enhance the rejection/maintenance of HPV transgenic skin grafts (as a model of subclinical infection) and/or HPV8-associated tumorigenesis. If the results demonstrate that LCs enhance HPV8-mediated tumorigenicity, they would imply a major paradigm shift in our understanding of this tumor type. Ultimately, the information would provide novel approaches for the prevention and treatment of HPV-associated cancers in high-risk individuals. PUBLIC HEALTH RELEVANCE: Human papillomavirus (HPV) infections can lead to the development of squamous cell carciomas although carcinoma is a rare outcome of infection. We hypothesize that Langerhans cells, a type of immune cell, facilitate HPV persistence and malignant progression by downregulating the development of benefical immune responses. If the results of this investigation substantiate our hypothesis, they will provide new insight into the regulation of HPV pathogenesis as well as novel targets for the development of immune-based strategies of direct clinical benefit to patients at high-risk of developing HPV-associated cancers.