Langerhans cell-mediated immune modulation of HPV8 expression and tumorgenesis

描述(由申请人提供)：感染致癌类型的人乳头瘤病毒(HPV)易患肿瘤。某些致癌的HPV，包括HPV8，与人类皮肤癌有关。Herbert Pfister使用K14-HPV8转基因小鼠模型实验证明了HPV8诱发皮肤癌的能力。皮肤癌是器官移植的主要并发症。它在艾滋病患者中也很常见，强烈表明是感染性病原学。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疗问题。艾滋病相关癌症在全世界的重要性怎么强调都不为过。这一建议的假设是朗格汉斯细胞(LCS)控制着HPV的持久性和相关的恶性进展。直到最近，LCS主要被认为是适应性免疫的刺激物。耶鲁大学的丹尼尔·卡普兰最近对这一观点提出了挑战，他指出，缺乏LC的转基因小鼠产生了夸大的接触超敏反应(CHS)，令人惊讶的是，LCS下调了CHS的反应。最近的研究表明，LC缺陷小鼠出人意料地免受化学诱导的肿瘤的发展(见初步研究)。因此，在化学致癌和慢性阻塞性肺疾病期间，LCS下调获得性免疫。我们建议使用Lc缺陷转基因小鼠、K14-HPV8转基因小鼠和一个新的HPV8转基因小鼠模型来严格测试LCS在HPV8相关皮肤恶性肿瘤发生中的作用。具体目的将测试LCS是否抑制或增强HPV转基因皮肤移植物(作为亚临床感染的模型)和/或HPV8相关肿瘤形成的排斥/维持。如果结果表明LCS增强了HPV8介导的致瘤性，这将意味着我们对这种肿瘤类型的理解发生了重大的范式转变。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：人类乳头瘤病毒(HPV)感染可导致鳞状细胞癌的发展，尽管癌症是一种罕见的感染结果。我们假设郎格汉斯细胞是一种免疫细胞，通过下调有益免疫反应的发展来促进HPV的持续和恶性进展。如果这项研究的结果证实了我们的假设，他们将为HPV发病机制的调控提供新的见解，并为开发基于免疫的策略提供新的靶点，使高风险患者患HPV相关癌症直接受益于临床。

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.