Langerhans cell-mediated immune modulation of HPV8 expression and tumorgenesis

朗格汉斯细胞介导的 HPV8 表达和肿瘤发生的免疫调节

• 批准号: 7624197
• 负责人: JANET L BRANDSMA
• 金额: $ 22.34万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7624197
• 关键词: AIDS related cancer; Acquired Immunodeficiency Syndrome; Anogenital cancer; Antigen Presentation; Antigen-Presenting Cells; Biological Assay; Carcinoma; Cell physiology; Cells; Cellular Immunity; Clinical; Complication; Contact hypersensitivity; Cutaneous; Defect; Development; Disease; Epidermis; Epidermodysplasia Verruciformis; Etiology; General Population; Genome; HIV Infections; Head and Neck Cancer; Human; Human Papillomavirus; Human papilloma virus infection; Immune; Immune response; Immunity; Immunologic Surveillance; Immunologics; Immunosuppression; Individual; Infection; Inherited; Investigation; Keratin; Langerhans cell; Lead; Lesion; Life; Link; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mediating; Mediator of activation protein; Medical; Modeling; Mucous Membrane; Mus; Neoplasms; Oncogenic; Organ Transplantation; Outcome; Papilloma; Pathogenesis; Patients; Phenotype; Predisposition; Prevention; Regulation; Reporting; Research; Role; Severities; Skin; Skin Cancer; Skin Transplantation; Skin graft; Squamous Cell; Squamous cell carcinoma; Testing; The Sun; Transgenes; Transgenic Mice; Transgenic Model; Transgenic Organisms; Transplant Recipients; Transplantation; Tumorigenicity; Ultraviolet Rays; base; chemical carcinogenesis; density; high risk; immunoregulation; innovation; insight; member; model design; mouse model; novel; novel strategies; promoter; public health relevance; response; skin squamous cell carcinoma; transgene expression; tumor; tumorigenesis

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.

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 HPV，包括 HPV8，与人类皮肤癌有关。 Herbert Pfister 使用 K14-HPV8 转基因小鼠模型通过实验证明了 HPV8 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，强烈表明其具有传染性病因。美国有 100,000 人接受器官移植，1,000,000 人患有艾滋病，因此皮肤癌是一个重大的医学问题。全世界与艾滋病相关的癌症的重要性怎么强调都不为过。该提议的假设是朗格汉斯细胞 (LC) 控制着 HPV 的持续存在和相关的恶性进展。直到最近，LC 主要被视为适应性免疫的刺激剂。这一观点最近受到耶鲁大学 Daniel Kaplan 的挑战，他发现 LC 缺陷的转基因小鼠出现了夸张的接触超敏反应 (CHS)，令人惊讶的是 LC 下调了 CHS 反应。最近的研究表明，LC 缺陷小鼠出乎意料地受到保护，免受化学诱导肿瘤的发展（参见初步研究）。因此，在化学致癌作用以及中枢性低通气综合征（CHS）过程中，LCs 下调适应性免疫。我们建议使用 LC 缺陷转基因小鼠、K14-HPV8 转基因小鼠和新型 HPV8 转基因小鼠模型严格测试 LC 在 HPV8 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。具体目标将测试 LC 是否抑制或增强 HPV 转基因皮肤移植（作为亚临床感染模型）和/或 HPV8 相关肿瘤发生的排斥/维持。如果结果证明 LC 增强 HPV8 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范式转变。最终，这些信息将为高危人群预防和治疗 HPV 相关癌症提供新方法。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，尽管癌症是一种罕见的感染结果。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来促进 HPV 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，使患有 HPV 相关癌症的高风险患者直接受益于临床。