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; 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）：具有癌性类型的人乳头瘤病毒（HPV）的感染倾向于肿瘤。包括HPV8在内的某些致癌HPV与人体皮肤癌有关。 Herbert Pfister使用K14-HPV8转基因小鼠模型在实验中证明了HPV8诱导皮肤癌的能力。皮肤癌是器官移植的主要并发症。在艾滋病患者中，它也异常常见，强烈表明感染性病因。由于美国有100,000人患有器官移植，有1,000,000人患有艾滋病，因此皮肤癌是一个重大的医疗问题。全球与艾滋病相关的癌症的重要性不能被夸大。该提议的假设是Langerhans细胞（LCS）控制HPV持久性和相关的恶性进展。直到最近的LCS主要被视为适应性免疫的刺激剂。耶鲁大学的丹尼尔·卡普兰（Daniel Kaplan）最近对这一观念进行了质疑，耶鲁大学表明LC缺陷的转基因小鼠产生了夸张的接触性高敏反应（CHS），这表明LCS下调了CHS反应。最近的研究表明，LC缺乏小鼠受到意外保护，以防止化学诱导的肿瘤的发展（见初步研究）。因此，在化学癌变和CHS期间，LCS下调适应性免疫。我们建议使用LC缺陷型转基因小鼠，K14-HPV8转基因小鼠和一种新型的HPV8转基因小鼠模型来严格测试LC在与HPV8相关的皮肤恶性肿瘤发展中的作用。具体目的将测试LCS是否抑制或增强HPV转基因皮肤移植物的排斥/维持（作为亚临床感染的模型）和/或与HPV8相关的肿瘤发生。如果结果表明LCS增强了HPV8介导的肿瘤性，它们将暗示我们对这种肿瘤类型的理解的主要范式转移。最终，这些信息将为预防和治疗高风险个体的HPV相关癌症提供新颖的方法。公共卫生相关性：人乳头瘤病毒（HPV）感染可能导致鳞状细胞癌的发展，尽管癌是感染的罕见结果。我们假设一种免疫细胞的Langerhans细胞通过下调受益免疫反应的发展来促进HPV持久性和恶性进展。如果这项调查的结果证实了我们的假设，他们将为HPV发病机理的调节以及开发基于免疫临床益处的免疫策略的新目标提供新的见解，从而向患者开发与HPV相关的癌症的高风险患者。