Mucosal immune response of the anus in women to HPV, intercourse, smoking and OCs

女性肛门对 HPV、性交、吸烟和口服避孕药的粘膜免疫反应

基本信息

批准号：
7813440
负责人：
ANNA-BARBARA MOSCICKI
金额：
$ 49.79万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-23 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7813440
关键词：
Address Affect Anogenital cancer Anus Area Automobile Driving Behavior Behavioral Biological Assay Cervical Cervix Uteri Clinical Research Cohort Studies Complex Contraceptive Agents Contraceptive Usage Cytology DNA Data Detection Development Down-Regulation Environment Environmental Exposure Environmental Risk Factor Epithelium Exposure to Goals HIV HPV-High Risk Hormonal Hormones Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 Human papillomavirus 18 Immune Immune Tolerance Immune response Immunologics Immunology Infection Infection prevention Inflammatory Inflammatory Response Interferon Type II Interferons Interleukin-12 Interleukin-6 Interleukin-8 Interview Lead Liquid substance Local Microbicides Low risk HPV Malignant Neoplasms Malignant neoplasm of anus Measures Mediating Methods Mucosal Immune Responses Mucous Membrane Mucous body substance Natural History Natural Immunity Nicotine Nucleic Acids Oral Contraceptives Organism Parents Pilot Projects Risk Role Sampling Sexually Transmitted Diseases Smoking Techniques Teenagers Testing Therapeutic Intervention Time TimeLine Tissues Tobacco Tobacco use Toll-like receptors Trauma Tumor Necrosis Factor-alpha Tumor Necrosis Factors Up-Regulation Vagina Viral Viral Load result Virus Visit Woman Work adaptive immunity chemokine cigarette smoking cohort cytokine human TLR3 protein insight mRNA Expression novel novel therapeutic intervention pathogen public health relevance receptor receptor expression response therapeutic development transmission process

项目摘要

DESCRIPTION (provided by applicant): This application addresses the Challenge area of Clinical research (04); Topic: A1-101: Develop novel methods and address key questions in mucosal immunology. The study of mucosal immunology of the anus (as with all mucosal epithelium) has been extremely challenging for numerous reasons: 1) the anus has a complex microbiologic environment which requires a level of immune tolerance to commensal organisms, 2) there are often frequent exposures to simultaneous pathogens as well as trauma induced by anal intercourse, 3) there has been a lack of techniques suitable to cohort studies to study immune parameters and 4) accessing tissue and fluids in longitudinal cohorts is often difficult. Anal mucosa has long been known to be vulnerable to sexually transmitted pathogens including HIV and human papillomavirus (HPV). Certainly, a greater understanding of these responses will be critical in the development of topical microbicides for sexually transmitted infection (STI) prevention as well as therapeutic interventions. In particular, therapeutic interventions are needed for viral pathogens such as HPV which is the most common STI and is responsible for 80-100% of anal cancers. Although HPV infections of the anus are common, even among women, most infection usually clear. Unfortunately, the risk of anal cancer continues for those with HPV persistence--the key in the development of all anogenital cancers. Fairly strong evidence suggests that immune mechanisms influence HPV clearance. Understanding the immunologic mechanisms that result in HPV persistence is critical in the development of therapeutic treatment for HPV-induced pre-cancers. In addition, HPV itself has been known to increase risks for HIV. Hence studying HPV may also give insight into mechanisms into which STIs contribute to HIV transmission. Over the past 15 years, we have attempted to address many of the immunologic questions in the cervix and vagina by incorporating immune assays in our ongoing longitudinal cohort: the natural history of HPV in teens (R37 CA51323) which began in 1990. This cohort undergoes close characterization for commensal and pathogenic organisms of the cervix, as well as behavioral interviews, at 4-month intervals. Over the years, we have adapted several assays focusing on innate and adaptive immunity that are suitable for study in the cohort including detection of cytokines and chemokines as well as measuring mRNA expression of Toll- like receptors (TLR) from cervical samples. In this well-established cohort, we have stored over 15,000 anal samples which have been collected since 1993 at 4 month intervals. We have the unprecedented and unique opportunity to examine mucosal immune responses over time in a well-characterized cohort. Aims of this study are to: 1) examine, in anal samples, the cytokines which are enhanced at time of HPV acquisition; 2) examine in anal samples, the association between cytokines that mediate innate immunity (IFN-a, TNF, IL-6 and IL-8) and adaptive immunity (IFN gamma and IL 12) and clearance of incident HPV infection. Co-factors or behaviors that may also mediate cytokine and chemokine profiles will be examined including frequent anal intercourse, smoking cigarettes and oral contraceptive use and 3) compare cytokines and chemokine profiles between the anus and the cervix in response to HPV acquisition and clearance, and 4) to compare the cytokine/chemokine profiles between HPV infected women with normal and abnormal anal cytology. We have over 15,000 stored anal samples available for HPV DNA testing and cytokine/chemokine analysis for aims 1-3. All stored anal samples will be tested for HPV DNA. Cytokine and chemokine analysis will be performed from samples obtained from visits with an incident HPV infection. For aim 3, samples from the cervix of women for HPV DNA and cytokine/chemokine analysis are already available through the parent study for comparison. We also propose a subaim in which we will examine TLR expression from anal samples in women who acquire anal HPV. Since the current anal samples are not suitable for measuring TLRs, we have now started collecting these samples prospectively. We expect that we will have 300 samples available for examination for this aim. In summary, we have the unique opportunity to examine anal mucosal immune responses in a well characterized cohort using stored samples which will allow us to keep to our strict timeline. This data will give us a greater understanding of environmental factors that affect mucosal immune profiles. PUBLIC HEALTH RELEVANCE: This application plans to examine anal mucosal immune responses to human papillomavirus, tobacco use, anal intercourse and hormonal contraceptives.

描述（由申请人提供）：本申请涉及临床研究的挑战领域（04）；主题：A1-101：开发新颖的方法并解决粘膜免疫学中的关键问题。肛门粘膜免疫学（与所有粘膜上皮一样）的研究非常具有挑战性：1）肛门具有复杂的微生物学环境，需要对共生生物的免疫性耐受性，2）经常有频繁的暴露于同时的病原体以及适用于Analige的研究，3）是3），3）是3）。免疫参数和4）访问纵向队列中的组织和流体通常很难。长期以来，肛门粘膜很容易受到包括艾滋病毒和人乳头瘤病毒（HPV）在内的性传播病原体的影响。当然，对这些反应的更多了解对于开发性传播感染（STI）和治疗干预措施的局部杀菌剂至关重要。特别是，对于HPV等病毒病原体，需要治疗干预措施，这是最常见的STI，是80-100％的肛门癌。尽管肛门的HPV感染也很常见，即使在女性中，大多数感染通常都清晰。不幸的是，患有HPV持久性的人会继续进行肛门癌的风险 - 所有肛门生殖器癌的发展的关键。相当有力的证据表明，免疫机制会影响HPV清除。了解导致HPV持久性的免疫机制对于HPV诱导的预癌治疗的发展至关重要。此外，众所周知，HPV本身会增加艾滋病毒的风险。因此，研究HPV也可能会深入了解性传播感染有助于HIV传播的机制。在过去的15年中，我们试图通过将免疫测定纳入我们正在进行的纵向纵向队列中：青少年的HPV自然历史（R37 CA51323）中的许多免疫学问题（R37 CA51323）开始，该法案始于1990年。这种同伴对年龄和情感有条理的态度进行了仔细的表征。多年来，我们已经改编了一些专注于先天性和适应性免疫的测定法，这些测定法适用于同类研究，包括检测细胞因子和趋化因子以及测量宫颈样品的TOLL-LIKE受体（TLR）的mRNA表达。在这个完善的队列中，我们存储了自1993年以来4个月以来收集的15,000多个肛门样品。我们有前所未有且独特的机会，可以随着时间的推移在一个良好的人群中检查粘膜免疫反应。这项研究的目的是：1）在肛门样品中检查HPV获取时会增强的细胞因子； 2）检查肛门样品，介导先天免疫（IFN-A，TNF，IL-6和IL-8）的细胞因子与适应性免疫（IFN Gamma和IL 12）与入射HPV感染的清除率之间的关联。将检查可能介导细胞因子和趋化因子谱的联合因素或行为，包括频繁的肛门性交，吸烟和口服避孕药的用途，以及3）比较肛门的细胞因子和趋化因子和趋化因子的特征，以响应HPV的收集性和清除率，以及4）响应于HPV的女性，以及4）与CYTOKINE相似的群体，以及4）的HEM。细胞学。我们有15,000多个存储的肛门样品可用于HPV DNA测试，而AIMS 1-3的细胞因子/趋化因子分析。所有存储的肛门样品将用于HPV DNA。细胞因子和趋化因子分析将从从患有HPV感染的访问中获得的样品进行。对于AIM 3，来自女性的HPV DNA和细胞因子/趋化因子分析的女性子宫颈样品已经可以通过家长研究进行比较。我们还提出了一个SubiaM，其中我们将检查获得肛门HPV的女性中肛门样品的TLR表达。由于当前的肛门样品不适合测量TLR，因此我们现在开始收集这些样品前瞻性。我们预计我们将有300个样本可用于此目标。总而言之，我们有独特的机会，可以使用存储的样品在具有良好特征的队列中检查肛门粘膜免疫反应，这将使我们能够保持严格的时间表。这些数据将使我们对影响粘膜免疫特征的环境因素有了更多的了解。公共卫生相关性：本应用计划检查对人乳头瘤病毒，烟草使用，肛门性交和荷尔蒙避孕药的肛门粘膜免疫反应。