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:
- 金额:$ 49.79万
- 依托单位:
- 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:
- 关键词:AddressAffectAnogenital cancerAnusAreaAutomobile DrivingBehaviorBehavioralBiological AssayCervicalCervix UteriClinical ResearchCohort StudiesComplexContraceptive AgentsContraceptive UsageCytologyDNADataDetectionDevelopmentDown-RegulationEnvironmentEnvironmental ExposureEnvironmental Risk FactorEpitheliumExposure toGoalsHIVHPV-High RiskHormonalHormonesHuman PapillomavirusHuman papilloma virus infectionHuman papillomavirus 16Human papillomavirus 18ImmuneImmune ToleranceImmune responseImmunologicsImmunologyInfectionInfection preventionInflammatoryInflammatory ResponseInterferon Type IIInterferonsInterleukin-12Interleukin-6Interleukin-8InterviewLeadLiquid substanceLocal MicrobicidesLow risk HPVMalignant NeoplasmsMalignant neoplasm of anusMeasuresMediatingMethodsMucosal Immune ResponsesMucous MembraneMucous body substanceNatural HistoryNatural ImmunityNicotineNucleic AcidsOral ContraceptivesOrganismParentsPilot ProjectsRiskRoleSamplingSexually Transmitted DiseasesSmokingTechniquesTeenagersTestingTherapeutic InterventionTimeTimeLineTissuesTobaccoTobacco useToll-like receptorsTraumaTumor Necrosis Factor-alphaTumor Necrosis FactorsUp-RegulationVaginaViralViral Load resultVirusVisitWomanWorkadaptive immunitychemokinecigarette smokingcohortcytokinehuman TLR3 proteininsightmRNA Expressionnovelnovel therapeutic interventionpathogenpublic health relevancereceptorreceptor expressionresponsetherapeutic developmenttransmission 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:开发新方法并解决粘膜免疫学中的关键问题。肛门粘膜免疫学的研究(与所有粘膜上皮一样)由于许多原因而极具挑战性:1)肛门具有复杂的微生物环境,其需要对肛门生物体具有一定程度的免疫耐受性,2)经常频繁地暴露于同时发生的病原体以及由肛交引起的创伤,3)缺乏适合于队列研究的技术来研究免疫参数,以及4)
组织和流体的纵向队列通常是困难的。长期以来,人们一直认为肛门粘膜容易受到性传播病原体的感染,包括HIV和人乳头瘤病毒(HPV)。当然,更好地了解这些反应将是至关重要的局部杀微生物剂的性传播感染(STI)的预防和治疗干预措施的发展。特别是,需要对病毒病原体进行治疗干预,如HPV,这是最常见的STI,并且是80-100%肛门癌的原因。虽然肛门HPV感染很常见,即使在女性中,大多数感染通常是明确的。不幸的是,肛门癌的风险仍然存在于HPV持续存在的人中-这是所有肛门生殖器癌发展的关键。相当有力的证据表明,免疫机制影响HPV清除。了解导致HPV持续存在的免疫机制对于开发HPV诱导的癌前病变的治疗性治疗至关重要。此外,已知HPV本身会增加感染艾滋病毒的风险。因此,研究HPV也可以深入了解性传播感染促进艾滋病毒传播的机制。
在过去的15年里,我们试图通过在我们正在进行的纵向队列中纳入免疫测定来解决宫颈和阴道中的许多免疫学问题:1990年开始的青少年HPV自然史(R37 CA 51323)。该队列每隔4个月进行一次宫颈细菌和致病微生物的密切表征以及行为访谈。多年来,我们已经采用了几种专注于先天性和适应性免疫的测定法,这些测定法适用于队列研究,包括检测细胞因子和趋化因子以及测量来自宫颈样品的Toll样受体(TLR)的mRNA表达。在这个成熟的队列中,我们储存了15,000多个肛门样本,这些样本是自1993年以来每隔4个月收集的。我们有前所未有的和独特的机会来检查粘膜免疫反应随着时间的推移,在一个良好的特征队列。本研究的目的是:1)检查肛门样本中HPV感染时增强的细胞因子; 2)检查肛门样本中HPV感染时增强的细胞因子。
在一些实施方案中,本发明的方法用于检测样本中的HPV感染、介导先天免疫(IFN-α、TNF、IL-6和IL-8)和适应性免疫(IFN γ和IL 12)的细胞因子之间的关联以及偶发HPV感染的清除。还将检查可能介导细胞因子和趋化因子谱的辅因子或行为,包括频繁肛交、吸烟和口服避孕药的使用,以及3)比较肛门和宫颈之间响应于HPV获得和清除的细胞因子和趋化因子谱,以及4)比较肛门细胞学正常和异常的HPV感染女性之间的细胞因子/趋化因子谱。我们有超过15,000个储存的肛门样本可用于HPV DNA检测和细胞因子/趋化因子分析,用于目标1-3。所有储存的肛门样本将进行HPV DNA检测。将对从发生HPV感染的访视中获得的样本进行细胞因子和趋化因子分析。对于目标3,通过母研究已经可以获得用于HPV DNA和细胞因子/趋化因子分析的女性宫颈样本,以进行比较。我们还提出了一个子目标,我们将检查TLR表达从肛门样本中获得肛门HPV的妇女。由于目前的肛门样本不适合测量TLR,我们现已开始收集
这些样本的前瞻性。我们预计将有300个样本可供检查。总之,我们有独特的机会使用储存的样本在一个充分表征的队列中检查肛门粘膜免疫应答,这将使我们能够保持严格的时间轴。这些数据将使我们更好地了解影响粘膜免疫的环境因素。
公共卫生相关性:本申请计划检查肛门粘膜对人乳头瘤病毒、烟草使用、肛交和激素避孕药的免疫反应。
项目成果
期刊论文数量(0)
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ANNA-BARBARA MOSCICKI其他文献
ANNA-BARBARA MOSCICKI的其他文献
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{{ truncateString('ANNA-BARBARA MOSCICKI', 18)}}的其他基金
Real-world effectiveness of HPV vaccine in women living with HIV and its impact on cervical cancer screening accuracies
HPV 疫苗对 HIV 感染女性的真实有效性及其对宫颈癌筛查准确性的影响
- 批准号:
10682184 - 财政年份:2023
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$ 49.79万 - 项目类别:
Natural History of CIN and HPV in HPV Vaccinated Youth with PHIV
接种 HPV 疫苗的感染 PHIV 青少年的 CIN 和 HPV 自然史
- 批准号:
10264954 - 财政年份:2020
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$ 49.79万 - 项目类别:
Natural History of CIN and HPV in HPV Vaccinated Youth with PHIV
接种 HPV 疫苗的感染 PHIV 青少年的 CIN 和 HPV 自然史
- 批准号:
10663930 - 财政年份:2020
- 资助金额:
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Natural History of CIN and HPV in HPV Vaccinated Youth with PHIV
接种 HPV 疫苗的感染 PHIV 青少年的 CIN 和 HPV 自然史
- 批准号:
10065445 - 财政年份:2020
- 资助金额:
$ 49.79万 - 项目类别:
METABOLIC ABNORMALITIES IN HIV-INFECTED AND UNINFECTED YOUNG WOMEN
感染艾滋病毒和未感染艾滋病毒的年轻女性的代谢异常
- 批准号:
7204898 - 财政年份:2005
- 资助金额:
$ 49.79万 - 项目类别:
NATURAL HISTORY OF HUMAN PAPILLOMAVIRUS FROM INFECTION TO NEOPLASIA
人乳头瘤病毒从感染到肿瘤的自然史
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$ 49.79万 - 项目类别:
Natural history of HPV from infection to neoplasia in young women
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7043531 - 财政年份:2004
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HEPATITIS B VACCINATION AND TOOLS TO BE USED IN FUTURE HIV PREVENTION TRIALS
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7049907 - 财政年份:2001
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$ 49.79万 - 项目类别:
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