Natural History of HPV Infection to Neoplasia

HPV 感染到肿瘤的自然史

基本信息

批准号：
7932621
负责人：
ANNA-BARBARA MOSCICKI
金额：
$ 14.09万
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：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7932621
关键词：
Address Adolescence Adolescent Anogenital venereal warts Anti-Inflammatory Agents Anti-inflammatory Antigens Appearance Attention Bacterial Vaginosis Behavioral Biological Assay Blood Blood Cells Cells Cervical Cervix Uteri Chronic Cohort Studies Complex Cytology DNA Data Dendritic cell activation Detection Development Disease Environment Enzymes Epidemiology Epithelium Evaluation Exposure to Failure Focal Infection Frequencies Funding Gene Proteins Genital Human Papilloma Virus Infection Goals Grant Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 IL8 gene Immune Immune Tolerance Immune response Immune system Immunity Infection Infectious Agent Inflammatory Interferon Type II Interferon-alpha Interleukin 6 Receptor Interleukin-10 Interleukin-13 Interleukin-5 Interleukin-6 Interview Knowledge Laboratories Langerhans cell Left Link Maintenance Measurable Measures Mediating Modeling Mucosal Immune Responses Mucosal Immunity Mucous Membrane Mucous body substance Natural History Natural Immunity Natural Killer Cells Nature Neoplasms Organism Pathway interactions Phase Phenotype Play Principal Investigator Receptor Signaling Relative (related person)Research Research Design Reverse Transcriptase Polymerase Chain Reaction Role Sampling Schedule Sexually Transmitted Diseases Shapes Site Spermatocidal Agents Spottings Squamous intraepithelial lesion T-Lymphocyte TNF gene Tampons Techniques Technology Testing Therapeutic Time Toll-like receptors Up-Regulation Upper arm Vaccines Vagina Vaginal Douching Viral Virus Visit Woman base cell mediated immune response cohort cytokine design disease natural history experience follow-up girls high risk mRNA Expression peripheral blood programs prophylactic protein expression receptor receptor expression response sperm cell vaccination strategy

项目摘要

DESCRIPTION (provided by applicant): This is a competitive renewal for our "Natural history of HPV; infection to neoplasia" grant. The natural history of HPV is most likely influenced by both innate and adaptive mucosal immunity. More specifically, we hypothesize that Tolllike receptors (TLRs) play an important role in cervical innate immunity to HPV through secretions of proinflammatory, chemotactic and anti-viral cytokines. Up-regulated TLR expression will also result in activation of dendritic cells and T cells that in turn will promote a Thl like response through secretion of several cytokines and consequently, the induction of a successful cell mediated immune (CMI) response. We propose to: 1) examine, in cervical cell samples, the association among TRL expression,TRL-associated cytokines that mediate innate immunity ( IFN alpha, TNF, IL-6 and IL-8) and clearance of incident HPV infection; 2) examine, in cervical cell samples, the association among TRL expression, TRL-associated cytokines that induce and mediate adaptive immunity (IFN-gamma, ILs- 12, 23, and 27) and HPV clearance; and 3) examine the association among TLR induced Th-1 responses measured in cervical cell samples, HPV specific CMI responses detected in peripheral blood (PB) and HPV clearance. Adolescent and young women who were a) entered into the cohort during the initial 1990-1995 period and have continued to be followed and b) entered into the cohort during the last recruitment wave (2000-2005) will be asked to continue follow-up for an additional five years (2005-2010). These women will have been well characterized at the time of the initiation of this study with HPV at their entry visit and 4-month interval sampling for HPV DNA, cytology, bacterial vaginosis, colpophotographs (assessment of cervical maturation), C. trachomatis and N. gonorrohea testing, cervical cell cytokines by RT-PCR (IFN-gamma, ILs 4,10 and 12) and PB CMI for HPV 16 positive women. Women will be continued to be characterized for the above at the same intervals through-out the follow-up. Measures of innate and adaptive immunity (TLRs, ILs-6, 8, 5, 13, 23, and 27, TNF, IFN alpha) by RT PCR using cervical cells and by Luminex technology using cervical mucous will be added to the same 4 month interval testing as HPV DNA, cytology and other cervical cytokines described. Women positive for HPV 16 will get additional blood for CMI using IFN-gamma EliSpot technique for detection of anti-E6 and E7 responses. We acknowledge that this design simplifies the pleiotropic nature of cytokines. However, we feel that this model reflects plausible mechanisms involved in HPV control and is feasible to test in our cohort. Information garnered from this type of study will be critical in developing vaccine strategies and therapies as well as illuminating immune responses developed in the mucosal epithelium.

描述（由申请人提供）：这是我们的“HPV 自然史；感染至肿瘤”赠款的竞争性续展。 HPV 的自然史很可能受到先天性和适应性粘膜免疫的影响。更具体地说，我们假设 Toll 样受体 (TLR) 通过分泌促炎、趋化和抗病毒细胞因子，在宫颈对 HPV 的先天免疫中发挥重要作用。上调的TLR表达还将导致树突细胞和T细胞的激活，进而通过分泌多种细胞因子促进Th1样反应，从而成功诱导细胞介导的免疫（CMI）反应。我们建议：1）在宫颈细胞样本中检查 TRL 表达、介导先天免疫的 TRL 相关细胞因子（IFN α、TNF、IL-6 和 IL-8）与清除 HPV 感染之间的关联； 2) 检查宫颈细胞样本中 TRL 表达、诱导和介导适应性免疫的 TRL 相关细胞因子（IFN-γ、ILs-12、23 和 27）与 HPV 清除之间的关联； 3) 检查宫颈细胞样本中检测到的 TLR 诱导的 Th-1 反应、外周血 (PB) 中检测到的 HPV 特异性 CMI 反应和 HPV 清除率之间的关联。 a) 在最初的 1990-1995 年期间进入队列并继续跟踪 b) 在上一次招募浪潮（2000-2005 年）期间进入队列的青少年和年轻女性将被要求继续随访再延长五年（2005-2010）。在本研究开始时，这些女性已在入院访视时对 HPV 进行了充分表征，并每隔 4 个月进行一次 HPV DNA 采样、细胞学检查、细菌性阴道病、阴道照片（评估宫颈成熟度）、沙眼衣原体和 N HPV 16 阳性女性的淋病检测、RT-PCR 宫颈细胞细胞因子（IFN-gamma、ILs 4,10 和 12）和 PB CMI。在整个随访过程中，将继续以相同的时间间隔对女性进行上述特征描述。使用宫颈细胞通过 RT PCR 以及使用宫颈粘液通过 Luminex 技术进行先天性和适应性免疫（TLR、ILs-6、8、5、13、23 和 27、TNF、IFN α）的测量将添加到相同的 4 个月中间隔检测如 HPV DNA、细胞学和其他宫颈细胞因子所述。 HPV 16 呈阳性的女性将使用 IFN-gamma EliSpot 技术获得额外的血液用于 CMI，以检测抗 E6 和 E7 反应。我们承认这种设计简化了细胞因子的多效性。然而，我们认为该模型反映了 HPV 控制的合理机制，并且在我们的队列中进行测试是可行的。从此类研究中获得的信息对于制定疫苗策略和疗法以及阐明粘膜上皮中产生的免疫反应至关重要。