Natural History of HPV Infection to Neoplasia

HPV 感染到肿瘤的自然史

• 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
• 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

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；感染到瘤变”。HPV的自然史很可能受到先天和适应性粘膜免疫的影响。更具体地说，我们假设toll样受体（TLRs）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。TLR表达上调还会导致树突状细胞和T细胞的激活，进而通过分泌多种细胞因子促进Thl样反应，从而诱导成功的细胞介导免疫（CMI）反应。我们建议：1)在宫颈细胞样本中检测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HPV感染清除之间的关系；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、il - 12、23和27）与HPV清除之间的关系；3)检测TLR诱导的宫颈细胞样本Th-1应答、外周血检测的HPV特异性CMI应答和HPV清除率之间的关系。a)在最初的1990-1995年期间进入队列并继续被跟踪的青少年和年轻妇女，b)在上一轮招募浪潮（2000-2005年）期间进入队列的青少年和年轻妇女，将被要求继续进行额外五年的随访（2005-2010年）。在研究开始时，这些妇女将被很好地描述为HPV的特征，在她们的初次就诊时，间隔4个月取样HPV DNA，细胞学，细菌性阴道病，阴道摄影（评估宫颈成熟），沙眼衣原体和淋病奈索菌检测，通过RT-PCR检测宫颈细胞因子（ifn - γ, il 4,10和12）和HPV 16阳性妇女的PB CMI。在整个随访过程中，将以相同的时间间隔继续对妇女进行上述特征分析。宫颈细胞RT PCR和宫颈黏膜Luminex技术的先天免疫和适应性免疫（TLRs、il -6、8、5、13、23和27、TNF、IFN α）检测将与HPV DNA、细胞学和其他宫颈细胞因子检测一样，加入4个月的间隔检测中。HPV 16阳性的妇女将使用ifn - γ EliSpot技术获得额外的血液用于CMI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。从这种类型的研究中获得的信息对于开发疫苗策略和治疗以及阐明粘膜上皮中产生的免疫反应至关重要。