HPV SPECIFIC CELLULAR IMMUNITY IN CERVICAL INTRAEPITHELI

宫颈上皮内 HPV 特异性细胞免疫

• 批准号: 6376685
• 负责人: Jagannadha K Sastry
• 金额: $ 42.92万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6376685
• 关键词: biomarker; cancer risk; cellular immunity; cervix neoplasms; clinical research; epitope mapping; female; human papillomavirus; human subject; neoplasm /cancer epidemiology; neoplasm /cancer relapse /recurrence; oncoproteins; virus protein; virus related neoplasm /cancer; women's health

DESCRIPTION: (Adapted from the Investigator's Abstract) Epidemiological studies have clearly established that human papillomas (HPV) infection is a major risk factor for cervical cancer. A number of individuals undergo remission either spontaneously or after clinical intervention, while others, particularly those exhibiting immudeficiency, seem to proceed to develop invasive cancer. It is important to understand the immunological basis for the clinical remission of HPV-associated cervical neoplasia for designing proper intervention strategies. We have determined cell-mediated immunity (CMI) responses specific to synthetic peptides from E6 and E7, the two major oncoproteins of high risk type HPV (HPV-16), in a subset of patients attending the colposcopic clinic. These patients underwent excisional or ablative treatment for cervical intra epithelial neoplasia (CIN) at least six months prior to enrolling in the study. Significant differences were observed in proliferative responses directed against peptides from both the E6 (p=0.002) and E7 (p<0.001) between women without cytological or histological evidence of CIN (disease-free group) and those with a histological diagnosis of recurrence for CIN. Additional pilot studies on in vitro cytokine production mediated by the E6 and E7 peptides, showed a predominant TH1-cytokine profile in women from the disease-free group, while women with disease recurrence exhibited TH2-cytokine responses. On the other hand, none of the women in any of the study groups exhibited circulating antibodies reactive with the E6 and E7 peptides used in the study. Based on our results showing significantly high levels of HPV-peptide-specific TH1 responses in disease-free patients only, we hypothesize that HPV-specific CMI directed against the E6 and E7 oncoproteins is important for protection/recovery from HPV-associated CIN. To test this hypothesis, we propose to conduct a prospective cohort study of women positive for high-risk HPV types and treated for CIN by loop electrosurgical procedure. Our goals are to identify HPV peptides that can potentially serve as markers of protective immunity and for inclusion in immunotherapeutic and/or immunoprophylactic vaccine formulations against HPV-associated CIN. We will assess the pattern of the HPV-specific immunological responses over time, in particular CMI against E6 and E7 peptides corresponding to high-risk HPV types. We will also determine as to whether an association exists between the immune responses and additional HPV-related factors (persistence of infection and HPV type), and other risk factors associated with CIN such as smoking, sexual behavior, intrinsic and extrinsic hormonal factors.

描述：（根据研究者的摘要改编）流行病学研究 已经清楚地确定人乳头瘤（HPV）感染是主要风险 宫颈癌的因素。许多人都接受缓解 自发或临床干预后，而其他人，尤其是那些 表现出不足的能力，似乎开始发展侵入性癌症。这是 了解临床缓解的免疫学基础 与HPV相关的宫颈肿瘤，用于设计适当的干预策略。 我们已经确定了细胞介导的免疫（CMI）反应，该反应针对合成 E6和E7的肽，高风险类型HPV的两个主要癌蛋白 （HPV-16），在一部分参加阴道镜诊所的患者中。这些 患者接受了宫颈内部的解剖或烧蚀治疗 上皮肿瘤（CIN）至少六个月前入学。 在定向的增殖反应中观察到显着差异 对E6（P = 0.002）和E7（P <0.001）的肽对抗肽 没有CIN的细胞学或组织学证据（无疾病组）和 那些对CIN复发的组织学诊断。其他飞行员 关于E6和E7肽介导的体外细胞因子产生的研究， 显示了无病群的女性中主要的Th1-循环特征， 而疾病复发的女性表现出Th2-胞素反应。在 另一方面，任何研究小组中的女性均未表现出循环 研究中使用的E6和E7肽反应抗体。基于我们 结果显示出明显高水平的HPV肽特异性TH1反应 仅在无病患者中，我们假设HPV特异性CMI指示 反对E6和E7癌蛋白对于保护/恢复至关重要 HPV相关CIN。为了检验这一假设，我们建议进行 对高风险HPV类型呈阳性的女性的前瞻性队列研究和治疗 用于CIN循环电外科手术。我们的目标是确定HPV 可能有可能用作保护性免疫标志的肽 纳入免疫治疗和/或免疫预防疫苗制剂 反对与HPV相关的CIN。我们将评估HPV特定的模式 随着时间的推移，免疫学反应，特别是针对E6和E7肽的CMI 对应于高风险的HPV类型。我们还将确定是否 免疫反应与其他HPV相关之间存在关联 因素（感染和HPV类型的持久性）和其他风险因素 与CIN相关，例如吸烟，性行为，内在和外在的 激素因素。