HPV SPECIFIC CELLULAR IMMUNITY IN CERVICAL INTRAEPITHELI

描述：(改编自《调查者摘要》)流行病学研究 已明确确定人类乳头状瘤(HPV)感染是一种主要风险 宫颈癌的致病因素。许多人要么得到缓解，要么 自发或在临床干预后，而其他人，特别是那些 表现出免疫缺陷，似乎会发展为浸润性癌症。它是 重要的是要了解临床缓解的免疫学基础 人乳头瘤病毒相关宫颈肿瘤的干预策略的设计。 我们已经确定了针对人工合成的细胞介导的免疫(CMI)反应 高危型HPV的两个主要癌蛋白E6和E7的多肽 (HPV-16)，在镜检查诊所就诊的患者中。这些 2例宫颈内瘤行切除或消融治疗 在参加研究前至少六个月发生上皮瘤变(CIN)。 在定向的增殖反应中观察到显著的差异 针对女性之间E6(p=0.002)和E7(p&lt；0.001)的多肽 无细胞学或组织学证据的CIN(无病组)和 组织学诊断为CIN复发的患者。额外的飞行员 E6和E7多肽介导的体外细胞因子产生研究， 在无疾病组的女性中显示出主要的TH1细胞因子谱， 而疾病复发的女性表现出TH2细胞因子反应。论 另一方面，任何研究组的女性都没有表现出血液循环 抗体与研究中使用的E6和E7多肽发生反应。基于我们的 结果显示显著高水平的HPV多肽特异性TH1反应 仅在无疾病的患者中，我们假设HPV特异性CMI 抗E6和E7癌蛋白对于保护/恢复 HPV相关的宫颈上皮内瘤变。为了检验这一假设，我们建议进行一项 高危型HPV阳性和治疗后妇女的前瞻性队列研究 对于CIN，采用环形电外科手术。我们的目标是确定HPV 可以潜在地作为保护性免疫的标志的多肽 包括在免疫治疗和/或免疫预防疫苗配方中 抗HPV相关的CIN。我们将评估HPV特异性感染的模式 随着时间的推移的免疫反应，特别是针对E6和E7多肽的CMI 与高危HPV类型相对应。我们还将决定是否会有一个 免疫反应和其他与HPV相关的病毒之间存在关联 因素(持续感染和HPV类型)和其他危险因素 与CIN相关，如吸烟、性行为、内在和外在 荷尔蒙因素。

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.