HPV SPECIFIC CELLULAR IMMUNITY IN CERVICAL INTRAEPITHELI

描述：（改编自研究者摘要）流行病学研究 已经明确确定，人乳头状瘤（HPV）感染是一个主要的风险， 宫颈癌的病因一些人经历缓解， 自发或临床干预后，而其他人，特别是那些 表现出免疫缺陷，似乎继续发展为侵袭性癌症。是 重要的是要了解临床缓解的免疫学基础 HPV相关宫颈瘤变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）反应特异性合成 来自高危型HPV的两种主要癌蛋白E6和E7的肽 （HPV-16），在参加阴道镜诊所的患者亚组中。这些 例患者接受了宫颈内切除或消融治疗 在入组本研究前至少6个月患有上皮瘤变（CIN）。 在定向的增殖反应中观察到显著差异， 针对来自E6（p=0.002）和E7（p<0.001）的肽， 无CIN的细胞学或组织学证据（无病组）， 组织学诊断为CIN复发的患者。附加导频 E6和E7肽介导的体外细胞因子产生的研究， 在无疾病组的女性中显示出占主导地位的TH 1-细胞因子谱， 而疾病复发的妇女表现出TH 2-细胞因子应答。上 另一方面，任何研究组中的女性都没有表现出循环 与研究中使用的E6和E7肽反应的抗体。基于我们 结果显示HPV-肽特异性TH 1应答的显著高水平 仅在无病患者中，我们假设HPV特异性CMI指导的 对E6和E7癌蛋白的保护/恢复是重要的 HPV相关CIN。为了验证这一假设，我们建议进行一次 高危型HPV阳性女性的前瞻性队列研究 用于宫颈上皮内瘤变。我们的目标是识别HPV 这些肽可以潜在地用作保护性免疫的标记物， 包含在免疫抑制剂和/或免疫预防性疫苗制剂中 HPV相关的CIN。我们将评估HPV特异性 随时间推移的免疫应答，特别是针对E6和E7肽的CMI 对应高危HPV类型。我们还将确定是否有 免疫反应与其他HPV相关的 因素（感染持续性和HPV类型）和其他风险因素 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.