Studies on immunological strategy against gynecological cancers through mucosal immunity of reproductive tract mucosa.

人类下生殖道（阴道、宫颈和阴茎尿道）粘膜上皮暴露于性传播微生物，包括沙眼衣原体和人乳头瘤病毒（HPV）。每种组织对沙眼衣原体感染的体内易感性是非常不同的。cdid在包括粘膜上皮细胞在内的抗原呈递细胞表面表达，并与不变的NKT细胞特异性相互作用。不变的NKT细胞在对微生物的先天和适应性免疫反应中发挥作用。我们检测了来自人类下生殖道（阴道、宫颈内和阴茎尿道）的永生化上皮细胞系的CD1d表达和CD1d交联诱导的配体诱导的细胞因子产生。CD1d在正常组织中的表达在阴道中较强，在宫颈内和阴茎尿道中较弱。流式细胞术显示CD1d在阴道和阴茎尿道上皮细胞表面表达，而在阴道和阴茎尿道上皮细胞表面不表达。使用单克隆抗体交联连接表面表达的CD1d可促进阴道和阴茎尿道细胞中IL-12和IL-15的产生，但不能促进IL-10的产生。宫颈内细胞未见诱导作用。cd1介导的免疫反应的基础缺乏可能导致对性传播媒介的易感性。cd1介导的信号减少可能有助于沙眼衣原体和HPV逃避先天免疫细胞的检测。以前针对人乳头瘤病毒（HPV） E6/E7致癌蛋白的治疗性疫苗是肌肉注射或皮下注射。我们在此研究了表达HPV16E7 （LacE7）的干酪乳杆菌口服免疫小鼠对HPV16E7的粘膜细胞毒免疫反应。细胞表面整合素α4β7是一种肠黏膜归巢受体，在70-80%的小鼠肠黏膜淋巴细胞中表达，在15%的人宫颈淋巴细胞中表达，表明肠黏膜T细胞在人宫颈粘膜中归巢。口服LacE7免疫诱导产生ifn γ的Th1细胞识别粘膜淋巴细胞中的E7 CTL表位，而单独用载体免疫则没有。第8周增强免疫可增强e7特异性Thl应答的诱导。LacE7口服免疫诱导粘膜淋巴细胞的e7特异性Thl反应强于脾细胞，而GST-E7肌内免疫诱导脾细胞的e7特异性Thl反应强于粘膜淋巴细胞。LacE7口服免疫比肌内免疫更能引起e7特异性粘膜细胞毒免疫反应。该策略可获得更有效的临床清除高级别CIN与粘膜细胞免疫反应。少

Mucosal epithelia of human lower reproductive tract (vagina, cervix, and penile urethra) are exposed to sexually transmitted microbes, including Chlamydia trachomatis and Human papillomavirus (HPV). The in vivo susceptibility of each tissue to infection by Chlamydia trachomatis is quite distinct. CD Id is expressed on the surface of antigen presenting cells, including mucosal epithelial cells, and interacts specifically with invariant NKT cells. Invariant NKT cells play a role in both innate and adaptive immune responses to microbes. Immortalized epithelial cell lines from the human lower reproductive tract (vagina, endocervix, and penile urethra) were examined for CD1d expression and for ligand-induced cytokine production induced by CD1d crosslinking. CD1d expression in normal tissues was strong in the vagina but weak in endocervix and penile urethra. Flow cytometry revealed that cell-surface expression of CD1d was observed in the vaginal and penile urethral epithelial cells but not e … More ndocervical cells. Ligation of surface-expressed CD1d using monoclonal antibody crosslinking promoted IL-12 and IL-15, but not IL-10, production in vaginal and penile urethral cells. No induction was demonstrated in endocervical cells. Basal deficiency in CD1d-mediated immune responsiveness may result in susceptibility to sexually transmitted agents. Decreased CD1d-mediated signaling may help Chlamydia trachomatis and HPV evade detection by innate immune cells.Previous therapeutic vaccines against human papillomavirus (HPV) E6/E7 oncogenic proteins have been administered intramuscularly or subcutaneously. We here addressed mucosal cytotoxic cellular immune response to HPV16 E7 on oral immunization of mice with Lactobacillus casei expressing HPV16E7 (LacE7). Cell-surface Integrin α4β7, a gut mucosal homing receptor, was expressed in 70-80% of murine intestinal mucosal lymphocyte and expressed in 15% of human cervical lymphocyte indicating that intestinal mucosal T cell homes to cervical mucosa in human. Oral immunization with LacE7 elicited IFNγ-producing Th1 cells recognizing E7 CTL epitope in the mucosal lymphocyte whereas that with vehicle alone did not. The induction of E7-specific Thl response was enhanced by boost immunization at week 8. Oral immunization with LacE7 induced E7-specific Thl response in the mucosal lymphocyte more strongly than splenocyte whereas intramuscularly immunization with GST-E7 did in splenocyte more strongly than mucosal lymphocyte. Oral immunization with LacE7 elicited E7-specific mucosal cytotoxic cellular immune response more effectively than intramuscularly immunization. This strategy may achieve more effective clinical clearance of high-grade CIN with mucosal cellular immune responses. Less