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

通过生殖道粘膜免疫研究抗妇科癌症的免疫策略。

• 批准号: 18591823
• 负责人: KAWANA Kei
• 金额: $ 2.57万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591823/
• 关键词: gynecologic oncology; reproductive tract mucosa; mucosal lymphocyte; cervical cancer; CD1d; HPV therapeutic vaccine; 粘膜免疫; ヒトパピローマウイルス(HPV); 子宮頸部リンパ球; CD1d

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

人类下生殖道（阴道、子宫颈和阴茎尿道）的粘液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）。体内各组织对沙眼衣原体感染的易感性是完全不同的。CD Id在抗原呈递细胞（包括粘膜上皮细胞）的表面上表达，并与不变的NKT细胞特异性相互作用。不变NKT细胞在对微生物的先天性和适应性免疫应答中发挥作用。从人类下生殖道（阴道，子宫颈内膜，阴茎尿道）的永生化上皮细胞系进行了检查CD 1d的表达和CD 1d交联诱导的配体诱导的细胞因子的产生。CD 1d在正常组织中的表达在阴道中强，而在宫颈管和阴茎尿道中弱。流式细胞术显示，在阴道和阴茎尿道上皮细胞中观察到CD 1d的细胞表面表达，而在阴道和阴茎尿道上皮细胞中没有CD 1d的表达。 ...更多信息 子宫颈内细胞使用单克隆抗体交联的表面表达的CD 1d的连接促进了IL-12和IL-15，但不是IL-10，在阴道和阴茎尿道细胞中的产生。在子宫颈内细胞中未发现诱导。CD 1d介导的免疫应答基础缺陷可能导致对性传播媒介的易感性。CD 1d介导的信号转导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已通过肌内或皮下注射给药。我们在此研究了用表达HPV 16 E7的干酪乳杆菌（Lactobacillus casei，LacE 7）口服免疫小鼠后对HPV 16 E7的粘膜细胞毒性细胞免疫应答。细胞表面整合素α4β7是一种肠粘膜归巢受体，在70-80%的小鼠肠粘膜淋巴细胞中表达，在15%的人宫颈淋巴细胞中表达，表明人肠粘膜T细胞归巢于宫颈粘膜。LacE 7口服免疫可诱导产生IFNγ的Th 1细胞识别粘膜淋巴细胞中的E7 CTL表位，而单独使用载体则不能。在第8周通过加强免疫增强E7特异性Thl应答的诱导。LacE 7口服免疫诱导粘膜淋巴细胞E7特异性Th 1反应强于脾细胞，而GST-E7肌肉免疫诱导脾细胞E7特异性Th 1反应强于粘膜淋巴细胞。LacE 7口服免疫诱导E7特异性粘膜细胞毒性细胞免疫应答比肌肉注射免疫更有效。该策略可通过粘膜细胞免疫应答实现更有效的高级别CIN临床清除。少

项目成果

CDld degradation in Chlatnydia trachomatis-infected epithelial cells is the resultof both cellular and Chlamydial proteasomal activities.

沙眼衣原体感染的上皮细胞中的CD1d降解是细胞和衣原体蛋白酶体活性的结果。

• 发表时间: 2007
• 作者: Kawana K;Kawana Y;Matsumoto J;Sato H;Nagamatsu T;Fujii T;Yasugi T;Schust DJ;Taketani Y.
• 通讯作者: Taketani Y.

CDld degradation in Chlamydia trachomatis-infected epithelial cells is a result of both cellular and chlamydial proteasomal activity.

沙眼衣原体感染的上皮细胞中的CD1d降解是细胞和衣原体蛋白酶体活性的结果。

• 发表时间: 2007
• 期刊: Journal of Biological Chemistry 282
• 作者: Kawana K;Quayle AJ;Ficarra M. Ibana JA;Shen L;Kawana Y;Greene S;Yang H;Yavagal S;Marrero L;Zhang YX;Pyles RB;Blumberg RS;Schust DJ
• 通讯作者: Schust DJ

Expression of surface CDld in the extra-villous trophoblast cells of early gestation placenta is downregulated through TGF-β1 in a manner dependent on trophoblast differentiation.

早期妊娠胎盘的绒毛外滋养层细胞中表面CD1d的表达通过TGF-β1以依赖于滋养层分化的方式下调。

• 发表时间: 2008
• 期刊: Biochemical and Biophysjological Research Commumcation 371
• 作者: Matsumoto J;Kawana K;Nagamatsu T;Schust DJ;Fujii T;Sato H;Yasugi T;Kozuma S;Taketani Y
• 通讯作者: Taketani Y

Expression of surface CD Id in the extra-villous trophoblast cells of early gestation placenta is downregulated through TGF-J31 in a manner dependent on trophoblast differentiation.

早期妊娠胎盘的绒毛外滋养层细胞中表面CD1d的表达通过TGF-J31以依赖于滋养层分化的方式下调。

• 发表时间: 2008
• 期刊: Biochem Biophys Res Commun 371
• 作者: Matsumoto J;KawanaK;Nagamatsu T;Schust DJ;Fujii T;Sato H;Yasugi T;Kozuma S;Taketani Y
• 通讯作者: Taketani Y

CD Id degradation in Chlamydia trachomatis-infected epithelial cells is the result of both cellular and Chlamydial proteasomal activities.

沙眼衣原体感染的上皮细胞中的CD1d降解是细胞和衣原体蛋白酶体活性的结果。

• 发表时间: 2007
• 作者: Kawana K;Kawana Y;Matsumoto J;Sato H;Nagamatsu T;Fujii T;Yasugi T;Schust DJ;Taketani Y.
• 通讯作者: Taketani Y.