CELLULAR TRAFFICKING TO INFLAMED FEMALE GENITAL MUCOSA

女性在慢性感染沙眼衣原体或淋球菌后，通常会出现盆腔炎、输卵管不孕和异位妊娠。由于衣原体感染的隐匿性，已经努力开发一种疫苗，这种疫苗将加强对生物体的清除，避免慢性感染，进而消除生殖障碍。根据共同粘膜免疫系统的理论，当淋巴细胞在远处的粘膜表面被激活时，淋巴细胞被预测为向生殖器粘膜募集。对小鼠生殖器衣原体感染的研究表明，在其他粘膜部位免疫后，生殖器粘膜中发现了效应性T细胞，需要T细胞来保护。目前，T细胞在其他粘膜表面传递抗原后向生殖器粘膜迁移的程度尚不清楚。在这项提案中，我们将检验这样一个假设，即在炎症过程中，在其他粘膜表面激活的T细胞可以被招募到生殖器粘膜。由于T细胞通常不会被招募到生殖器粘膜，我们将研究感染沙眼衣原体或淋病奈瑟菌的女性作为模型来检验这一假设。这项提议的具体目的是：1)开发一种方法，利用性传播疾病(STD)患者在体内识别属于生殖器粘膜的T细胞。2)确定远距离粘膜免疫是否促进T细胞向生殖器粘膜的转运。我们将使用流式细胞仪技术确定STD感染志愿者宫颈内T细胞和IFNGamma+外周血细胞上归巢受体的表达模式(肠道粘膜、其他粘膜和非粘膜)。我们还将利用活组织的体外输卵管培养和免疫组织学染色来确定在STD感染期间女性生殖器粘膜中诱导了哪些黏附分子。候选归巢受体：黏附分子对将在生殖器粘膜黏附试验中进行测试。通过不同途径接种伤寒沙门氏菌疫苗后，将监测志愿者生殖器粘膜归巢T细胞和成熟树突状细胞的频率。这些研究将有助于设计在女性生殖器粘膜中提供持久免疫力的STD疫苗。

Pelvic inflammatory disease, tubal infertility and ectopic pregnancy typically emerge in females after a chronic infection with Chlamydia trachomatis or Neisseria gonorrhoeae. Due to the insidious nature of chlamydial infections, efforts have been put forth to develop a vaccine that would enhance the clearance of organisms, avoid chronic infections, and in turn, eliminate reproductive disability. Based on the theory of a common mucosal immune system, lymphocyte recruitment to the genital mucosa is predicted to occur when lymphocytes are activated at distant mucosal surfaces. Studies of Chlamydia genital infection in the mouse have shown that T cells are required for protection and effector T cells are found in the genital mucosa following immunization at other mucosal sites. Currently, the degree of T cell migration to the genital mucosa following antigen delivery at other mucosal surfaces is unknown in humans. In this proposal, we will test the hypothesis that T cells activated at other mucosal surfaces can be recruited to the genital mucosa during an inflammatory process. Since T cells are not commonly recruited to the genital mucosa, we will study females infected with C. trachomatis or N. gonorrhoeae as a model to test this hypothesis. The specific aims of this proposal are to: 1) Develop a method to identify T cells that home to the genital mucosa in vivo using individuals with a sexually transmitted disease (STD). 2) Determine if immunization by a distant mucosal route promotes T cell trafficking to the genital mucosa. We will define the homing receptor expression pattern (gut mucosal, other mucosal, non-mucosal) on endocervical T cells and IFNgamma+ peripheral blood cells from STD infected volunteers using flow cytometric techniques. We will also determine which adhesion molecules are induced within the female genital mucosa during STD infection by utilizing an in vitro fallopian tube culture of living tissue followed by immunohistological staining. The candidate homing receptor: adhesion molecule pairs will be tested in a genital mucosa adhesion assay. The frequency of genital mucosa homing T cells and mature dendritic cells will be monitored in volunteers following immunization with Salmonella typhi vaccine via different routes. These studies will contribute to the design of STD vaccines that would provide lasting immunity in the female genital mucosa.