异位灶微环境调节性T细胞的功能调节及其作用机制

Endometriosis,an endocrine and chronic inflammatory disease, is a very frequent gynecological disorder in the fertile phase, which is characterized by ectopic implantation and growth of endometrium.It has seriously affected the reproductive health of fertile women because of dysmenorrhea and infertility. The retrograde menstruation occurs in almost all cycles,suggesting that the onset of endometriosis involves inefficient clearance of the mestrual efflux from the pelvis with the abnormal immune microenvironment in abdominal cavity. Previous work on primates has shown that exposure to the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with an increased prevalence and severity of endometriosis. Our previous work has found that among the endometriosis-associated cells, ESC is the main source of chemokine TECK. We have recently discovered that there is much more regulatory T cells (Treg) and higher IL-10, TGF-β1 in abdominal cavity of endometriosis compared to the non-endometriosis, and there is also higher TECK in pelvic cavity. Our studies in vitro showed that the combination of estradiol with TCDD as internal and external environment factors could promote TECK secretion by ESC which therefore has stronger chemotaxis to Treg. In this project, we will establish Treg-ESC co-culture with recombinant cytokines or corresponding antibodies to explore if the combination of estrogen with TCDD upregulates TECK secretion by ESC that results in Treg expansion, phenotype change and immunosuppression;then we will investigate whether Treg has the effect on proliferation, adhesion and invasion of ESC and its molecular mechanism. The present research may provide new strategies for endometriosis's prevention and treatment.

子宫内膜异位症（简称内异症）以子宫内膜在异位种植、生长为特征，所致的痛经、不孕等严重影响生育期妇女的生殖健康。异位子宫内膜不能被有效清除，提示盆腹腔浆膜免疫功能障碍。我们已研究发现，内异症腹腔内调节性T细胞（Treg）数目增加，且IL-10、TGF-β1的水平升高；同时具有更高水平的趋化因子TECK存在。体外研究表明，雌激素（E2）与二噁英（TCDD）作为内外环境因素协同作用，通过促进子宫内膜间质细胞（ESC）分泌TECK趋化Treg细胞。本研究将通过建立Treg与ESC细胞的共培养体系，应用重组细胞因子或特异性中和抗体，探讨在E2与TCDD作用下，ESC通过分泌TECK介导Treg扩增，调节功能表型及免疫抑制作用；进一步研究Treg对ESC增殖、粘附、侵袭的升调节作用及其分子机制；以解析异位灶微环境Treg免疫抑制功能增强，介导异位内膜的种植与生长的分子机制,最终为内异症防治提供新策略。

子宫内膜异位症（简称内异症）是一种妇科常见疾病，以子宫内膜在子宫腔以外种植、生长为特征，近年来发病率呈增高趋势。由于异位病灶造成盆腔解剖结构异常及盆腹腔微环境的改变，导致了临床常见的慢性盆腔痛、痛经、不孕不育等症状，给患者带来很多疾苦，随着人类工业化进程的发展，内异症的发病率近年有明显升高的趋势，药物加手术治疗仍是主要治疗措施，然而，复发是个很让人头疼的问题，究其原因，还是我们对于内异症的发病机制不甚了解，因此，深入解析内异症的发病机理将为我们更好的理解这种疾病并找到更有效的治疗措施奠定基础。.内异症患者的盆腹腔内局部的免疫微环境很可能发生了改变，免疫细胞功能异常不能够有效的清除异位的子宫内膜细胞，甚至帮助子宫内膜在异位种植、生长。在该项基金的资助下，我们研究发现，内异症患者较非内异症妇女腹腔液内具有更多数目的Treg细胞以及更高水平的IL-10和TGF-β1，同时具有更高水平的趋化因子TECK存在。Treg是维持免疫耐受的关键细胞，Treg的数目或功能异常与自身免疫性疾病密切相关。体外研究表明，雌激素和环境污染物二噁英（TCDD）作为内外环境因素协同作用，通过促进异位病灶关键靶细胞—子宫内膜间质细胞（ESC）分泌TECK趋化Treg细胞。TECK在将Treg细胞募集至异位病灶的同时能够促进其扩增，并调节其免疫抑制功能。我们发现Treg细胞能够在异位病灶高水平趋化因子CCL17，CCL22的作用下向病灶局部募集，且CCL17，CCL22能够促进Treg细胞分泌其重要的免疫效应功能分子TGF-β1，TGF-β1又能够与内异症患者盆腹腔高水平的促炎细胞因子IL-1β、TNF-a协同作用促进ESC表达血管形成因子IL-8和VEGF，从而有利于异位病灶血管形成。我们近期的研究还发现，异位病灶高表达TLR4，作为LPS的受体，TLR4在异位病灶的高表达促进了ESC IL-8的分泌及其受体CXCR1的表达，这种作用通过活化ESC p38/ERK信号通路实现，进而，IL-8能够通过活化FAK信号通路增强ESC的侵袭和增殖。ESC亦能够促进Treg细胞转录因子Foxp3及表面分子CTLA-4的表达。ESC能够明显促进Treg细胞分泌TGF-β1及其转录因子Stat3和Stat6的表达。我们的研究为以Treg细胞为靶点进行子宫内膜异位症的免疫治疗提供了新思路。