IL-22R/STAT3通路调控Aire对异基因造血干细胞移植中枢免疫耐受的作用和机制研究

Immune rejection is still the major obstacle for the recipient survival and living quality after allogeneic haematopoietic stem cell transplantation. However, it is hard to resolve the issue only by T cell function inhibition or peripheral immune tolerance induction. Thymus play very important role in T cells central immune tolerance. Recipients thymic epithelial cell were seriously damaged after allo-HSCT, which leading to the donor deriving self-reactive T cells output inducing long time immune rejection. Thus, repairmen of TEC structure and function are the key step for the establishment of central immune tolerance. Our previous study confirmed that IL-22 was an important factor to promote TEC repair, and further study found that IL-22 and its downstream signal IL-22R/STAT3 played positive regulating role to Aire which was a central immune tolerance moderator. In this project, based on the evidence of IL-22R/STAT3 induction to central immune tolerance, we will further explore their role and potential mechanism to Aire expression. If succeed, it will help to broaden the perspective of new strategies to prevent immune rejection, and more theoretical information to be given on the immune reconstruction delay and immune rejection disease.

异基因造血干细胞移植（allo-HSCT）后免疫排斥的发生，仍严重影响患者生存和生活质量。然而，单纯抑制T细胞或诱导外周免疫耐受的策略难以从根本上解决此问题。胸腺是诱导T细胞中枢免疫耐受形成的重要器官，而移植后受者胸腺上皮细胞（TEC）严重受损，供者源自身反应性T细胞输出外周是诱导长期免疫排斥发生的根本原因。因此，TEC结构和功能修复是实现中枢免疫耐受的关键环节。我们前期实验证实IL-22是促进TEC修复的重要因子，进一步研究发现IL-22及其下游IL-22R/STAT3信号通路对中枢免疫耐受的调节子Aire具有正向调控作用。本课题拟在明确IL-22R/STAT3调控中枢免疫耐受的基础上，探索其对Aire表达调控的影响，并深入解析其调控Arie表达的机理。若获成功，将拓宽人们探索免疫排斥防治策略的视野，为移植后胸腺依赖的免疫重建延迟和免疫排斥型疾病的防治提供理论依据。

异基因造血干细胞移植（allo-HSCT）后细胞免疫重建迟缓是其发挥疗效的不利因素。移植预处理常导致胸腺功能严重受损，同时胸腺也可成为移植物抗宿主病（GVHD）的靶器官。移植后胸腺修复的机制尚不清楚，促进胸腺修复是否有利于免疫耐受重建也不甚明确。我们在小鼠allo-HSCT模型和胸腺损伤模型中，研究了IL-22促进胸腺修复的机制及其对移植后免疫耐受重建的影响。结果发现：① Allo-HSCT受者体内IL-22+细胞主要来源于供者T细胞，仅少量胸腺和结肠内的IL-22+细胞来源于受者自身。受者体内分泌IL-22的T细胞集中分布在胸腺和结肠组织中；② 供者T细胞来源的IL-22可刺激胸腺上皮细胞（TEC）的增殖，加速胸腺修复，供者T细胞来源的IL-22具有减轻慢性皮肤GVHD的效应；③ 受者IL-22的缺失可导致急性GVHD程度的加重，受者巨噬细胞来源的IL-22具有抑制同种异型反应的作用；④ 在allo-HSCT中应用外源性IL-22可通过激活转录因子STAT3上调AIRE的mRNA和蛋白表达水平，促进受者胸腺修复并促进胸腺阴性选择功能的恢复；⑤ IL-22通过STAT3/Mcl-1通路促进小鼠胸腺受损后胸腺上皮细胞的增殖，加速胸腺修复并减轻慢性GVHD；⑥ JAK/STAT抑制剂ruxolitinib通过降低Fgfr2，Egfr，Igf1r和Rank的表达水平阻断胸腺受损后的自我修复功能。我们的研究表明：IL-22及其下游的JAK/STAT通路是介导胸腺修复的重要机制，allo-HSCT中应用IL-22可促进胸腺修复和免疫耐受的形成。