次级淋巴器官微环境对MDSC及相关细胞的调控及其在诱导异基因造血干细胞移植免疫耐受中的作用

研究证据表明，次级淋巴器官（SLO）是诱导免疫耐受发生的重要场所，这种现象可发生于肿瘤和异体器官移植诱导的免疫耐受，其MDSC及其相关细胞可能起重要作用。该研究拟确定SLO中微环境FRC为诱导免疫耐受的中心环节，不仅直接抑制T细胞增殖和活化，也可促使MDSC及相关细胞生成发挥对T细胞活化的抑制作用。应用已建立的GVHD模型和阻断T细胞趋化使T细胞滞留于SLO而预防GVHD模型证明T细胞在SLO中的活化程度低于GVHD靶器官中T细胞活化程度，靶向阻断趋化因子受体使T细胞滞留于SLO可进一步抑制T细胞活化，这种免疫抑制作用与MDSC生成有关。本研究拟通过对比分析SLO和GVHD靶器官免疫细胞和免疫相关分子的差异，初步阐明SLO诱导免疫耐受机制。该研究的意义在于确定在allo-HSCT条件下SLO是免疫耐受诱导器官，FRC及其诱导扩增的MDSC及其相应细胞是诱导免疫耐受的中心环节。

More and more evidences demonstrated that secondary lymphatic organs (SLOs) are important sites for immune tolerance induction. This phenomenon not only take place in tumor-induced but also in allograft-induced immune tolerance.MDSC and its related antigen-presenting cells may be important in this process. In this study, we will probe the microenvironment in SLOs, especially fibroblastic reticular cells (FRC),play a central role in immune tolerance. It not only directly inhibit proliferation and activation of conventional T cells, but it may promote the expension of MDSC and its related cells in SLOs. Also, FRC might promote the expression of checkpoint molecular PD-L1/2 and other immune inhibitory moleculars on antigen-presenting cells which may induce T cell tolerance. We will try to conform that T cells in SLOs is less activated than that in GVHD organ such as liver through a murine GVHD model. Our previous studies showed that blockade of chemokine receptors could lead to retention of donor-derived T cells to SLOs and attenuate murine acute GVHD. We try to use established murine GVHD model and T cell SLO retention model by blockage of chemokine receptors to illuminate the cellular and molecular mechanisms underlying SLO-induced immune tolerance through comparative study of immune cells and immune-related molecular in SLOs and GVHD-targeted organs. Though these series studies, we might confirm that SLOs are immune tolerance-induced organs under the condition of allo-HSCT，FRC as well as MDSC and its related cells expended from myeloid progenitor cells in graft may play a central role in inducing immune tolerance.