近来实验表明髓系抑制细胞（MDSCs）在多种自身免疫疾病小鼠体内聚集并参与炎症免疫应答。申请者前期实验证明MDSCs在SLE患者中增多，除在体外具有抑制T细胞功能外，在体外及SLE人源化小鼠体内还具有促Th17分化的功能（Sci Transl Med. 2016: In press）。糖皮质激素（GC）是治疗SLE的主要药物，其对MDSCs功能的影响尚不明确。申请者前期实验发现SLE患者应用GC治疗后MDSCs会进一步增高。结合前期工作，申请者提出GC治疗影响MDSCs抑制T细胞及促Th17分化功能的假说。为证实该假说，本研究拟利用细胞学、免疫学等技术，通过对SLE患者GC治疗前后外周血的MDSCs进行动态检测，来揭示MDSCs在激素治疗过程中的变化规律，并在体外研究激素干预对MDSCs免疫抑制功能及促Th17分化功能的影响，进一步筛选其中起关键作用的效应分子，为临床治疗SLE提供新思路。

Recently, an increasing number of reports has been published describing the expansion of MDSCs in murine models of autoimmune diseases. Our recent studies demonstrated that circulating MDSCs, which are capable of inhibiting anti-CD3/CD28-stimulated T cell proliferation, are increased in the patients with systemic lupus erythematosus (SLE). Interestingly MDSCs from SLE patients could profoundly promote Th17 cells differentiation under Th17-polorizing conditions in vitro and in humanized SLE mice (Sci. Transl. Med. 2016: In press). Glucocorticoid is one of the main drugs for the treatment of autoimmune diseases such as SLE. At present, the effect of glucocorticoid on MDSC function and its mechanism are not completely clear. Our pilot study showed that MDSCs were increased after glucocorticoids treatment in SLE patients. Based on these previous data, we hypothesize that glucocorticoid affects not only the number of MDSCs in the circulation, but also the function of MDSCs in SLE. To test this hypothesis, we will investigate the changes of blood MDSCs (in both number and function) in SLE patients during glucocorticoid treatment. For functional analysis, we will measure the effect on Th17 differentiation and if glucocorticoid is found to affect MDSC function, we will further identify the downstream mechanism. Successful completion of the proposed studies is expected to determine the effect of glucocorticoids on MDSCs and the underlying mechanism in SLE, and provide new information and therapeutic targets for the treatment of SLE in the clinic.

髓系抑制细胞（myeloid-derived suppressor cells，MDSCs）是一群来源于骨髓的非成熟细胞，近来发现参与多发性硬化（multiple sclerosis, MS）、系统性红斑狼疮、自身免疫性肝炎等多种自身免疫疾病的炎症免疫应答。糖皮质激素（Glucocorticoid，GC）是治疗MS等自身免疫疾病的主要药物之一，其对T细胞、B细胞、DC细胞等免疫细胞的存活、活性及一些炎症生物标志物的表达均有影响。而在自身免疫性疾病中，糖皮质激素对MDSCs扩增、活性的影响尚不完全明确，亟待进一步研究。项目申请者及课题组按照研究计划，通过流式分析动态检测自身免疫疾病中糖皮质激素治疗前后MDSCs及其亚群、Treg细胞的表达，分析激素治疗前后MDSCs分泌的酶及分子变化，激素治疗后体外MDSCs的功能检测来探讨糖皮质激素对MDSCs表达和功能的影响。自身免疫疾病MS患者应用糖皮质激素治疗后，MDSCs在外周血的表达明显增多，MDSCs两个亚群--单核细胞样（(Monocytic, M）-MDSCs和粒细胞样(Granulocytic, G)-MDSCs在外周血表达均显著增高，而外周血Treg细胞的表达无变化。同时应用糖皮质激素后，患者病情评分下降，病情好转。激素治疗前后MDSCs均分泌精氨酸酶（arginase, Arg）-1酶，激素治疗后，患者血清中Arg-1酶活性增加，并且患者激素治疗后血清中的Arg-1活性和外周血MDSCs的比例呈正相关，而激素治疗前后血清中MDSCs分泌的诱导型一氧化氮合酶（inducible nitric oxide synthetase, iNOS）无明显变化。MS患者应用糖皮质激素后，扩增的MDSCs在体外具有抑制naïve CD4+T细胞的增殖，G-MDSCs亚群与M-MDSCs亚群的抑制功能无明显差别。本研究初步在自身免疫疾病MS患者中，证实了糖皮质激素对MDSCs扩增和功能的影响。研究结果表明MS患者中，GC治疗可显著扩增体内MDSCs及其亚群，增加MDSCs分泌的Arg-1的表达，扩增的MDSCs有抑制T细胞的功能，并通过其抑制功能减轻病情。这为在自身免疫疾病中深入研究糖皮质激素对MDSCs扩增及功能影响的的分子靶点、开发新的治疗药物提供了可能。