髓系抑制细胞对Th17/Treg平衡的影响及其在系统性红斑狼疮中的应用

Systemic lupus erythematosus (SLE) is a remarkably complex and heterogeneous systemic autoimmune disorder in which the interaction between genetic and environmental factors leads to breakdown of self-tolerance eventually triggering autoimmune response. An imbalance between Th17 and regulatory T cells (Treg) subsets has been observed in SLE patients and animal models. Myeloid-derived suppresor cells (MDSC) are a novel population with immune suppressive function, however, our preliminary studies showed that the percentage of MDSC was.significantly higher in peritpheral blood mononuclear cells and the level of arginase 1 (Arg1) was elevated in serum compared with healthy volunteers, and both of them were positively corrrelated with disease activity SLEDAI and Th17 cells. inhibiting Arg1 or depleting MDSC remarkably alleviate tissue damage in kidney which was induced by adotively transferring PBMC from SLE patients into NOD/SCID mice. Therefore we hypotheized that MDSC-derived Arg1 promote Th17 differentiation to break the balance between Th17 and Treg, which play a vital role in the pathagenesis of SLE. Here, we will explore the effect and molecular mechanisms of Arg1 on the development of SLE by establishing conditional knockout Arg1 MRL/lpr mice and observe the changes of number and dunction of MDSC,Th17 and Treg. At the same time, we also clarify whether it is feasiable for MDSC to prevent SLE by adoptively transfer Arg1 deficient MDSC to SLE mice. This research.will expand our knowledge on how Arg1 influence Th17/Treg balance in SLE and on how we may therapeutically target MDSC in order to restore tolerance.

系统性红斑狼疮（SLE）是遗传、环境等多因素导致自身免疫耐受缺失引起的自身免疫病，SLE患者和动物模型均表明Th17/Treg平衡失调；髓系抑制细胞（MDSC）是一类新的免疫调节细胞，但申请人预实验表明SLE患者外周血髓系抑制细胞（MDSC）和精氨酸酶1（Arg1）显著增加，并与疾病活动及Th17水平相关，抑制Arg1或剔除MDSC显著减轻PBMC转输引起的肾脏病变。因此，我们假设：MDSC来源Arg1促进Th17分化打破Th17/Treg平衡，是SLE发病的重要原因。申请人将建立MDSC条件性Arg1敲除SLE小鼠，观察对SLE疾病的影响，并通过MDSC抑制功能、Th17/Treg数量和功能的变化，阐明MDSC通过Arg1影响SLE的分子机制，并观察Arg1敲除MDSC过继回输对SLE的治疗效果。本研究从全新的视角观察Th17/Treg影响SLE的发病机制，为临床治疗SLE提供新的策略。

系统性红斑狼疮（Systemic lupus erythematosus，SLE）是典型的全身性自身免疫病，几乎所有器官都可在SLE疾病进展过程中受累。同时，由于病程长、多器官、多系统的损害等特点，导致患者致残率较高。目前SLE治疗通过长期应用糖皮质激素等免疫抑制剂来缓解症状，具有严重的副作用。因此，进一步探索SLE的发病机制，并开发有效、合理的临床治疗策略，对提高SLE治疗水平，改善患者生活质量具有重要的意义。.项目申请者及课题组在前期研究中发现MDSC分泌Arg-1通过GCN2/RORt促进Th17分化，从而加重SLE活动程度。本项目按照预期计划构建了基因工程小鼠，利用不同的模型及患者，对其分子机制进行了深入探讨，并初步评价了以MDSC 和 Arg-1为基础的治疗策略。.研究结果显示应用降植烷诱导的SLE肾炎小鼠模型，发现Arg-1通过miR322/TGF-/SMAD3通路促进Th17和Treg分化，体内应用miR322 inhibitor转染能显著减少Th17以及缓解疾病进展。在膜性肾病患者中MDSC也有促Th17分化的作用，对Th2却有明显抑制作用，但不影响Treg的比例。在DSS诱导的肠炎模型中，我们发现MDSC通过 Arg-1促进IL-17A产生抑制IL-17F，从而对肠道起保护作用，这与SLE肾病及膜性肾病不同；天然中药成分橡黄素能够通过ESR/STAT3通路扩增MDSC及Arg-1分泌，促进IL-17A，但抑制IL-17F分泌，从而起保护肠道作用，缓解炎症。.研究结果表明本项目成功构建了相关基因工程小鼠，明确了MDSC通过Arg-1促进Th17分化的分子机制，初步建立了以MDSC为基础的自身免疫病的治疗策略。