Myeloid-derived Suppressor Cells in Autoimmune Arthritis

描述(由申请人提供)：将包括抗细胞因子和B细胞耗尽抗体在内的生物制剂引入治疗武器库，在类风湿性关节炎(RA)的临床治疗方面取得了相当大的进展，RA是一种影响滑膜关节的衰弱自身免疫性疾病。然而，相当大比例的类风湿关节炎患者对生物制剂没有足够的反应，对于这些患者，需要新的治疗方法。临床试验数据表明，许多患有严重难治性疾病的RA患者对自体骨髓移植(ABMT)反应良好。ABMT的临床成功主要归功于造血干细胞通过诱导免疫抑制调节性T细胞(Tregs)恢复免疫稳态和自身耐受。我们推测，骨髓来源的抑制细胞(MDSCs)等先天免疫细胞可能存在于患者的骨髓(BM)中，并从患者的骨髓(BM)释放到循环中，有助于改善ABMT受者的RA症状。我们的假设是基于观察到在蛋白多糖(PG)诱导的关节炎(PGIA)小鼠中存在MDSCs，PGIA是RA的一种可诱导的自身免疫动物模型，并且PGIA小鼠的ABMT也显示出显著的改善。在初步研究中，我们在关节炎小鼠的滑液、骨髓和脾中发现了天然免疫细胞，它们在体外表现出一种未成熟的髓系细胞表型和对激活的T淋巴细胞的强烈抑制活性，部分是通过抑制树突状细胞成熟为强大的抗原提呈细胞。能够对抗T细胞活化的MDSCs在肿瘤患者体内积聚，并抑制抗肿瘤免疫反应。尽管具有抑制自身免疫潜能的MDSCs可能存在于RA和RA动物模型中，但迄今为止，在自身免疫性关节炎患者中还没有这种细胞的存在。目标1中描述的研究将确定在PGIA小鼠不同解剖部位积累的MDSC亚群，并分析MDSC的运输模式、抑制活性以及在关节炎发生和发展过程中的抑制机制。在目标2中，我们将通过在PGIA发生之前或之后将MDCSs从关节炎小鼠转移到同基因动物来测试MDCSs预防或抑制疾病的潜力。虽然在概念上与ABMT相似，但这种治疗将被简化为MDSCs的过继转移，即纯化的天然免疫细胞群体，有可能颠覆受体体内自身反应性T细胞的激活。作为一种翻译方法(目标3)，我们建议在RA患者的血液和滑液中鉴定和鉴定MDSCs，并确定是否可以通过体外细胞浓缩策略产生治疗有用的MDSCs数量。我们的研究结果将为未来研究MDSC在自身免疫性关节炎中的作用提供基础和实验框架，并可能为开发基于自体MDCS转移的RA治疗策略开辟新的方向。 公共卫生相关性：类风湿性关节炎(RA)是一种关节自身免疫性疾病，影响近1%的人类人口，并导致疼痛的关节破坏。并不是所有的类风湿关节炎患者对目前的药物都有反应，因此需要新的治疗方法。在类风湿性关节炎的小鼠模型中，我们确定了一种独特的细胞群，具有抑制自身免疫性疾病的潜力。在这项探索性研究中，我们将确定这些细胞是否能够抑制免疫系统的过度激活，并在关节炎造成不可逆转的关节损伤之前促进关节炎的消退。我们还将确定类风湿关节炎患者中具有类似治疗潜力的细胞群。

DESCRIPTION (provided by applicant): Introduction of biologic agents, including anti-cytokine and B cell-depleting antibodies, into the therapeutic arsenal has resulted in considerable progress in the clinical management of rheumatoid arthritis (RA), a debilitating autoimmune disease affecting the synovial joints. However, a significant proportion of patients with RA do not respond adequately to biologic agents, and for those, novel therapeutic approaches are needed. Data from clinical trials indicate that many RA patients with severe treatment-refractory disease respond well to autologous bone marrow transplantation (ABMT). The clinical success of ABMT is primarily attributed to hematopoietic stem cell-mediated restoration of immune homeostasis and self tolerance through induction of immunosuppressive regulatory T cells (Tregs). We hypothesize that innate immune cells such as myeloid- derived suppressor cells (MDSCs) that are likely present in, and released from, the patients' bone marrow (BM) to the circulation, contribute to the improvement of RA symptoms in ABMT recipients. Our hypothesis is based on the observations that MDSCs are present in mice with proteoglycan (PG)-induced arthritis (PGIA), an inducible autoimmune animal model of RA, and that mice with PGIA also show significant improvement upon ABMT. In preliminary studies we have identified innate immune cells in the synovial fluid, BM, and spleens of arthritic mice, which exhibit an "immature" myeloid cell phenotype and profound suppressor activity toward activated T lymphocytes in vitro, partly by inhibiting the maturation of dendritic cells into potent antigen presenting cells. MDSCs that are able to antagonize T cell activation accumulate in tumor-bearing individuals and suppress anti-tumor immune responses. Although MDSCs with a potential to suppress autoimmunity likely exist in RA and animal models of RA, the presence of such cells in individuals with autoimmune arthritis has not been reported to date. The studies described in Aim 1 will identify MDSC subsets that accumulate at distinct anatomical sites in mice with PGIA, and analyze the trafficking patterns, suppressor activity of MDSCs, and the mechanisms of suppression, upon the induction and progression of arthritis. In Aim 2, we will test the potential of MDCSs to prevent or suppress disease by transferring these cells from arthritic mice to syngeneic animals before or after the development of PGIA. Although conceptually similar to ABMT, this treatment will be reduced to the adoptive transfer of MDSCs, i.e., purified populations of innate immune cells that have the potential to subvert the activation of autoreactive T cells in the recipient. As a translational approach (Aim 3), we propose to identify and functionally characterize MDSCs in the blood and synovial fluid of RA patients, and determine whether therapeutically useful quantities of MDSCs can be generated through an in vitro cell enrichment strategy. The results of our studies should provide the foundation and experimental framework of future investigations into MDSC function in autoimmune arthritis, and may also open a new direction toward the development of autologous MDCS transfer-based treatment strategies in RA. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is an autoimmune disease of the joints affecting nearly 1% of the human population and causing painful joint destruction. Not all RA patients respond to current medications, and there is a need for novel therapeutic approaches. In a mouse model of RA, we identified a unique cell population with a potential to suppress autoimmune disease. In this exploratory study we will determine whether such cells can inhibit the superfluous activation of the immune system and promote the resolution of arthritis before it can cause irreversible joint damage in mice. We will also identify cell populations with similar therapeutic potential in patients with RA.