Myeloid-derived Suppressor Cells in Autoimmune Arthritis

描述（由申请人提供）：将生物制剂（包括抗细胞因子和B细胞耗竭抗体）引入治疗药物库，已导致类风湿性关节炎（RA）（一种影响滑膜关节的衰弱性自身免疫性疾病）的临床管理取得相当大的进展。然而，相当一部分RA患者对生物制剂的反应不充分，因此需要新的治疗方法。来自临床试验的数据表明，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的临床成功主要归因于造血干细胞介导的免疫稳态的恢复和通过诱导免疫抑制调节性T细胞（T细胞）的自身耐受。我们假设先天性免疫细胞如髓源性抑制细胞（MDSC）可能存在于患者骨髓（BM）中并从患者骨髓（BM）释放到循环中，有助于ABMT接受者中RA症状的改善。我们的假设是基于以下观察结果：MDSC存在于患有蛋白聚糖（PG）诱导的关节炎（PGIA）的小鼠中，这是一种诱导型自身免疫性RA动物模型，并且患有PGIA的小鼠在ABMT后也显示出显著改善。在初步研究中，我们已经确定了关节炎小鼠的滑液，骨髓和脾脏中的先天性免疫细胞，其表现出“不成熟”的骨髓细胞表型和对体外活化T淋巴细胞的显著抑制活性，部分通过抑制树突状细胞成熟为有效的抗原呈递细胞。能够拮抗T细胞活化的MDSC在荷瘤个体中积累并抑制抗肿瘤免疫应答。尽管具有抑制自身免疫潜力的MDSC可能存在于RA和RA动物模型中，但迄今为止尚未报道此类细胞在自身免疫性关节炎个体中的存在。目的1中描述的研究将鉴定在PGIA小鼠不同解剖部位积累的MDSC亚群，并分析在关节炎诱导和进展后MDSC的运输模式、抑制活性和抑制机制。在目标2中，我们将通过在PGIA发展之前或之后将这些细胞从关节炎小鼠转移到同基因动物来测试MDCS预防或抑制疾病的潜力。尽管在概念上类似于ABMT，但这种治疗将被简化为MDSC的过继转移，即，纯化的先天免疫细胞群，其具有破坏受体中自身反应性T细胞活化的潜力。作为一种转化方法（目的3），我们建议在RA患者的血液和滑液中识别和功能表征MDSC，并确定是否可以通过体外细胞富集策略产生治疗有用量的MDSC。我们的研究结果应该提供的基础和实验框架，未来的调查MDSC在自身免疫性关节炎的功能，也可能打开一个新的方向，对发展自体MDCS转移为基础的治疗策略在RA。

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.