Myeloid-derived Suppressor Cells in Autoimmune Arthritis

自身免疫性关节炎中的骨髓源性抑制细胞

• 批准号: 8227601
• 负责人: KATALIN MIKECZ
• 金额: $ 20.66万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-22 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8227601
• 关键词: Adoptive Transfer; Affect; Animal Disease Models; Animal Model; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Arginine; Arthritis; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Autologous; Autologous Bone Marrow Transplantation; B-Lymphocytes; Blood; Blood Circulation; Bone Marrow; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Proliferation; Cell physiology; Cells; Characteristics; Chronic; Clinical; Clinical Management; Clinical Trials; Coculture Techniques; Commit; Consent; Consumption; Data; Dendritic Cells; Development; Diagnostic; Disease; Exhibits; Experimental Autoimmune Encephalomyelitis; Foundations; Future; Goals; Greater sac of peritoneum; Growth Factor; Helper-Inducer T-Lymphocyte; Hematopoietic stem cells; Homeostasis; Human; ITGAM gene; Immune; Immune response; Immune system; Immunization; Immunosuppression; Immunosuppressive Agents; In Vitro; Inbred BALB C Mice; Individual; Injury; Integrins; Investigation; Joints; Location; Malignant Neoplasms; Mediating; Methods; Modeling; Mus; Myelogenous; Myeloid Cells; Nitric Oxide; Nitric Oxide Synthase; Organ; Pain; Patients; Pattern; Peroxonitrite; Pharmaceutical Preparations; Phenotype; Pilot Projects; Population; Population Heterogeneity; Production; Proteoglycan; Reactive Oxygen Species; Recruitment Activity; Refractory Disease; Regulatory T-Lymphocyte; Reporting; Resolution; Rheumatoid Arthritis; Sampling; Self Tolerance; Site; Spleen; Suppressor-Effector T-Lymphocytes; Symptoms; Synovial Fluid; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Therapeutic procedure; Tissues; Up-Regulation; arginase; autoimmune arthritis; autoreactive T cell; base; cytokine; cytotoxic; human NOS2A protein; in vivo; insight; joint destruction; joint injury; mouse model; novel therapeutic intervention; peripheral blood; prevent; response; restoration; success; tool; trafficking; translational approach; treatment strategy; tumor

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.

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。 公共卫生相关性：风湿性关节炎（RA）是一种关节的自身免疫性疾病，影响近1%的人口，并导致疼痛的关节破坏。并不是所有的RA患者都对目前的药物有反应，因此需要新的治疗方法。在RA小鼠模型中，我们发现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可以抑制免疫系统的过度激活，并在关节炎对小鼠造成不可逆的关节损伤之前促进关节炎的消退。我们还将鉴定在RA患者中具有相似治疗潜力的细胞群。