Kavousanaki Melina, Makrigiannakis Antonis, Boumpas Dimitrios, Verginis Panayotis
University of Crete, Crete, Greece.
Arthritis Rheum. 2010 Jan;62(1):53-63. doi: 10.1002/art.25037.
Reestablishing immune tolerance and long-term suppression of disease represent major therapeutic goals in rheumatoid arthritis (RA). Dendritic cells (DCs) likely play a central role in such regulation via the expansion and/or induction of Treg cells. The present study was undertaken to explore the contribution of DCs to the development of Treg cells in a human autoimmune disease setting.
DC subsets were characterized by flow cytometry in the peripheral blood and synovial fluid of patients with RA. Proliferation of and cytokine release by naive CD4+CD25- T cells were measured in cocultures of these cells with DCs from patients with RA and healthy controls. The suppressive capacity of DC-polarized T cells was explored in vitro by a standard suppression assay.
Only very low numbers of both plasmacytoid DCs (CD303+) and myeloid DCs (CD1c+) were present in the peripheral blood of patients with active RA. In contrast, patients with therapy-induced remission of RA exhibited higher numbers of circulating plasmacytoid DCs. Mature plasmacytoid DCs from RA patients with low disease activity, but not those from healthy controls, expressed high levels of indoleamine 2,3-dioxygenase and promoted the differentiation of allogeneic naive CD4+CD25- T cells into interleukin-10-secreting Treg cells, or Tr1 cells, that showed poor proliferation in vitro. Importantly, these plasmacytoid DC-primed Treg cells potently suppressed the proliferation of autologous naive CD4+ T cells, in a dose-dependent manner.
These results demonstrate, for the first time, that human plasmacytoid DCs may be educated within the rheumatoid microenvironment to acquire a tolerogenic phenotype. Modulation of the immune response by plasmacytoid DCs might provide novel immune-based therapies in autoimmunity and transplantation.
重建免疫耐受和长期抑制疾病是类风湿关节炎（RA）的主要治疗目标。树突状细胞（DCs）可能通过Treg细胞的扩增和/或诱导在这种调节中发挥核心作用。本研究旨在探讨DCs在人类自身免疫性疾病背景下对Treg细胞发育的贡献。
通过流式细胞术对RA患者外周血和滑液中的DC亚群进行表征。在这些细胞与RA患者和健康对照的DC共培养物中，测量初始CD4+CD25-T细胞的增殖和细胞因子释放。通过标准抑制试验在体外探索DC极化T细胞的抑制能力。
活动期RA患者外周血中仅存在极少量的浆细胞样DCs（CD303+）和髓样DCs（CD1c+）。相比之下，经治疗诱导缓解的RA患者循环浆细胞样DCs数量较高。疾病活动度低的RA患者的成熟浆细胞样DCs，而非健康对照的成熟浆细胞样DCs，表达高水平的吲哚胺2,3-双加氧酶，并促进同种异体初始CD4+CD25-T细胞分化为分泌白细胞介素-10的Treg细胞或Tr1细胞，这些细胞在体外增殖能力较差。重要的是，这些浆细胞样DC启动的Treg细胞以剂量依赖的方式有效抑制自体初始CD4+T细胞的增殖。
这些结果首次证明，人类浆细胞样DCs可能在类风湿微环境中被诱导获得致耐受性表型。浆细胞样DCs对免疫反应的调节可能为自身免疫和移植提供基于免疫的新疗法。
