Min So-Youn, Park Kyung-Su, Cho Mi-La, Kang Jung-Won, Cho Young-Gyu, Hwang Sue-Yun, Park Min-Jung, Yoon Chong-Hyeon, Min Jun-Ki, Lee Sang-Heon, Park Sung-Hwan, Kim Ho-Youn
Rheumatism Research Center, The Catholic University of Korea, Seocho-Ku, Seoul, Korea.
Arthritis Rheum. 2006 Mar;54(3):887-98. doi: 10.1002/art.21647.
Although oral tolerance is a well-known phenomenon, the role of dendritic cells (DCs) is not well characterized. This study was conducted to better understand the differential role played by each Peyer's patch DC subset in the induction of oral tolerance to type II collagen (CII) in murine collagen-induced arthritis (CIA).
CII was fed 6 times to DBA/1 mice beginning 2 weeks before immunization, and the effect on arthritis was assessed. We compared the proportion of CD11c+,CD11b+ DCs and CD11c+,CD8alpha+ DCs in the Peyer's patches of CII-fed tolerized and phosphate buffered saline-fed nontolerized mice after the induction of CIA. The immunosuppressive properties of each DC subset were determined using fluorescence-activated cell sorter analysis for intracellular interleukin-10 (IL-10) and IL-12 and mixed lymphocyte culture. The ability of each DC subset to induce CD4+,CD25+ T regulatory cells was also examined. Mice were injected with CII-pulsed CD11c+,CD11b+ DCs isolated from Peyer's patches of tolerized mice, and the effect on CIA was examined.
The severity of arthritis was significantly lower in tolerized mice. The proportion of CD11c+,CD11b+ DCs was increased in the Peyer's patches of tolerized mice and those DCs exhibited immunosuppressive characteristics, such as increased IL-10 production, inhibition of T cell proliferative responses to CII, and CD4+,CD25+ regulatory T cell induction. Furthermore, the CD11c+,CD11b+ DCs suppressed the severity of arthritis upon adoptive transfer.
Our observations demonstrate that CD11c+,CD11b+ DCs, which are abundant in Peyer's patches during the induction of oral tolerance to CII, are crucial for the suppression of CIA and could be exploited for immunotherapy of autoimmune diseases.
尽管口服耐受是一种广为人知的现象，但树突状细胞（DCs）的作用尚未得到充分表征。本研究旨在更好地了解派尔集合淋巴结中各DC亚群在小鼠胶原诱导性关节炎（CIA）中对II型胶原（CII）口服耐受诱导过程中所起的不同作用。
在免疫前2周开始，给DBA/1小鼠喂食CII 6次，并评估其对关节炎的影响。我们比较了诱导CIA后，喂食CII的耐受小鼠和喂食磷酸盐缓冲盐水的未耐受小鼠派尔集合淋巴结中CD11c⁺、CD11b⁺ DCs和CD11c⁺、CD8α⁺ DCs的比例。使用荧光激活细胞分选分析细胞内白细胞介素-10（IL-10）和IL-12以及混合淋巴细胞培养来确定每个DC亚群的免疫抑制特性。还检测了每个DC亚群诱导CD4⁺、CD25⁺ T调节细胞的能力。给小鼠注射从耐受小鼠派尔集合淋巴结中分离出的CII脉冲处理的CD11c⁺、CD11b⁺ DCs，并检测其对CIA的影响。
耐受小鼠的关节炎严重程度明显较低。耐受小鼠派尔集合淋巴结中CD11c⁺、CD11b⁺ DCs的比例增加，并且这些DCs表现出免疫抑制特性，如IL-10产生增加、对CII的T细胞增殖反应受到抑制以及诱导CD4⁺、CD25⁺调节性T细胞。此外，CD11c⁺、CD11b⁺ DCs在过继转移后抑制了关节炎的严重程度。
我们的观察结果表明，在对CII口服耐受诱导过程中，派尔集合淋巴结中丰富的CD11c⁺、CD11b⁺ DCs对于抑制CIA至关重要，并且可用于自身免疫性疾病的免疫治疗。
