Blockade of the Interleukin-7 Receptor Inhibits Collagen-Induced Arthritis and Is Associated With Reduction of T Cell Activity and Proinflammatory Mediators
Blockade of the Interleukin-7 Receptor Inhibits Collagen-Induced Arthritis and Is Associated With Reduction of T Cell Activity and Proinflammatory Mediators
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DOI：
10.1002/art.27578
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发表时间：
2010-09-01
影响因子：
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通讯作者：
van Roon, Joel A. G.
中科院分区：
文献类型：
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作者：
Hartgring, Sarita A. Y.;Willis, Cynthia R.;van Roon, Joel A. G.
目标。目的：研究白细胞介素-7受体α链（IL-7R α）阻断对胶原性关节炎（CIA）的影响，探讨其对T细胞数量、T细胞活性及促炎介质水平的影响。我们研究了抗il - 7r α抗体治疗对小鼠CIA炎症和关节破坏的影响。评估胸腺细胞、脾细胞、T细胞亚群、B细胞、巨噬细胞和树突状细胞的数量。通过多分析物谱分析爪子裂解液中Th1、Th2和Th17活性的细胞因子和几种促炎介质。此外，在淋巴结细胞培养的上清液中检测T细胞相关细胞因子。抗il - 7r α治疗显著降低临床关节炎严重程度，减少放射关节损伤。抗il - 7r α治疗后胸腺和脾脏细胞数量均减少。IL-7R α阻断特异性地减少了脾脏的细胞总数以及幼稚、记忆、CD4+和CD8+ T细胞的数量，并显著减少了T细胞相关的细胞因子（干扰素- γ、IL-5和IL-17）。IL-7R α阻断也降低了局部促炎细胞因子和组织破坏相关因子的水平，包括肿瘤坏死因子α、IL-1 β、IL-6、基质金属蛋白酶9和RANKL。IL-7R α阻断对B细胞、巨噬细胞和树突状细胞无显著影响。血清抗胶原IgG抗体显示B细胞活性无明显变化。阻断IL-7R α能有效抑制关节炎症和破坏，这与T细胞数量、T细胞相关细胞因子和许多诱导炎症和组织破坏的介质的特异性减少有关。本研究证明了IL-7R驱动免疫在实验性关节炎中的重要作用，并表明IL-7R α阻断在人类关节炎疾病中的治疗潜力。
Objective. To study the effects of interleukin-7 receptor alpha-chain (IL-7R alpha) blockade on collagen-induced arthritis (CIA) and to investigate the effects on T cell numbers, T cell activity, and levels of proinflammatory mediators.Methods. We studied the effect of anti-IL-7R alpha antibody treatment on inflammation and joint destruction in CIA in mice. Numbers of thymocytes, splenocytes, T cell subsets, B cells, macrophages, and dendritic cells were assessed. Cytokines indicative of Th1, Th2, and Th17 activity and several proinflammatory mediators were assessed by multianalyte profiling in paw lysates. In addition, T cell-associated cytokines were measured in supernatants of lymph node cell cultures.Results. Anti-IL-7R alpha treatment significantly reduced clinical arthritis severity in association with reduced radiographic joint damage. Both thymic and splenic cellularity were reduced after treatment with anti-IL-7R alpha. IL-7R alpha blockade specifically reduced the total number of cells as well as numbers of naive, memory, CD4+, and CD8+ T cells from the spleen and significantly reduced T cell-associated cytokines (interferon-gamma, IL-5, and IL-17). IL-7R alpha blockade also decreased local levels of proinflammatory cytokines and factors associated with tissue destruction, including tumor necrosis factor alpha, IL-1 beta, IL-6, matrix metallo-proteinase 9, and RANKL. IL-7R alpha blockade did not significantly affect B cells, macrophages, and dendritic cells. B cell activity, indicated by serum anticollagen IgG antibodies, was not significantly altered.Conclusion. Blockade of IL-7R alpha potently inhibited joint inflammation and destruction in association with specific reductions of T cell numbers, T cell-associated cytokines, and numerous mediators that induce inflammation and tissue destruction. This study demonstrates an important role of IL-7R-driven immunity in experimental arthritis and indicates the therapeutic potential of IL-7R alpha blockade in human arthritic conditions.