抗C-X-C基序趋化因子10（CXCL10）抗体对C蛋白诱导的小鼠肌炎的治疗作用
Therapeutic effect of anti-C-X-C motif chemokine 10 (CXCL10) antibody on C protein-induced myositis mouse.
作者信息
Kim Jinhyun, Choi Ji Yong, Park Sung-Hye, Yang Seung Hee, Park Ji Ah, Shin Kichul, Lee Eun Young, Kawachi Hiroshi, Kohsaka Hitoshi, Song Yeong Wook
出版信息
Arthritis Res Ther. 2014 Jun 17;16(3):R126. doi: 10.1186/ar4583.
INTRODUCTION
C-X-C motif chemokine 10 (CXCL10) is a chemokine that plays a critical role in the infiltration of T cells in autoimmune diseases and is reported to be expressed in muscle tissue of polymyositis. To determine the therapeutic efficacy of CXCL10 blockade, we investigated the role of CXCL10 and the effect of anti-CXCL10 antibody treatment in C protein-induced myositis (CIM), an animal model of polymyositis.
METHODS
CIM was induced with human skeletal muscle C protein fragment in female C57BL/6 mice. Immunohistochemistry of CXCL10 and C-X-C motif chemokine receptor 3 (CXCR3) and measurement of serum CXCL10 were performed. Cell surface markers and interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in CIM lymph node cells was investigated by flow cytometry. Mice with CIM were treated with anti-CXCL10 antibody or control antibody (anti-RVG1) and the inflammation in muscle tissue was assessed.
RESULTS
Immunohistochemistry showed increased expression of CXCL10 and CXCR3 in the inflammatory lesions of muscle in CIM. Especially, CD8+ T cells invading myofiber expressed CXCR3. Serum level of CXCL10 was increased in CIM compared to the level in normal mice (normal mouse, 14.3 ± 5.3 pg/ml vs. CIM, 368.5 ± 135.6 pg/ml, P < 0.001). CXCR3 positivity in CD8+ T cells was increased compared to that of CD4+ T cells in the lymph node cells of CIM (CXCR3+ among CD8+ T cell, 65.9 ± 2.1% vs. CXCR3+ among CD4+ T cell, 23.5 ± 4.7%, P <0.001). Moreover, IFN-γ+ cells were increased among CXCR3+CD8+ T cells compared to CXCR3-CD8+ T cells (CXCR3+CD8+ T cell, 28.0 ± 4.2% vs. CXCR3-CD8+ T cell, 9.5 ± 1.5%, P = 0.016). Migration of lymph node cells was increased in response to CXCL10 (chemotactic index was 1.91 ± 0.45). CIM mice treated with anti-CXCL10 antibody showed a lower inflammation score in muscles than those with anti-RVG1 (median, anti-CXCL10 treatment group, 0.625 vs. anti-RVG1 treatment group, 1.25, P = 0.007).
CONCLUSIONS
CXCL10/CXCR3 expression was increased in the inflammation of CIM model and its blockade suppressed inflammation in muscle.
引言
C-X-C基序趋化因子10（CXCL10）是一种趋化因子，在自身免疫性疾病中T细胞浸润过程中起关键作用，据报道其在多发性肌炎的肌肉组织中表达。为了确定CXCL10阻断的治疗效果，我们研究了CXCL10在C蛋白诱导的肌炎（CIM）（一种多发性肌炎的动物模型）中的作用以及抗CXCL10抗体治疗的效果。
方法
用人类骨骼肌C蛋白片段在雌性C57BL/6小鼠中诱导CIM。进行CXCL10和C-X-C基序趋化因子受体3（CXCR3）的免疫组织化学检测以及血清CXCL10的测定。通过流式细胞术研究CIM淋巴结细胞中的细胞表面标志物、干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）。用抗CXCL10抗体或对照抗体（抗RVG1）治疗CIM小鼠，并评估肌肉组织中的炎症。
结果
免疫组织化学显示CIM肌肉炎症病变中CXCL10和CXCR3表达增加。特别是，侵入肌纤维的CD8 + T细胞表达CXCR3。与正常小鼠相比，CIM小鼠血清CXCL10水平升高（正常小鼠，14.3±5.3 pg/ml vs. CIM，368.5±135.6 pg/ml，P <0.001）。与CIM淋巴结细胞中的CD4 + T细胞相比，CD8 + T细胞中CXCR3阳性增加（CD8 + T细胞中CXCR3 +，65.9±2.1% vs. CD4 + T细胞中CXCR3 +，23.5±4.7%，P <0.001）。此外，与CXCR3 - CD8 + T细胞相比，CXCR3 + CD8 + T细胞中IFN-γ +细胞增加（CXCR3 + CD8 + T细胞，28.0±4.2% vs. CXCR3 - CD8 + T细胞，9.5±1.5%，P = 0.016）。淋巴结细胞对CXCL10的迁移反应增加（趋化指数为1.91±0.45）。用抗CXCL10抗体治疗的CIM小鼠肌肉中的炎症评分低于用抗RVG1治疗的小鼠（中位数，抗CXCL10治疗组，0.625 vs.抗RVG1治疗组，1.25，P = 0.007）。
结论
CXCL10/CXCR3在CIM模型炎症中表达增加，其阻断可抑制肌肉炎症。
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