Anti-IL-12/23 p40 antibody attenuates chronic graft-versus-host disease with lupus nephritis via inhibiting Tfh cell in mice
Anti-IL-12/23 p40 antibody attenuates chronic graft-versus-host disease with lupus nephritis via inhibiting Tfh cell in mice
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DOI：
10.1016/j.biopha.2020.110396
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发表时间：
2020-09-01
影响因子：
7.5
通讯作者：
Guo, Wei
中科院分区：
文献类型：
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作者：
Gao, Yue;Zeng, Yu;Guo, Wei
系统性红斑狼疮(SLE)是一种自身免疫性疾病，主要由针对核酸等自身抗体的自身抗体过度积累引起。辅助性T细胞(Th)与SLE的发生发展密切相关。通常，不同的Th细胞亚群会分泌不同的细胞因子来调节疾病的进展。IL-12和IL-23参与多种Th细胞亚群的分化和激活，包括Th1、Th2、Th9、Th17、调节性T细胞(Treg)和滤泡辅助T细胞(Tfh)。由于IL-12和IL-23具有共同的p40亚基，阻断IL-12/IL-23信号通路可能干扰Th细胞的分化，直接抑制促炎细胞因子的分泌。在本研究中，我们检测了抗IL-12/23 p40抗体对慢性移植物抗宿主病狼疮性肾炎的治疗作用，发现其治疗作用是通过抑制小鼠的Tfh细胞来实现的。此外，抗IL-12/23p40抗体在体外对人TFH细胞的分化有抑制作用。这些结果强烈提示TFH细胞参与了SLE的发病过程，而TFH细胞分化过程中IL-12/IL-23信号的中和可能是SLE治疗的关键。
Systemic lupus erythematosus (SLE) is an autoimmune disease that is mainly caused by excessive accumulation of autoantibodies that target autoantibodies such as nucleic acids. T helper (Th) cell have been associated with the development of SLE. Typically, different subsets of Th cells secrete various cytokines to regulate the disease progression. IL-12 and IL-23 participate in the differentiation and activation of multiple Th cell subsets, including Th1, Th2, Th9, Th17, regulatory T (Treg) and follicular helper T (Tfh) cells. Because of the signature p40 subunit shared by IL-12 and IL-23, blocking IL-12/IL-23 signaling may interfere the differentiation of Th cell and directly inhibit the secretion of proinflammatory cytokines. In this study, we examined the effects of anti-IL-12/23 p40 antibody on chronic graft-versus-host disease with lupus nephritis, and found that the therapeutic effectiveness was mediated through the inhibition of Tfh cell in mice. Moreover, anti-IL-12/23 p40 antibody inhibited human Tfh cell differentiation in vitro. These results strongly suggest that Tfh cell contribute to the pathogenesis of SLE, and the neutralization of IL-12/IL-23 signaling during Tfh cell differentiation may be critical for the treatment of SLE.