Biologicals targeting T helper cell subset differentiating cytokines are effective in the treatment of murine anti-myeloperoxidase glomerulonephritis
Biologicals targeting T helper cell subset differentiating cytokines are effective in the treatment of murine anti-myeloperoxidase glomerulonephritis
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DOI：
10.1016/j.kint.2019.05.012
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发表时间：
2019-11-01
影响因子：
19.6
通讯作者：
Holdsworth, Stephen R.
中科院分区：
文献类型：
--
作者：
Gan, Poh-Yi;Chan, Amy;Holdsworth, Stephen R.
抗髓过氧化物酶致肾炎性自身免疫诱导严重肾小球肾炎。为了评估靶向辅助性T细胞（Th）亚群分化决定细胞因子的单克隆抗体的治疗潜力，我们研究了抗髓过氧化物酶肾小球肾炎的小鼠模型。辅助性T细胞亚群的时间参与通过定量从肾炎肾分离的CD 4（+）T细胞的基因表达和从髓过氧化物酶免疫部位引流的淋巴结的淋巴细胞的细胞因子产生来确定。Th 17细胞因子（IL-17 A和IL-6）迅速上升，但随着自身免疫成熟而下降，当Th 1细胞因子（IL-12和TNF）占主导地位时。因此，辅助性T细胞亚群参与抗髓过氧化物酶自身免疫是双相的，Th 17早期和Th 1晚期。为了证实这种双相模式的功能相关性，我们比较了野生型、Th 17缺陷型和Th 1缺陷型小鼠的全身性抗髓过氧化物酶自身免疫。早期，Th 1缺陷型小鼠与野生型小鼠发生相似的自身免疫和肾小球肾炎。然而，Th 17缺陷型小鼠的抗髓过氧化物酶自身免疫性显著降低。在晚期自身免疫中，Th 1缺陷型小鼠自身免疫减少，并免受抗髓过氧化物酶肾小球肾炎的影响。这些发现的治疗潜力通过中和单克隆抗体得到证实。靶向IL-23 p19减弱早期Th 17主导的抗髓过氧化物酶自身免疫和肾小球肾炎，但不减弱晚期疾病。靶向IL-12 p35减弱晚期Th 1主导的抗髓过氧化物酶自身免疫和肾小球肾炎，但不减弱早期自身免疫或肾小球肾炎。在抗髓过氧化物酶肾小球肾炎的早期和晚期，用抗IL-12 p40单克隆抗体靶向两种辅助性T细胞亚群都是有效的。因此，通过肾CD 4（+）T细胞细胞因子基因表达确定抗髓过氧化物酶肾小球肾炎中的显性T辅助细胞分化亚群允许有效的抗髓过氧化物酶肾小球肾炎的适当时相单克隆抗体治疗。
Anti-myeloperoxidase nephritogenic autoimmunity induces severe glomerulonephritis. To assess the therapeutic potential of monoclonal antibodies targeting T helper (Th) subset differentiation determining cytokines, we studied a murine model of anti-myeloperoxidase glomerulonephritis. The temporal participation of T helper subsets was determined by quantitating gene expression of CD4(+) T-cells isolated from nephritic kidneys and cytokine production by lymphocytes from nodes draining myeloperoxidase immunization sites. Th17 cytokines (IL-17A and IL-6) rose rapidly but declined as autoimmunity matured when Th1 cytokines (IL-12 and TNF) predominated. Therefore, T helper subset participation in anti-myeloperoxidase autoimmunity is biphasic, with Th17 early and Th1 late. To confirm the functional relevance of this biphasic pattern, we compared systemic anti-myeloperoxidase autoimmunity in wild type, Th17 deficient and Th1 deficient mice. Early, Th1 deficient mice developed similar autoimmunity and glomerulonephritis to wild type mice. However, Th17 deficient mice had significantly reduced anti-myeloperoxidase autoimmunity. In late autoimmunity, Th1 deficient mice developed reduced autoimmunity and were protected from anti-myeloperoxidase glomerulonephritis. The therapeutic potential of these findings were demonstrated by neutralizing monoclonal antibodies. Targeting IL-23p19 attenuated early Th17 dominated anti-myeloperoxidase autoimmunity and glomerulonephritis but not late phase disease. Targeting IL-12p35 attenuated late phase Th1 dominated anti-myeloperoxidase autoimmunity and glomerulonephritis but not early autoimmunity or glomerulonephritis. Targeting both T helper subsets with an anti-IL-12p40 monoclonal antibody was effective during both early and late phases of anti-myeloperoxidase glomerulonephritis. Thus, definition of dominant T helper differentiating subsets in anti-myeloperoxidase glomerulonephritis by renal CD4(+) T-cell cytokine gene expression allows effective proper phase monoclonal antibody treatment of anti-myeloperoxidase glomerulonephritis.