Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia.
Department of Pediatric Nephrology, Monash Health, Clayton, Victoria, Australia.
Nephrol Dial Transplant. 2019 Mar 1;34(3):429-441. doi: 10.1093/ndt/gfy177.
The functional relevance of OX40 ligand (OX40L) in the effector phase of crescentic glomerulonephritis (GN) is unknown. These studies defined the role of endogenous OX40L during the effector stage of murine crescentic GN.
GN was induced by immunization with sheep globulin/adjuvant on Day 0 and injection of sheep anti-mouse glomerular basement membrane immunoglobulin (Ig) on Day 10. Rat IgG or neutralizing anti-OX40L antibody was administered on Days 10-18 and immune responses and renal injury assessed on Day 20.
Compared with naïve animals, OX40L was upregulated in the lymph nodes (LNs) and on leucocytes and resident non-immune cells in the kidneys of mice with GN. Inhibition of OX40L in GN augmented renal injury, as indicated by increased crescent formation, proteinuria and glomerular leucocyte accumulation. In line with increased injury, anti-OX40L treatment increased proliferation and decreased apoptosis of CD4 T cells in the LNs, without affecting LN CD4 cytokine production and CD8 T-cell responses. Blockade of OX40L decreased LN regulatory T-cell (Treg) proliferation, transforming growth factor β production and foxp3 expression. OX40L inhibition did not affect B cell expansion or circulating antibody levels. In the kidney, neutralization of OX40L augmented interferon γ (IFNγ) expression by CD4 and CD8 T cells and shifted macrophage polarization towards the pro-inflammatory M1 phenotype.
OX40L is protective during the effector phase of murine crescentic GN by reducing the expansion of CD4 T cells and enhancing Treg responses in the LNs, and by locally inhibiting T-cell IFNγ production and pro-inflammatory macrophage phenotype in the kidney.
OX40 配体（OX40L）在新月体性肾小球肾炎（GN）效应期的功能相关性尚不清楚。本研究旨在确定内源性 OX40L 在小鼠新月体性 GN 的效应期的作用。
于第 0 天用绵羊球蛋白/佐剂免疫，第 10 天注射绵羊抗鼠肾小球基底膜免疫球蛋白（Ig）诱导 GN。第 10-18 天给予大鼠 IgG 或中和性抗-OX40L 抗体，并于第 20 天评估免疫反应和肾脏损伤。
与未致敏动物相比，GN 小鼠的淋巴结（LN）和白细胞以及肾脏固有非免疫细胞中 OX40L 上调。在 GN 中抑制 OX40L 可加重肾脏损伤，表现为新月体形成增加、蛋白尿和肾小球白细胞积聚增加。与损伤增加一致，抗-OX40L 治疗增加了 LN 中 CD4 T 细胞的增殖，减少了其凋亡，但不影响 LN CD4 细胞因子的产生和 CD8 T 细胞反应。阻断 OX40L 减少了 LN 调节性 T 细胞（Treg）的增殖、转化生长因子β的产生和 foxp3 的表达。OX40L 抑制不影响 B 细胞的扩增或循环抗体水平。在肾脏中，中和 OX40L 增加了 CD4 和 CD8 T 细胞的干扰素γ（IFNγ）表达，并使巨噬细胞向促炎 M1 表型极化。
OX40L 通过减少 LN 中 CD4 T 细胞的扩增并增强 Treg 反应，并通过局部抑制 T 细胞 IFNγ的产生和肾脏中促炎巨噬细胞表型，在小鼠新月体性 GN 的效应期具有保护作用。
