Odobasic Dragana, Kitching A Richard, Tipping Peter G, Holdsworth Stephen R
Centre for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
Kidney Int. 2005 Aug;68(2):584-94. doi: 10.1111/j.1523-1755.2005.00436.x.
CD80 and CD86 costimulatory molecules have been shown to affect the induction of Th1-mediated crescentic antiglomerular basement membrane (GBM) antibody-initiated glomerulonephritis (GN). The aim of the current studies was to define the mechanisms by which CD80 and CD86 regulate the development of this disease.
Anti-GBM GN was induced in CD80-/-, CD86-/-, and CD80/86-/- mice, as well as in C57BL/6 controls. Renal injury and immune responses were assessed after 21 days. To examine whether costimulation by OX40-ligand compensates for the absence of CD80 and CD86 in inducing GN, OX40-ligand was blocked in wild-type and CD80/86-/- mice.
Crescentic GN and glomerular accumulation of CD4+ T cells and macrophages were attenuated in CD80-/- mice, correlating with significantly enhanced apoptosis and decreased proliferation of spleen CD4+ T cells. GN was exacerbated in CD86-/- mice, which was associated with attenuated IL-4 and enhanced IFN-gamma levels. In contrast, CD80/86-/- mice developed crescentic GN similar to that in controls. Inhibition of OX40-ligand exacerbated GN in wild-type mice by enhancing IFN-gamma production, and attenuated disease in CD80/86-/- mice by reducing glomerular CD4+ T-cell and macrophage accumulation.
CD80 is pathogenic in crescentic GN by enhancing survival and proliferation of CD4+ T cells, whereas CD86 is protective by enhancing Th2 and attenuating Th1 responses. Furthermore, in the presence of CD80 and CD86, OX40-ligand attenuates, whereas in their absence it enhances GN, suggesting that, in the absence of CD80 and CD86, the OX40/OX40-ligand pathway is an alternative costimulatory pathway in inducing crescentic GN.
共刺激分子CD80和CD86已被证明会影响Th1介导的新月体性抗肾小球基底膜（GBM）抗体引发的肾小球肾炎（GN）的诱导。当前研究的目的是确定CD80和CD86调节该疾病发展的机制。
在CD80基因敲除小鼠、CD86基因敲除小鼠、CD80/86双基因敲除小鼠以及C57BL/6对照小鼠中诱导抗GBM GN。21天后评估肾脏损伤和免疫反应。为了检查OX40配体的共刺激是否能弥补诱导GN时CD80和CD86的缺失，在野生型和CD80/86双基因敲除小鼠中阻断OX40配体。
CD80基因敲除小鼠中新月体性GN以及CD4⁺ T细胞和巨噬细胞在肾小球的积聚减弱，这与脾脏CD4⁺ T细胞凋亡显著增强和增殖减少相关。CD86基因敲除小鼠中的GN加重，这与IL-4水平降低和IFN-γ水平升高有关。相比之下，CD80/86双基因敲除小鼠发生的新月体性GN与对照小鼠相似。抑制OX40配体通过增强IFN-γ的产生使野生型小鼠中的GN加重，而通过减少肾小球CD4⁺ T细胞和巨噬细胞的积聚使CD80/86双基因敲除小鼠中的疾病减轻。
CD80通过增强CD4⁺ T细胞的存活和增殖在新月体性GN中具有致病性，而CD86通过增强Th2反应和减弱Th1反应起到保护作用。此外，在存在CD80和CD86的情况下，OX40配体减轻疾病，而在其缺失时则加重GN，这表明在没有CD80和CD86的情况下，OX40/OX40配体途径是诱导新月体性GN的一种替代共刺激途径。
