Tipping P G, Kitching A R, Huang X R, Mutch D A, Holdsworth S R
Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Australia.
Eur J Immunol. 1997 Feb;27(2):530-7. doi: 10.1002/eji.1830270226.
Crescentic glomerulonephritis (GN) demonstrates immunopathological features of a T helper (Th)1-directed delayed-type hypersensitivity (DTH) response. The capacity of Th2 cytokines to attenuate crescentic glomerular injury in this disease was examined by administering interleukin (IL)-4 and IL-10, singly and in combination. GN was induced by i.v. administration of sheep anti-mouse glomerular basement membrane (GBM) globulin to mice sensitized to sheep globulin 10 days earlier. Treatment (2.5 microg, i.p.) with IL-4, IL-10, or both IL-4 and IL-10 (IL-4 + 10), was started 1 h before sensitization and continued daily until the end of the study (10 days after administration of anti-GBM globulin). Control mice treated with PBS developed GN with glomerular accumulation of T cells and macrophages, crescents in 42.5 +/- 4.5 % of glomeruli (normal 0 %), proteinuria (8.3 +/- 0.9 mg/24 h, normal 0.74 +/- 0.08 mg/24 h, p <0.001) and renal impairment (creatinine clearance [cr/cl]: 93 +/- 12 microl/min, normal 193 +/- 10 microl/min, p < 0.001). Treatment with either IL-4, IL-10, or IL-4 + 10 prevented crescent formation (crescentic glomeruli: 0.8 +/- 0.5, 1.2 +/- 0.9, and 1.4 +/- 1.0 %, respectively, all p < 0.01 compared to control) and attenuated proteinuria (3.6 +/- 1.0, 2.2 +/- 0.5, and 2.9 +/- 0.5 mg/24 h, respectively, all p < 0.01 compared to control). IL-4 + 10 prevented development of renal impairment (cr/cl: 183 +/- 22 microl/min); IL-10 given alone limited the decline in renal function (cr/cl: 150 +/- 20 microl/min), but IL-4 alone did not provide any significant protection (cr/cl: 121 +/- 17 microl/min). All treatments markedly diminished glomerular T cell and macrophage accumulation, reduced interferon-gamma production by splenic T cells, prevented cutaneous DTH to the disease-initiating antigen and reduced antigen-specific immunoglobulin of the IgG2a and IgG3 isotypes. These data demonstrate that crescentic GN and renal impairment can be prevented by administration of Th2 cytokines and that this effect is associated with attenuation of the Th1 response to the disease-initiating antigen.
新月体性肾小球肾炎（GN）表现出辅助性T细胞（Th）1介导的迟发型超敏反应（DTH）的免疫病理特征。通过单独或联合给予白细胞介素（IL）-4和IL-10，研究了Th2细胞因子减轻该疾病中新月体性肾小球损伤的能力。通过静脉注射羊抗小鼠肾小球基底膜（GBM）球蛋白，对10天前致敏至羊球蛋白的小鼠诱导GN。在致敏前1小时开始用IL-4、IL-10或IL-4与IL-10联合（IL-4 + 10）进行治疗（腹腔注射2.5μg），并持续每日给药直至研究结束（给予抗GBM球蛋白后10天）。用PBS处理的对照小鼠发生了GN，伴有T细胞和巨噬细胞在肾小球的积聚，42.5±4.5%的肾小球出现新月体（正常为0%），蛋白尿（8.3±0.9mg/24小时，正常为0.74±0.08mg/24小时，p<0.001）和肾功能损害（肌酐清除率[cr/cl]：93±12μl/min，正常为193±10μl/min，p<0.001）。用IL-4、IL-10或IL-4 + 10治疗均可预防新月体形成（新月体性肾小球分别为：0.8±0.5、1.2±0.9和1.4±1.0%，与对照组相比均p<0.01）并减轻蛋白尿（分别为3.6±1.0、2.2±0.5和2.9±0.5mg/24小时，与对照组相比均p<0.01）。IL-4 + 10可预防肾功能损害的发生（cr/cl：183±22μl/min）；单独给予IL-10可限制肾功能下降（cr/cl：150±20μl/min），但单独给予IL-4未提供任何显著保护（cr/cl：121±17μl/min）。所有治疗均显著减少肾小球T细胞和巨噬细胞的积聚，降低脾T细胞产生的干扰素-γ，预防针对引发疾病抗原的皮肤DTH，并减少IgG2a和IgG3同种型的抗原特异性免疫球蛋白。这些数据表明，给予Th2细胞因子可预防新月体性GN和肾功能损害，且这种作用与对引发疾病抗原的Th1反应减弱有关。
