Yang J J, Jennette J C, Falk R J
Department of Medicine, University of North Carolina at Chapel Hill.
Clin Exp Immunol. 1994 Sep;97(3):466-73. doi: 10.1111/j.1365-2249.1994.tb06111.x.
Anti-neutrophil cytoplasmic antibodies (ANCA), including anti-myeloperoxidase (MPO) antibodies, are associated with pauci-immune necrotizing small vessel vasculitis or glomerulonephritis. In order to substantiate a pathogenic role for ANCA, an animal model of pauci-immune ANCA-induced glomerulonephritis or vasculitis is required. Brouwer et al. reported pauci-immune glomerulonephritis in rats immunized with human MPO followed by perfusion of kidneys with lysosomal enzyme extract combined with H2O2, and suggested that this could serve as a model of ANCA-induced disease. We repeated these studies in spontaneously hypertensive rats (SHR) and Brown Norway rats (BNR). We immunized rats with human MPO. When circulating anti-MPO antibodies were detectable by indirect immunofluorescence microscopy and ELISA, blood pressure was measured, then perfusion of the left kidney of each rat was done via the renal artery in a closed, blood-free circuit with either MPO + H2O2, MPO, H2O2 alone or MPO + H2O2 + neutral protease. Rats were killed on day 4 or day 10 after perfusion, and specimens were examined by light and immunofluorescence microscopy. Pathological lesions and deposits of IgG, C3, and MPO were found in immunized rats perfused with MPO + H2O2 with or without neutral protease, or MPO alone, in both rat strains and on both day 4 and day 10. The degree of histologic injury was proportional in intensity to the amount of IgG immune deposits. Spontaneously hypertensive rats sustained more damage and higher blood pressure than Brown Norway rats. No lesion was observed in immunized rats perfused with H2O2 or in the non-perfused right kidneys. Some of the non-immunized rats perfused with MPO + H2O2 developed pathological lesions. In conclusion, these rat models are examples of immune complex-mediated glomerulonephritis, and therefore are not similar to human ANCA-associated disease.
抗中性粒细胞胞浆抗体（ANCA），包括抗髓过氧化物酶（MPO）抗体，与寡免疫性坏死性小血管血管炎或肾小球肾炎相关。为了证实ANCA的致病作用，需要一种寡免疫性ANCA诱导的肾小球肾炎或血管炎的动物模型。布劳威尔等人报道，在用人类MPO免疫大鼠后，用溶酶体酶提取物联合过氧化氢灌注肾脏，大鼠出现了寡免疫性肾小球肾炎，并认为这可以作为ANCA诱导疾病的模型。我们在自发性高血压大鼠（SHR）和布朗挪威大鼠（BNR）中重复了这些研究。我们用人类MPO免疫大鼠。当通过间接免疫荧光显微镜和酶联免疫吸附测定法可检测到循环抗MPO抗体时，测量血压，然后在封闭的无血循环中通过肾动脉对每只大鼠的左肾进行灌注，灌注液分别为MPO + 过氧化氢、MPO、单独的过氧化氢或MPO + 过氧化氢 + 中性蛋白酶。在灌注后第4天或第10天处死大鼠，并通过光镜和免疫荧光显微镜检查标本。在两种大鼠品系中，在灌注后第4天和第10天，用MPO + 过氧化氢（无论有无中性蛋白酶）或单独用MPO灌注的免疫大鼠中发现了病理病变以及IgG、C3和MPO的沉积。组织学损伤程度与IgG免疫沉积物的量在强度上成正比。自发性高血压大鼠比布朗挪威大鼠遭受的损伤更大，血压更高。在用过氧化氢灌注的免疫大鼠或未灌注的右肾中未观察到病变。一些用MPO + 过氧化氢灌注的未免疫大鼠出现了病理病变。总之，这些大鼠模型是免疫复合物介导的肾小球肾炎的例子，因此与人类ANCA相关疾病不相似。
