Characterisation of an enhanced preclinical model of experimental MPO-ANCA autoimmune vasculitis.
Characterisation of an enhanced preclinical model of experimental MPO-ANCA autoimmune vasculitis.
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实验性 MPO-ANCA 自身免疫性血管炎的增强临床前模型的表征。
DOI：
10.1002/path.5746
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Prendecki M
中科院分区：
文献类型：
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作者：
Prendecki M
实验性自身免疫性血管炎(EAV)是一种抗中性粒细胞胞浆抗体(ANCA)相关性小血管炎(AAV)的模型，用髓过氧化物酶(MPO)免疫易感的大鼠品系。动物发生循环MPO-ANCA、肺出血和肾小球肾炎，尽管肾损伤轻微，无需治疗即可自行恢复。在这项研究中，我们的目的是增加肾小球肾炎的严重性。在第0天诱导EAV后，在第14天给予肾炎下剂量的肾毒性血清(NTS)，其中含有针对肾小球基底膜的异源抗体。这导致在第28天的疾病严重程度显著高于单独接种MPO-随着更多的尿液异常、肾小球白细胞的浸润性和新月体的形成，在第56天进展为肾小球和肾小管间质瘢痕，概括了人类疾病的重要特征。重要的是，肾小球肾炎仍然缺乏免疫力，并且严格依赖于MPO自身免疫的存在，因为没有证据表明单独应用亚肾炎NTS或在用对照蛋白替代MPO免疫后出现肾脏疾病。肾小球白细胞的详细表型鉴定表明，NTS给药后早期非经典单核细胞的渗透，在存在对MPO的自身免疫的情况下，可能启动随后经典单核细胞的流入，从而加剧肾小球损伤。我们还表明，通过使用小分子激酶抑制剂(福斯塔替尼)可以在4天的治疗期间迅速减轻肾小球和肺损伤，该模型可以用于测试新的治疗方法。我们相信，这种增强的MPO-AAV模型将被证明对未来AAV的肾小球白细胞行为的研究和新的治疗方法是有用的。《病理学杂志》由John Wiley&Sons，Ltd.代表大不列颠和爱尔兰病理学会出版。
Experimental autoimmune vasculitis (EAV) is a model of antineutrophil cytoplasm antibody (ANCA)‐associated vasculitis (AAV) induced by immunisation of susceptible rat strains with myeloperoxidase (MPO). Animals develop circulating MPO‐ANCA, pulmonary haemorrhage, and glomerulonephritis, although renal injury is mild and recovers spontaneously without treatment. In this study we aimed to augment the severity of glomerulonephritis. Following induction of EAV on day 0, a sub‐nephritogenic dose of nephrotoxic serum (NTS) containing heterologous antibodies to glomerular basement membrane was administered on day 14. This resulted in a significant increase in disease severity at day 28 compared to MPO immunisation alone – with more urinary abnormalities, infiltrating glomerular leucocytes, and crescent formation that progressed to glomerular and tubulointerstitial scarring by day 56, recapitulating important features of human disease. Importantly, the glomerulonephritis remained pauci‐immune, and was strictly dependent on the presence of autoimmunity to MPO, as there was no evidence of renal disease following administration of sub‐nephritogenic NTS alone or after immunisation with a control protein in place of MPO. Detailed phenotyping of glomerular leucocytes identified an early infiltrate of non‐classical monocytes following NTS administration that, in the presence of autoimmunity to MPO, may initiate the subsequent influx of classical monocytes which augment glomerular injury. We also showed that this model can be used to test novel therapeutics by using a small molecule kinase inhibitor (fostamatinib) that rapidly attenuated both glomerular and pulmonary injury over a 4‐day treatment period. We believe that this enhanced model of MPO‐AAV will prove useful for the study of glomerular leucocyte behaviour and novel therapeutics in AAV in the future. © 2021 The Authors.The Journal of Pathologypublished by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.