Nishikawa K, Guo Y J, Miyasaka M, Tamatani T, Collins A B, Sy M S, McCluskey R T, Andres G
Department of Pathology, Massachusetts General Hospital, Boston.
J Exp Med. 1993 Mar 1;177(3):667-77. doi: 10.1084/jem.177.3.667.
In patients with glomerulonephritis widespread crescents are associated with a poor prognosis. Crescent formation appears to depend on the migration of mononuclear cells into Bowman's space, and therefore the interaction between leukocytes and glomerular endothelium may be a critical event in the genesis of crescents. We performed the present study to determine the effects of mouse monoclonal antibodies to the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function-associated antigen 1 (LFA-1) in a model of crescentic glomerulonephritis in Wistar-Kyoto rats, induced by immunization with bovine glomerular basement membrane (GBM). By 10-14 d after immunization, the rats had developed circulating anti-GBM antibodies, reactive with the alpha 3 chain of type IV collagen (the Goodpasture antigen), accompanied by proteinuria, accumulation of rat immunoglobulin (Ig)G in the GBM, increased expression of ICAM-1 by glomerular endothelial cells, infiltration of glomerular tufts with LFA-1+ T cells and monocyte/macrophages, and early crescents. At 5 wk all rats had diffuse fibrocellular crescents, glomerular sclerosis, and tubulointerstitial damage. All rats developed severe renal insufficiency and died by 5 or 6 wk. The administration of monoclonal antibodies to rat ICAM-1 and LFA-1 markedly decreased the severity of the renal disease. In a group of rats injected three times a week with the monoclonal antibodies, from 2 d before immunization with GBM to day 14, glomerular abnormalities and proteinuria were virtually absent at day 14; even at 5 wk glomerular disease was quite mild, with only slight crescent formation and with only a mild decrease in renal function. When treatment was continued until 5 wk, the beneficial effects were even more marked, with virtual absence of crescents and with preservation of normal renal function. In a group of rats in which treatment was initiated on day 14, shortly after the appearance of glomerular abnormalities, progression of the disease was appreciably retarded, and the decrease in renal function was inhibited. The kidneys of rats treated from days -2 to 14 with antibodies to ICAM-1 and LFA-1 showed bright linear staining for rat IgG along the GBM, which did not differ in intensity from that seen in untreated rats. Furthermore, the titers of anti-GBM antibodies at 2 wk in treated rats were not lower than that seen in most of the untreated rats. There was, however, moderate reduction of anti-GBM antibodies at 5 wk in the treated rats.(ABSTRACT TRUNCATED AT 400 WORDS)
在肾小球肾炎患者中，广泛的新月体形成与预后不良相关。新月体形成似乎依赖于单核细胞向鲍曼囊腔的迁移，因此白细胞与肾小球内皮细胞之间的相互作用可能是新月体形成过程中的关键事件。我们进行了本研究，以确定针对细胞间黏附分子1（ICAM-1）和淋巴细胞功能相关抗原1（LFA-1）的小鼠单克隆抗体在Wistar-Kyoto大鼠新月体性肾小球肾炎模型中的作用，该模型由牛肾小球基底膜（GBM）免疫诱导。免疫后10 - 14天，大鼠产生了循环抗GBM抗体，与IV型胶原的α3链（Goodpasture抗原）反应，伴有蛋白尿、GBM中大鼠免疫球蛋白（Ig）G的积聚、肾小球内皮细胞ICAM-1表达增加、LFA-1 + T细胞和单核细胞/巨噬细胞浸润肾小球丛以及早期新月体形成。5周时，所有大鼠均出现弥漫性纤维细胞性新月体、肾小球硬化和肾小管间质损伤。所有大鼠均发展为严重肾功能不全，并在5或6周时死亡。给予抗大鼠ICAM-1和LFA-1单克隆抗体可显著降低肾脏疾病的严重程度。在一组每周注射三次单克隆抗体的大鼠中，从用GBM免疫前2天至第14天，第14天时肾小球异常和蛋白尿几乎不存在；即使在5周时，肾小球疾病也相当轻微，仅有轻微的新月体形成，肾功能仅有轻微下降。当治疗持续至5周时，有益效果更为明显，几乎没有新月体形成，肾功能保持正常。在一组于第14天（肾小球异常出现后不久）开始治疗的大鼠中，疾病进展明显延迟，肾功能下降受到抑制。用抗ICAM-1和LFA-1抗体从第 - 2天至第14天治疗的大鼠肾脏，沿GBM显示出明亮的线性大鼠IgG染色，其强度与未治疗大鼠所见无异。此外，治疗大鼠在2周时抗GBM抗体滴度不低于大多数未治疗大鼠。然而，治疗大鼠在5周时抗GBM抗体有适度降低。（摘要截短至400字）
