最新动态

Soluble CR1 Therapy Improves Complement Regulation in C3 Glomerulopathy

发布于：2013年8月19日    文字：【大】【中】【小】

J Am Soc Nephrol. 2013 Aug 1. [Epub ahead of print]

Soluble CR1 Therapy Improves Complement Regulation in C3 Glomerulopathy.

Zhang Y, Nester CM, Holanda DG, Marsh HC, Hammond RA, Thomas LJ, Meyer NC, Hunsicker LG, Sethi S, Smith RJ.

Source

Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, Iowa;

Abstract

Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are widely recognized subtypes of C3 glomerulopathy. These ultra-rare renal diseases are characterized by fluid-phase dysregulation of the alternative complement pathway that leads to deposition of complement proteins in the renal glomerulus. Disease triggers are unknown and because targeted treatments are lacking, progress to end stage renal failure is a common final outcome. We studied soluble CR1, a potent regulator of complement activity, to test whether it restores complement regulation in C3 glomerulopathy.In vitro studies using sera from patients with DDD showed that soluble CR1 prevents dysregulation of the alternative pathway C3 convertase, even in the presence of C3 nephritic factors.

In mice deficient in complement factor H and transgenic for human CR1, soluble CR1 therapy stopped alternative pathway activation, resulting in normalization of serum C3 levels and clearance of iC3b from glomerular basement membranes. Short-term use of soluble CR1 in a pediatric patient with end stage renal failure demonstrated its safety and ability to normalize activity of the terminal complement pathway. Overall, these data indicate that soluble CR1 re-establishes regulation of the alternative complement pathway and provide support for a limited trial to evaluate soluble CR1 as a treatment for DDD and C3GN.

致密物沉积病(DDD)和C3肾小球肾炎 (C3GN)是C3肾小球病的两种常见的亚型。这些极其少见的肾脏疾病以液相中补体旁路途径因子失调为特点。补体旁路因子失调可以导致肾小球补体蛋白的沉积。目前由于此种疾病的诱导因素还不明确、靶向治疗缺乏，终末期肾衰竭成为自种疾病的常见肾脏预后。我们研究了可溶性的CR1（一种潜在的补体活性的调节因子），检测其是否能在C3肾小球病患者中使补体活性保持。体外实验采用DDD患者的血清，发现在C3肾炎因子存在的条件下，可溶性CR1可以抑制旁路途径C3转化酶的失调。在H因子基因缺陷而转入人源性的CR1基因的小鼠中，可溶性CR1治疗可以是旁路的活化暂停，进而导致血清C水平恢复正常，肾小球基底膜上沉积的IC3b沉积被清除。在一个进入终末期肾衰竭的儿科患者体内短期应用可溶性的CR1后证实了其安全性以及抑制补体活化至终末途径的能力。总体来讲这些数据提示：可溶性CR1可以调节补体旁路途径，并为用可溶性CR1治疗DDD和C3肾小球病做出了有限的尝试。