An experimental model of acute humoral rejection of renal allografts associated with concomitant cellular rejection
An experimental model of acute humoral rejection of renal allografts associated with concomitant cellular rejection
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DOI：
10.2353/ajpath.2008.070391
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发表时间：
2008-08-01
影响因子：
6
通讯作者：
Naclasdy, Tibor
中科院分区：
文献类型：
--
作者：
Bickerstaff, Alice;Pelletier, Ronald;Naclasdy, Tibor
急性体液性排斥反应（AHR）发生在高达8%的肾移植受者中，是导致肾移植物功能障碍和损失的重要原因。需要更有效的治疗方式来消除或减少同种抗体的产生及其对肾脏的有害影响。模拟人类AHR的动物模型的可用性对于了解其病理生理学和开发新的治疗策略至关重要。使用小鼠肾移植模型，我们证明了受体与供体皮肤移植物的预致敏导致随后的肾移植物排斥。移植后8.6 +/- 4.3天，所有预致敏小鼠均发生肾衰竭，血清肌酐值接近100 μ mol/dl。移植物组织学显示轻度、弥漫性、间质性单核细胞浸润;显著的肾小管周围毛细血管炎性细胞边缘化;斑片状间质出血;间质水肿;局灶性肾小球纤维蛋白沉积。补体（C3 d）沉积是弥漫性的，在肾小管周围毛细血管突出。血清分析表明，高水平的循环同种抗体具有广泛的交叉反应，许多MHC单倍型。我们的模型的临床背景和组织学结果与AHR非常相似，AHR经常与细胞排斥反应相关，这是人类肾移植受者常见的情况。该动物模型为研究AHR的发病机制、其与细胞同种免疫的关系、其对移植物损伤的贡献以及各种潜在治疗干预的效果提供了有价值的工具。
Acute humoral rejection (AHR), which occurs in up to 8% of kidney transplant recipients, is a significant cause of renal allograft dysfunction and loss. More efficacious treatment modalities are needed to eliminate or curtail alloantibody production and its deleterious effects on the kidney. The availability of animal models mimicking human AHR is essential to understand its pathophysiology and develop new treatment strategies. Using a mouse kidney transplant model, we demonstrate that presensitization of recipients with donor skin grafts results in rejection of subsequent renal allografts. All presensitized mice developed renal failure 8.6 +/- 4.3 days after engraftment, with serum creatinine values near 100 mu mol/dl Graft histology revealed mild, diffuse, interstitial, mononuclear cell infiltrates; prominent peritubular capillary inflammatory cell margination; patchy interstitial hemorrhage; interstitial edema; and focal glomerular fibrin deposition. Complement (C3d) deposition was diffuse and prominent in peritubular capillaries. Serum analysis demonstrated high levels of circulating alloantibodies with broad cross-reactivity to many MHC haplotypes. The clinical setting and histological findings of our model strongly resemble AHR, which is frequently associated with cellular rejection, a situation commonly encountered in human renal allograft recipients. This animal model provides a valuable tool to study the pathogenesis of AHR, its relationship to cellular alloimmunity, its contribution to graft injury, and the effects of various potential therapeutic interventions.