Smith R N, Kawai T, Boskovic S, Nadazdin O, Sachs D H, Cosimi A B, Colvin R B
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Am J Transplant. 2008 Aug;8(8):1662-72. doi: 10.1111/j.1600-6143.2008.02303.x. Epub 2008 Jun 28.
The etiology of immunologically mediated chronic renal allograft failure is unclear. One cause is thought to be alloantibodies. Previously in Cynomolgus monkeys, we observed a relationship among donor-specific alloantibodies (DSA), C4d staining, allograft glomerulopathy, allograft arteriopathy and progressive renal failure. To define the natural history of chronic antibody-mediated rejection and its effect on renal allograft survival, we now extend this report to include 417 specimens from 143 Cynomolgus monkeys with renal allografts. A subset of animals with long-term renal allografts made DSA (48%), were C4d positive (29%), developed transplant glomerulopathy (TG) (22%) and chronic allograft arteriopathy (CAA) (19%). These four features were highly correlated and associated with statistically significant shortened allograft survival. Acute cellular rejection, either Banff type 1 or 2, did not correlate with alloantibodies, C4d deposition or TG. However, endarteritis (Banff type 2) correlated with later CAA. Sequential analysis identified four progressive stages of chronic antibody-mediated rejection: (1) DSA, (2) deposition of C4d, (3) TG and (4) rising creatinine/renal failure. These new findings provide strong evidence that chronic antibody-mediated rejection develops without enduring stable accommodation, progresses through four defined clinical pathological stages and shortens renal allograft survival.
免疫介导的慢性肾移植失败的病因尚不清楚。一种原因被认为是同种异体抗体。此前在食蟹猴中，我们观察到供体特异性同种异体抗体（DSA）、C4d染色、移植肾肾小球病、移植肾动脉病与进行性肾衰竭之间的关系。为了明确慢性抗体介导排斥反应的自然病程及其对肾移植存活的影响，我们现将本报告扩展至纳入143只接受肾移植的食蟹猴的417份标本。一部分长期肾移植的动物产生了DSA（48%），C4d呈阳性（29%），发生了移植肾小球病（TG）（22%）和慢性移植肾动脉病（CAA）（19%）。这四个特征高度相关，且与移植肾存活时间在统计学上显著缩短相关。急性细胞排斥反应，无论是班夫1型还是2型，均与同种异体抗体、C4d沉积或TG无关。然而，动脉内膜炎（班夫2型）与后期的CAA相关。序贯分析确定了慢性抗体介导排斥反应的四个进展阶段：（1）DSA，（2）C4d沉积，（3）TG，（4）肌酐升高/肾衰竭。这些新发现提供了强有力的证据，表明慢性抗体介导的排斥反应在没有持久稳定适应的情况下发生，通过四个明确的临床病理阶段进展，并缩短肾移植存活时间。
