Magro Cynthia M, Pope Harman Amy, Klinger Dana, Orosz Charles, Adams Patrick, Waldman James, Knight Deborah, Kelsey Moira, Ross Patrick
Department of Pathology, The Ohio State University, Columbus, OH, USA.
Am J Transplant. 2003 Sep;3(9):1143-54. doi: 10.1034/j.1600-6143.2003.00152.x.
Humoral allograft rejection is a defined mechanism for cardiac and renal graft dysfunction; C4d deposition, a stable component of complement activation, inversely correlates with graft survival. With the recent recognition of humoral rejection in lung grafts, we examined C4d's role as a prognostic adjunct in lung allografts.
Twenty-three lung recipients underwent biopsies for deterioration in clinical status or routine surveillance. Clinically unwell patients possessed acute rejection or bronchiolitis obliterans syndrome (BOS). Biopsies attributable to infection were excluded from the study. In addition to routine light microscopy, an attempt was made to correlate the clinical status and morphologic findings with the pattern of C4d deposition and also to compare these clinical and morphologic parameters with the other assessed immunoreactants. Panel reactive antibody testing was also carried out at various points in their post transplantation course whereby in 6 of the cases the samples were procured at exactly the same time as the tissue samples.
The patients were segregated into two groups: those patients with recurrent acute rejection and those with BOS. In those patients with symptomatic acute rejection, all biopsies showed light microscopic and immunofluorescent evidence of humoral allograft rejection. The level of C4d was positively correlated with the degree of parenchymal injury, the hallmark being one of septal capillary necrosis. In addition, high and intermediate levels of C4d correlated with a clinical diagnosis of acute rejection. C4d was the strongest predictor of parenchymal injury and of the clinical status (p <.0001) compared to other the immunoreactants C1q, C5b-9 and immunoglobulin. There was no specific correlation between C4d deposition and the presence of acute cellular rejection. In those patients fulfilling clinical criteria of BOS, deposits of C4d as well as other immunoreactants were found in the bronchial wall as opposed to the rarity of this finding in bon-BOS patients. However the only statistically significant predictor of BOS was bronchial wall deposition of C1q. In no case were panel reactive antibodies at significant levels discovered post transplantation.
In the context of acute rejection, C4d deposition correlates with clinical evidence of rejection and the degree of humoral rejection assessed pathologically; there is no association with the presence of histocompatibility related antibodies. It is a more specific predictor of allograft status compared to other immunoreactants. C4d deposition within the bronchial wall is a feature of BOS and hence may be used as a marker of chronic graft dysfunction. The antigenic target resulting in C4d deposition may not be histocompatibility related.
体液性同种异体移植排斥反应是心脏和肾脏移植功能障碍的一种明确机制；C4d沉积作为补体激活的一个稳定成分，与移植器官的存活呈负相关。随着近期对肺移植中体液性排斥反应的认识，我们研究了C4d在肺同种异体移植中作为预后辅助指标的作用。
23例肺移植受者因临床状况恶化或进行常规监测而接受活检。临床不适的患者存在急性排斥反应或闭塞性细支气管炎综合征（BOS）。将归因于感染的活检标本排除在研究之外。除常规光学显微镜检查外，还试图将临床状况和形态学发现与C4d沉积模式相关联，并将这些临床和形态学参数与其他评估的免疫反应物进行比较。在移植后的不同时间点还进行了群体反应性抗体检测，其中6例患者的样本采集时间与组织样本完全相同。
患者被分为两组：反复发生急性排斥反应的患者和患有BOS的患者。在有症状性急性排斥反应的患者中，所有活检标本均显示有体液性同种异体移植排斥反应的光学显微镜和免疫荧光证据。C4d水平与实质损伤程度呈正相关，其特征之一是间隔毛细血管坏死。此外，C4d的高、中水平与急性排斥反应的临床诊断相关。与其他免疫反应物C1q、C5b-9和免疫球蛋白相比，C4d是实质损伤和临床状况的最强预测指标（p<.0001）。C4d沉积与急性细胞排斥反应的存在之间没有特定的相关性。在符合BOS临床标准的患者中，在支气管壁发现了C4d以及其他免疫反应物的沉积，而在非BOS患者中这种发现很少见。然而，BOS唯一具有统计学意义的预测指标是支气管壁C1q沉积。在任何情况下，移植后均未发现群体反应性抗体水平显著升高。
在急性排斥反应的背景下，C4d沉积与排斥反应的临床证据以及病理评估的体液性排斥反应程度相关；与组织相容性相关抗体的存在无关。与其他免疫反应物相比，它是同种异体移植状态更具特异性的预测指标。支气管壁内的C4d沉积是BOS的一个特征，因此可作为慢性移植功能障碍的标志物。导致C4d沉积的抗原靶点可能与组织相容性无关。
