Glickman Urological and Kidney Institute, Department of Immunology, Cleveland, OH, USA.
Am J Transplant. 2010 Jan;10(1):59-68. doi: 10.1111/j.1600-6143.2009.02921.x. Epub 2009 Dec 2.
The acute phase cytokines IL-1beta, IL-6 and TNFalpha are produced early during inflammatory processes, including ischemia-reperfusion. The appearance and role of these cytokines in the early inflammation following reperfusion of grafts remain poorly defined. This study investigated the role of TNFalpha in the induction of early leukocyte infiltration into vascularized heart allografts. TNFalpha and IL-6 mRNA levels reached an initial peak 3 h posttransplant and a second peak at 9-12 h with equivalent levels in iso- and allografts. A single dose of anti-TNFalpha mAb given at reperfusion decreased neutrophil and macrophage chemoattractant levels and early neutrophil, macrophage and memory CD8 T-cell infiltration into allografts. Anti-TNFalpha mAb also extended graft survival from 8.6+/-0.6 days to 14.1+/-0.8 days. When assessed on day 7 posttransplant, the number of donor-reactive CD8 T cells producing IFN-gamma in the spleen was reduced almost 70% in recipients treated with anti-TNFalpha mAb. Whereas anti-CD154 mAb prolonged survival to day 21, administration of anti-TNFalpha and anti-CD154 mAb delayed rejection to day 32 and resulted in long-term (>80 days) survival of 40% of the heart allografts. These data implicate TNFalpha as an important mediator of early inflammatory events in allografts that undermine graft survival.
在包括缺血再灌注在内的炎症过程中，早期就会产生急性相细胞因子白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）。这些细胞因子在再灌注后移植物早期炎症中的出现和作用仍未得到明确界定。本研究探讨了 TNF-α在诱导血管化心脏同种异体移植物早期白细胞浸润中的作用。TNF-α和 IL-6mRNA 水平在移植后 3 小时达到初始峰值，9-12 小时达到第二个峰值，同基因和同种异体移植物的水平相当。在再灌注时给予单次剂量的抗 TNF-α mAb 可降低中性粒细胞和巨噬细胞趋化因子水平，并减少早期中性粒细胞、巨噬细胞和记忆 CD8 T 细胞浸润同种异体移植物。抗 TNF-α mAb 还将移植物存活期从 8.6+/-0.6 天延长至 14.1+/-0.8 天。在移植后第 7 天评估时，接受抗 TNF-α mAb 治疗的受者脾脏中产生 IFN-γ的供体反应性 CD8 T 细胞数量减少了近 70%。虽然抗 CD154 mAb 将存活期延长至第 21 天，但给予抗 TNF-α和抗 CD154 mAb 可将排斥反应延迟至第 32 天，并导致 40%的心脏同种异体移植物长期（>80 天）存活。这些数据表明 TNF-α是同种异体移植物中早期炎症事件的重要介质，破坏移植物存活。
