Role of TNFα in Early Chemokine Production and Leukocyte Infiltration into Heart Allografts

The acute phase cytokines IL-1 beta, IL-6 and TNF alpha 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 TNF alpha in the induction of early leukocyte infiltration into vascularized heart allografts. TNF alpha 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-TNF alpha mAb given at reperfusion decreased neutrophil and macrophage chemoattractant levels and early neutrophil, macrophage and memory CD8 T-cell infiltration into allografts. Anti-TNF alpha 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-TNF alpha mAb. Whereas anti-CD154 mAb prolonged survival to day 21, administration of anti-TNF alpha 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 TNF alpha as an important mediator of early inflammatory events in allografts that undermine graft survival.