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

The acute phase cytokines IL-1β, IL-6 and TNFα 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 TNFα in the induction of early leukocyte infiltration into vascularized heart allografts. TNFα and IL-6 mRNA levels reached an initial peak 3 hrs post-transplant and a second peak at 9-12 hrs with equivalent levels in iso- and allo-grafts. A single dose of anti-TNFα mAb given at reperfusion decreased neutrophil and macrophage chemoattractant levels and early neutrophil, macrophage and memory CD8 T cell infiltration into allografts. Anti-TNFα mAb also extended graft survival from 8.6 ± 0.6 days to 14.1 ± 0.8 days. When assessed on day 7 post-transplant, the number of donor-reactive CD8 T cells producing IFN-γ in the spleen was reduced almost 70% in recipients treated with anti-TNFα mAb. Whereas anti-CD154 mAb prolonged survival to day 21, administration of anti-TNFα 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 TNFα as an important mediator of early inflammatory events in allografts that undermine graft survival.