Anti-tumor necrosis factor antibody enhances allograft survival in rats

We have recently observed significantly elevated serum tumor necrosis factor-α (TNF-α) levels during human liver allograft rejection. Although increased TNF activity has been reported in rejecting rat cardiac and renal allografts, this represents the first report of an animal model utilizing immunotherapy directed against TNF. Intraabdominal heart transplants (Buffalo to Lewis) were performed. Cardiac rejection was defined as cessation of a palpable beat and confirmed at laparotomy. Control animals received no immunotherapy and experienced rejection on Postoperative Day 11 ± 0.4 (mean ± SEM). Experimental animals received immunotherapy either intraperitoneally (ip) or intravenously (iv) from Days 1 to 10. Intraperitoneally administered anti-TNF-α prolonged graft survival to 16 ± 2.7 days (P < 0.05 vs controls), iv administration prolonged survival to 15 ± 1.4 days (P < 0.004). Animals treated with ip anti-TNF-β survived 17 ± 1.7 days (P < 0.002 vs controls). Conversely, administration of purified TNF-α to graft recipients decreased graft survival to 7 ± 0.4 days (P < 0.001 vs controls). Serum samples analyzed in an L929 bioassay showed increased cytotoxic activity in control animals, corresponding to an increase in circulating TNF. This activity was partially abrogated in animals receiving immunotherapy. These data demonstrate that circulating levels of TNF are increased during rejection. Immunotherapy with anti-TNF-α or anti-TNF-β prolongs graft survival, suggesting that TNF may play a role in the pathogenesis of acute allograft rejection.