THE ROLE OF TUMOR-NECROSIS-FACTOR IN ALLOGRAFT-REJECTION .2. EVIDENCE THAT ANTIBODY THERAPY AGAINST TUMOR NECROSIS FACTOR-ALPHA AND LYMPHOTOXIN ENHANCES CARDIAC ALLOGRAFT SURVIVAL IN RATS

In the previous study we demonstrated that circulating levels of TNF-α are elevated during liver allograft rejection and may precede clinical manifestations. The current study was designed to investigate the efficacy of antibody therapy against tumor necrosis factor-alpha and lymphotoxin (LT) in a rat heterotopic cardiac transplant model utilizing Buffalo donors and Lewis recipients. Control animals received no immunotherapy and experienced rejection on postoperative day 11 ± 0.4 (mean ± SEM). Experimental animals received immunotherapy either intraperitoneal or intravenous from days 1 to 10. The i.p. administered anti-TNF-α prolonged graft survival to 16 ± 2.7 days (P < 0.05 vs. controls); the i.v. administration prolonged survival to 15 ± 1.4 days (P < 0.004). Animals treated with i.p. anti-LT survived 17 ± 1.7 days (P < 0.002 vs. controls). Combination immunotherapy of anti-TNF-α and anti-LT increased function to 21 ± 2.2 days (P < 0.001 vs. controls). Conversely, administration of purified TNF-α or LT to graft recipients accelerated the time to rejection. Mean survival for both treatments was 7 days (P < 0.001 vs. controls). Histologic examination of the transplanted cardiac tissue showed a typical pattern for acute rejection; there was no evidence of hemorrhagic or coagulative necrosis. In contrast, administration of purified TNF-α or LT to recipients of a syngeneic heart did not stimulate rejection. These data suggest that TNF-α and LT may play a role in the pathogenesis of acute allograft rejection. In addition, the mechanism appears to be distinct from that seen in TNF-α or LT-mediated cytotoxicity of tumor cells.