THE ROLE OF TUMOR-NECROSIS-FACTOR IN ALLOGRAFT-REJECTION .3. EVIDENCE THAT ANTI-TNF ANTIBODY THERAPY PROLONGS ALLOGRAFT SURVIVAL IN RATS WITH ACUTE REJECTION

We have previously demonstrated that TNF-alpha-levels are elevated in liver transplant patients experiencing acute rejection. In addition, prophylactic administration of anti-TNF-alpha-or anti-TNF-beta-antibodies prolonged graft survival in a rat heterotopic cardiac transplant model. This experiment was designed to evaluate anti-TNF therapy in the treatment of acute allograft rejection. Heterotopic cardiac transplants were performed using Buffalo donors and Lewis recipients. Histologic sections of transplanted grafts from untreated animals revealed significant rejection at day 4 with terminal rejection occurring on day 10.8 +/- 0.4. Animals in the experimental groups received antirejection therapy from postoperative days 4-13. Treatment with cyclosporine at 2 mg/kg/day prolonged graft survival to 16.5 +/- 2.0 days (P = 0.01 versus controls). Administration of polyclonal anti-TNF-alpha-in combination with polyclonal anti-TNF-beta increased graft survival to 14.6 +/- 0.4 days (P < 0.001 versus controls). Use of monoclonal anti-TNF-alpha anti-body was even more effective, with graft survival of 17.4 +/- 0.7 days (P < 0.001 versus controls). Combination immunotherapy with monoclonal anti-TNF-alpha in conjunction with CsA extended survival to greater than 30 days. In contrast, recombinant TNF-alpha (5-mu-g/day, i.p.) markedly accelerated the time to graft failure (7.4 +/- 0.2 days, P < 0.001 versus controls). Examination of explanted graft tissue on postoperative day 9 from animals treated with anti-TNF showed decreased mononuclear cell infiltrate when compared to untreated animals. Treatment with TNF-alpha-markedly increased the inflammatory process. These results suggest that TNF may play a role in the pathogenesis of acute rejection.