Antibodies against tumor necrosis factor prolong cardiac allograft survival in the rat.

Tumor necrosis factor (TNF)-alpha has significant biologic actions in many circumstances, such as infectious diseases, ischemia/reperfusion injury, and delayed-type hypersensitivity reactions. Based on the hypothesis that manipulation of TNF can play an important role in treatment of heart transplant rejection, the objective of this study was to determine whether anti-TNF antibodies could prolong cardiac allograft survival. Hearts from brown rats were transplanted to the necks of recipient Lewis rats. Graft survival was determined by direct palpation of the heart; complete graft rejection was defined by cessation of contraction. In untreated rats, the hearts were rejected 6.8 +/- 0.6 days (n = 10; mean +/- SEM) after transplantation. The mononuclear cell infiltrate in the transplanted hearts stained intensely for TNF by immunohistochemistry, indicating that TNF was present within the inflammatory cells associated with the rejection process. In rats receiving a single injection of anti-TNF antibody at the time of transplantation (n = 6), however, graft survival was nearly doubled (12.7 +/- 1.4 days; p less than 0.001 vs controls). Prolonged cardiac graft survival was also evident if the anti-TNF treatment was delayed until 1 day (n = 5; rejection at 16.2 +/- 2.4 days; p less than 0.001 vs controls) or even 3 days after transplantation (n = 5; rejection at 11.4 +/- 2.3 days; p less than 0.005 vs controls). Treatment at 5 days after transplantation, however, was not effective (n = 3; rejection at 7.7 +/- 0.6 days; p, not significant vs controls). The data indicate that a single bolus of anti-TNF antibodies can delay heart transplant rejection, even when administered up to 3 days after implantation, supporting the potential utility of anti-TNF therapy for treatment of heart transplant rejection.