The role of tumor necrosis factor in allograft rejection. II. 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-alpha 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 heterotropic 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-alpha prolonged graft survival to 16 +/- 2.7 days (P less than 0.05 vs. controls); the i.v. administration prolonged survival to 15 +/- 1.4 days (P less than 0.004). Animals treated with i.p. anti-LT survived 17 +/- 1.7 days (P less than 0.002 vs. controls). Combination immunotherapy of anti-TNF-alpha and anti-LT increased function to 21 +/- 2.2 days (P less than 0.001 vs controls). Conversely, administration of purified TNF-alpha or LT to graft recipients accelerated the time to rejection. Mean survival for both treatments was 7 days (P less than 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-alpha or LT to recipients of a syngeneic heart did not stimulate rejection. These data suggest that TNF-alpha 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-alpha or LT-mediated cytotoxicity of tumor cells.
Department of Surgery, University of California, Los Angeles School of Medicine 90024.
D K
DK
Imagawa
J M
JM
Millis
K M
KM
Olthoff
P
P
Seu
R A
RA
Dempsey
J
J
Hart
P I
PI
Terasaki
E M
EM
Wasef
R W
RW
Busuttil
D000818:Animals; D006084:Graft Rejection; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D007158:Immunologic Techniques; D008233:Lymphotoxin-alpha / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha