Inhibition of Tumor Necrosis Factor Production by Lymphocytes from Anti-TNF Antibody-Treated, Cardiac-Allografted Rats

Abstract

Tumor necrosis factor-α (TNF) is a multifunctional cytokine involved in the immunopathologic consequences of allograft rejection. We have previously demonstrated that anti-TNF antibody treatment prolongs cardiac allograft survival in rats. To elucidate the mechanism of anti-TNF antibody in modulating the immune response, we investigated TNF production by spleen and lymph node cells from anti-TNF antibody-treated Lewis rats who received MHC-mismatched Brown Norway rat cardiac allografts. In 10 untreated rats, cardiac allografts were rejected at 6.8 ± 0.6 days after transplantation (mean ± SD). Anti-TNF antibody treatment enhanced graft survival to 12.7 ± 1.4 days (P < 0.001 vs controls). In other anti-TNF antibody-treated recipients spleen and lymph node cells were isolated on Day 5 after transplant. TNF production was measured and showed significantly less TNF than those from untreated (no anti-TNF antibody), transplanted recipient rats (28.7 u/106 spleen cells vs 76.4 u/106 spleen cells at 2 hr and 4.6 u/106 lymph node cells vs 9.2 u/106 lymph node cells at 24 hr). Furthermore, following lipopolysaccharide stimulation, spleen cells from anti-TNF-treated rats again produced significantly less TNF than those from untreated transplanted rats (68.9 u/106 cells vs 189.4 u/106 cells at 2 hr). Finally, with allogeneic cell stimulation, anti-TNF treated rats again produced significantly less TNF than untreated transplanted rats (spleen cells, 2.2 u/106 cells vs 40.4 u/106 cells at 24 hr; lymph node cells, 1.2 u/106 cells vs 22.2 u/106 cells at 72 hr). These findings suggest that anti-TNF antibody treatment may not only neutralize TNF activity, but also suppress TNF production itself, providing a new insight into the regulation of TNF by anti-TNF antibody.