Inhibition of tumor necrosis factor production by lymphocytes from anti-TNF antibody-treated, cardiac-allografted rats.
Tumor necrosis factor-alpha (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/10(6) spleen cells vs 76.4 u/10(6) spleen cells at 2 hr and 4.6 u/10(6) lymph node cells vs 9.2 u/10(6) 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/10(6) cells vs 189.4 u/10(6) 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/10(6) cells vs 40.4 u/10(6) cells at 24 hr; lymph node cells, 1.2 u/10(6) cells vs 22.2 u/10(6) 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.
Section of Thoracic Surgery, University of Michigan Medical Center, Ann Arbor 48109.
R Q
RQ
Wei
H
H
Lin
G H
GH
Chen
D G
DG
Beer
S L
SL
Kunkel
S F
SF
Bolling
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D017690:Cell Transplantation; D006085:Graft Survival; D016027:Heart Transplantation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008198:Lymph Nodes / Q000166:cytology / Q000000981:diagnostic imaging / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D011859:Radiography; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000166:cytology / Q000000981:diagnostic imaging / Q000378:metabolism; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000276:immunology*
D000906:Antibodies; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha