Monoclonal anti-tumor necrosis factor-alpha antibody treatment of rat cardiac allografts: synergism with low-dose cyclosporine and immunohistological studies.
Tumor necrosis factor (TNF) levels have been reported to be elevated during episodes of human renal, hepatic, and cardiac transplant rejection. In addition, we have shown polyclonal anti-TNF antibodies to have immunosuppressive effects. The present study was performed to evaluate the efficacy of a monoclonal anti-TNF-alpha antibody in rat cardiac transplantation as the sole immunosuppressant and in conjunction with low-dose cyclosporine (CsA). We also performed immunohistological studies to localize intragraft TNF and evaluate graft infiltrating cells (GICs), and we measured serum TNF levels by an ELISA. Untreated Buffalo to Lewis heterotopic rat cardiac transplants reject in 10.5 +/- 0.4 days. A 10-day induction course of CsA (2 mg/kg/day, po) prolonged survival to 16.7 +/- 2.7 days (P less than 0.05 vs control), and 10 days of anti-TNF (2000 U/day, ip) prolonged survival to 22.6 +/- 0.8 days (P less than 0.05 vs control). Combination of anti-TNF plus CsA synergistically prolonged graft survival to 40.7 +/- 1.8 days. Three-day courses of anti-TNF were moderately effective (13.7 +/- 0.5 days, P less than 0.05 vs control) and were also synergistic with CsA (27.8 +/- 2.2). Intragraft TNF localization using immunoperoxidase showed extensive perivascular and mononuclear cell staining in control hearts vs minimal staining in anti-TNF-treated groups. Likewise, serum TNF levels were significantly lowered for treated groups vs control (83.1 +/- 14.0 pg/ml for control; 39.5 +/- 13.8 for anti-TNF; and 13.4 +/- 5.4 for anti-TNF + CsA; P less than 0.05 vs control for all groups).(ABSTRACT TRUNCATED AT 250 WORDS)
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Department of Surgery, University of California, School of Medicine, Los Angeles 90024.
Imagawa
D K
DK
Wasef
E
E
Olthoff
K M
KM
Hart
J
J
Stephens
S
S
Dempsey
R A
RA
Busuttil
R W
RW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D003524:Cyclosporins / Q000008:administration & dosage* / Q000627:therapeutic use; D004357:Drug Synergism; D006085:Graft Survival; D016027:Heart Transplantation; D007124:Immunoenzyme Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011915:Rats, Inbred BUF; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D003524:Cyclosporins; D014409:Tumor Necrosis Factor-alpha