Monoclonal anti-tumor necrosis factor-α antibody treatment of rat cardiac allografts: Synergism with low-dose cyclosporine and immunohistological studies

Philip Seu, David K. Imagawa, Evette Wasef, Kim M. Olthoff, John Hart, Sue Stephens, Roy A. Dempsey, Ronald W. Busuttil

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16 Scopus citations


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-α antibody in rat cardiac transplantation as the sole immunosuppressant and in conjunction with low-dose cyclosporine (CsA). We also performed immuno-histological 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 < 0.05 vs control), and 10 days of anti-TNF (2000 U/day, ip) prolonged survival to 22.6 ± 0.8 days (P < 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 < 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 < 0.05 vs control for all groups). Evaluation of GICs by peroxidase staining showed a significantly lower fraction of cytotoxic T-lymphocytes in anti-TNF-treated grafts (71% OX-8+ leukocytes for control vs 33% in anti-TNF grafts, P < 0.05). In conclusion, monoclonal anti-TNF-α antibody is effective in induction therapy of rat cardiac allografts in highly histoincompatible strains, and this effect is synergistic with low-dose CsA. Therapy with anti-TNF lowers serum TNF activity, as well as intragraft TNF production, and decreases infiltration by cytotoxic T-cells. This confirms that TNF is an important mediator of allograft rejection in our model and suggests mechanisms of action of anti-TNF immunotherapy.

Original languageEnglish (US)
Pages (from-to)520-528
Number of pages9
JournalJournal of Surgical Research
Issue number5
StatePublished - May 1991

ASJC Scopus subject areas

  • Surgery


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