TY - JOUR
T1 - Monoclonal anti-tumor necrosis factor-α antibody treatment of rat cardiac allografts
T2 - Synergism with low-dose cyclosporine and immunohistological studies
AU - Seu, Philip
AU - Imagawa, David K.
AU - Wasef, Evette
AU - Olthoff, Kim M.
AU - Hart, John
AU - Stephens, Sue
AU - Dempsey, Roy A.
AU - Busuttil, Ronald W.
N1 - Funding Information:
r This work was supported Liver Transplant Foundation. ’ D. K. Imagawa was supported Training Grant, CA 09120, from 3 Address correspondence and til M.D., Ph.D. UCLA Department gram, University of California geles, CA 90024.
Funding Information:
in part by the Tumor Immunology the National Institutes of Health. reprint requests to Ronald W. Busut-of Surgery, Liver Transplant Pro-at Los Angeles, CHS 77-132, An-
PY - 1991/5
Y1 - 1991/5
N2 - 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.
AB - 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.
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U2 - 10.1016/0022-4804(91)90035-K
DO - 10.1016/0022-4804(91)90035-K
M3 - Article
C2 - 2038191
AN - SCOPUS:0025779107
SN - 0022-4804
VL - 50
SP - 520
EP - 528
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 5
ER -