Induction of tolerance to heart allografts in high responder rats by combining anti-CD4 with CTLA4Ig.
It has been difficult to induce donor-specific transplantation tolerance in high responder Lewis rats. Results presented below demonstrate that amounts of pretransplant anti-CD4 sufficient to allow allograft tolerance in low responder strains (5 mg/kg x 4 days) did not prevent the acute rejection of ACI heart allografts in high responder Lewis recipients. Higher doses of pretransplant anti-CD4 (10 mg/kg, 15 mg/kg, and 20 mg/kg) given alone could delay but not prevent allograft rejection. Pretransplant anti-CD4 combined with anti-CD8, thymectomy, and total lymphoid irradiation all failed to produce tolerance to ACI heart allografts. However, a regimen of anti-CD4 combined with CTLA4Ig allowed indefinite survival of ACI heart allografts (mean survival time, > 100 day). Second-donor matched heart grafts were permanently accepted, and third-party heart grafts were permanently accepted, and third-party heart allografts were rejected by the tolerant recipients. These results suggest a new combination therapeutic strategy for clinical transplantation.
Yin
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Department of Medicine, Stanford University School of Medicine, CA 94305, USA.
Fathman
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CG
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance; D018796:Immunoconjugates; D008297:Male; D051379:Mice; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D000069594:Abatacept