Studies investigating pretransplant donor-specific blood transfusion, rapamycin, and the CD154-specific antibody IDEC-131 in a nonhuman primate model of skin allotransplantation.
Anti-CD154 variably prolongs allograft survival in nonhuman primates. Rodent studies suggest that adding pretransplant donor-specific transfusion (DST) and/or rapamycin to anti-CD154 improves survival. The CD154-specific Ab IDEC-131 was tested alone and in combination with rapamycin for its ability to inhibit rhesus MLRs. The ability of the Ab to block endothelial activation was also assessed. IDEC-131 was then tested alone and in combination with DST and/or rapamycin for its ability to prevent rejection of full-thickness, MHC-mismatched rhesus skin allografts. Animals were monitored for donor-specific hyporesponsiveness by MLR and alloantibody determination. IDEC-131 modestly inhibited rhesus MLRs and inhibited CD154-dependent endothelial cell activation. Rapamycin combined with IDEC-131 additively inhibited MLRs. IDEC-131 modestly prolonged allograft survival when compared with no treatment, rapamycin alone, or DST plus rapamycin. Adding DST to IDEC-131 did not prolong survival beyond IDEC-131 alone. IDEC-131 plus rapamycin was effective in prolonging graft survival, although animals had episodes of acute rejection before graft demise. Therapy with IDEC-131, rapamycin, and DST induced long-term allograft survival without intermittent acute rejection. However, no evidence for MLR inhibition was seen, and most animals eventually developed alloantibody. All animals ultimately rejected their grafts after drug withdrawal. IDEC-131 modestly prolongs rhesus skin allograft survival. Rapamycin and rapamycin plus DST improves the efficacy of IDEC-131 in prolonging allograft survival. IDEC-131, rapamycin, and DST are a promising combination for clinical evaluation in allotransplantation.
Xu
He
H
Transplantation and Autoimmunity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
Montgomery
Sean P
SP
Preston
Edwin H
EH
Tadaki
Douglas K
DK
Hale
Douglas A
DA
Harlan
David M
DM
Kirk
Allan D
AD
D000284:Administration, Oral; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001803:Blood Transfusion / Q000379:methods; D017252:CD3 Complex / Q000276:immunology; D023201:CD40 Ligand / Q000096:biosynthesis / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006082:Graft Enhancement, Immunologic / Q000379:methods; D006801:Humans; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007275:Injections, Intravenous; D007518:Isoantibodies / Q000096:biosynthesis; D007959:Lymphocyte Culture Test, Mixed; D008253:Macaca mulatta; D018448:Models, Immunological; D020123:Sirolimus / Q000008:administration & dosage / Q000627:therapeutic use*; D016038:Skin Transplantation / Q000276:immunology* / Q000379:methods / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019172:Transplantation Conditioning / Q000379:methods
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D017252:CD3 Complex; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D023201:CD40 Ligand; C470330:toralizumab; D020123:Sirolimus