title: Successful induction of long-term specific tolerance to fully allogeneic renal allografts in miniature swine.
abstract: Major histocompatibility complex class II matching is of overwhelming importance for achieving tolerance to kidney transplants (KTX) in miniature swine. When class II antigens are matched, long-term specific tolerance across complete MHC class I antigen barriers can uniformly be induced by a 12-day perioperative course of cyclosporine. This same regimen is ineffective in fully MHC-mismatched combinations. We hypothesized that initial induction of tolerance to kidney donor class II antigens by bone marrow transplantation might allow tolerance to be induced to a subsequent fully allogeneic KTX in combination with CsA therapy. We report here the results of such fully allogeneic KTX performed in 4 recipients of prior single-haplotype class II-mismatched BMT. All animals received KTX from donors class II matched to the BMT donor and received a 12-day course of intravenous CsA (10 mg/kg/day). All four animals have maintained normal serum creatinine values (less than 2.0 mg/dl) for greater than 200 days posttransplant. Specific hyporesponsiveness to both BMT and KTX donor-type MHC antigens was found in mixed lymphocyte culture and cell-mediated lympholysis assays. Compared with third-party grafts, significantly prolonged survival of BMT donor-specific (P = 0.031) and KTX donor-specific (P = 0.031) skin grafts was observed. These results demonstrate that induction of tolerance to class II antigens by BMT allows a short course of CsA to induce specific tolerance to fully allogeneic renal allografts.
authors.affiliation: Transplantation Biology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: C V
authors.initials: CV
authors.lastname: Smith
authors.forename: K
authors.initials: K
authors.lastname: Nakajima
authors.forename: A
authors.initials: A
authors.lastname: Mixon
authors.forename: P C
authors.initials: PC
authors.lastname: Guzzetta
authors.forename: B R
authors.initials: BR
authors.lastname: Rosengard
authors.forename: J M
authors.initials: JM
authors.lastname: Fishbein
authors.forename: D H
authors.initials: DH
authors.lastname: Sachs
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D016572:Cyclosporine / Q000627:therapeutic use; D006085:Graft Survival; D007108:Immune Tolerance / Q000187:drug effects; D007109:Immunity / Q000187:drug effects; D016030:Kidney Transplantation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D016038:Skin Transplantation / Q000276:immunology; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D016572:Cyclosporine