title: Combination treatment with donor-specific transfusions and cyclosporine a induces long-term survival of cardiac allografts in miniature Swine.
abstract: BACKGROUND
  To evaluate whether pretransplant donor-specific transfusions (DST) can induce tolerance to cardiac allografts in large animals, heterotopic cardiac transplants were performed across a class I MHC barrier in inbred miniature swine.
  
  
  METHODS
  Experimental animals received two DSTs, each containing 1.4x10 viable peripheral blood mononuclear cells, 14 and 7 days prior to transplantation together with a 12-day course of cyclosporine (CyA) (13 mg/kg IV) starting on postoperative day (POD) 0.
  
  
  RESULTS
  Untreated (n=2) and DST-only (n=2) treated control animals rejected between POD 6 and 8. Animals treated with CyA alone (n=3) exhibited graft survival to 53, 52 and 59 days. In contrast, the combination of DST and CyA (n=3) led to stable graft function for >200 days. Long-term survivors maintained peripheral CML response against donor antigen. Following DSTs, the donor-specific proliferative response of CD8+ recipient T cells was significantly increased (P=0.011), and a significant number of CD8+ T cells underwent apoptosis (10.1% on POD 0; 5.2% on POD -14; P=0.04). None of the DST-treated animals developed donor-specific antibodies.
  
  
  CONCLUSIONS
  These results are the first to demonstrate the ability of DST to induce operational tolerance to cardiac allografts in large animals, and they suggest that peripheral mechanisms of tolerance mediate this effect.
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ruediger
authors.initials: R
authors.lastname: Hoerbelt
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Johnston
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shoji
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Houser
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Hasse
authors.forename: Levi G
authors.initials: LG
authors.lastname: Ledgerwood
authors.forename: Alexander
authors.initials: A
authors.lastname: Iribarne
authors.forename: James S
authors.initials: JS
authors.lastname: Allan
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: David H
authors.initials: DH
authors.lastname: Sachs
authors.forename: Joren C
authors.initials: JC
authors.lastname: Madsen
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D001803:Blood Transfusion; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D049109:Cell Proliferation; D003331:Coronary Vessels / Q000473:pathology; D016572:Cyclosporine / Q000627:therapeutic use*; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D013552:Swine; D013556:Swine, Miniature; D013602:T-Lymphocytes, Cytotoxic / Q000473:pathology; D013997:Time Factors; D014019:Tissue Donors; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine