title: Tacrolimus-based partial conditioning produces stable mixed lymphohematopoietic chimerism and tolerance for cardiac allografts.
abstract: BACKGROUND
  Thoracic organ transplantation remains limited by the reciprocal problems of rejection and the toxicities of nonspecific immunosuppression. Mixed bone marrow chimerism reliably produces donor-specific transplantation tolerance without immunosuppressive drugs. We have previously described a nonmyeloablative conditioning regimen based on recipient treatment with antilymphocyte serum, tacrolimus, and low-dose total-body irradiation that yields long-term multilineage allogeneic bone marrow chimerism in the rat. We have now investigated whether mixed bone marrow chimerism that arises from this partial conditioning strategy produces permanent acceptance of donor-specific cardiac allografts.
  
  
  RESULTS
  Mixed allogeneic chimeras (ACI-->WF) were prepared by treating Wistar Furth recipients with a single dose of antilymphocyte serum 5 days before bone marrow transplantation and tacrolimus 1 mg/kg/d from days -1 to 10. Five hundred cGy total-body irradiation was administered immediately before infusion of 1 x 10(8) donor (ACI) T-cell depleted marrow cells. All recipients were chimeric, with a mean level of donor chimerism = 26.3 +/- 3.5%. Chimeras underwent heterotopic cardiac transplantation 4 weeks after bone marrow transplantation. All donor-specific (ACI) grafts were permanently accepted (follow-up, 230 to 360 days). Third-party grafts were rapidly rejected. Histology of long-surviving donor-specific grafts was without evidence of acute or chronic rejection. Second-set donor-specific skin grafts transplanted to chimeras 135 days after heart transplantation showed long-term survival (> 130 days), whereas third-party skin grafts were rapidly rejected. Mixed lymphocyte reaction demonstrated in vitro donor-specific hyporeactivity.
  
  
  CONCLUSIONS
  A tacrolimus-based nonmyeloablative recipient conditioning regimen produces mixed bone marrow chimerism and donor-specific tolerance to cardiac allografts in the rat.
authors.affiliation: Division of Cardiothoracic Surgery, University of Pittsburgh Medical Center, PA 15261, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Gammie
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: A
authors.initials: A
authors.lastname: Zeevi
authors.forename: A J
authors.initials: AJ
authors.lastname: Demetris
authors.forename: S T
authors.initials: ST
authors.lastname: Ildstad
authors.forename: S M
authors.initials: SM
authors.lastname: Pham
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D002678:Chimera; D003213:Conditioning, Psychological / Q000502:physiology*; D006085:Graft Survival / Q000502:physiology; D016027:Heart Transplantation / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000502:physiology; D007108:Immune Tolerance / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000502:physiology; D051381:Rats; D011912:Rats, Inbred ACI; D011920:Rats, Inbred WF; D016038:Skin Transplantation / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology*; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus