title: Specific tolerance induction across a xenogeneic barrier: production of mixed rat/mouse lymphohematopoietic chimeras using a nonlethal preparative regimen.
abstract: The development of safe methods for inducing donor-specific tolerance across xenogeneic barriers could potentially relieve the critical shortage of allograft donors that currently limits the applicability of organ transplantation. We report here that such tolerance can be induced in a xenogeneic combination (rat----mouse) using a nonmyeloablative and nonlethal preparative regimen. Successful induction of chimerism and donor-specific transplantation tolerance required pretreatment of recipients with monoclonal antibodies (mAbs) against NK1.1, Thy-1.2, CD4 and CD8, followed by administration of 3 Gy whole body radiation (WBI), 7 Gy thymic irradiation, and infusion of T cell-depleted rat bone marrow cells (BMC). Rat cells appeared among peripheral blood lymphocytes (PBL) of such recipients by 2-3 wk, and rat T cells by 2-5 wk following bone marrow transplantation (BMT). Donor-type rat skin grafts placed 4 mo after BMT were accepted, while simultaneously placed non-donor-type rat skin grafts were promptly rejected. In addition to its clinical potential, the ability to induce donor-specific tolerance across xenogeneic barriers using such a nonlethal preparative regimen provides a valuable model for the study of mechanisms of xenogeneic transplantation tolerance.
authors.affiliation: Transplantation Biology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Y
authors.initials: Y
authors.lastname: Sharabi
authors.forename: I
authors.initials: I
authors.lastname: Aksentijevich
authors.forename: T M
authors.initials: TM
authors.lastname: Sundt
authors.forename: D H
authors.initials: DH
authors.lastname: Sachs
authors.forename: M
authors.initials: M
authors.lastname: Sykes
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology / Q000528:radiation effects; D016026:Bone Marrow Transplantation / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens; D002678:Chimera / Q000276:immunology*; D005434:Flow Cytometry; D006085:Graft Survival / Q000276:immunology / Q000528:radiation effects; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology* / Q000528:radiation effects; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D011919:Rats, Inbred Strains; D016038:Skin Transplantation / Q000276:immunology; D018800:Thy-1 Antigens; D013950:Thymus Gland / Q000528:radiation effects; D014183:Transplantation, Heterologous / Q000276:immunology / Q000379:methods*; D014916:Whole-Body Irradiation
chemical_list: D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D015704:CD4 Antigens; D016827:CD8 Antigens; D018800:Thy-1 Antigens