Stable mixed chimerism and tolerance using a nonmyeloablative preparative regimen in a large-animal model.
Bone marrow transplantation (BMT) has considerable potential for the treatment of malignancies, hemoglobinopathies, and autoimmune diseases, as well as the induction of transplantation allograft tolerance. Toxicities associated with standard preparative regimens for bone marrow transplantation, however, make this approach unacceptable for all but the most severe of these clinical situations. Here, we demonstrate that stable mixed hematopoietic cell chimerism and donor-specific tolerance can be established in miniature swine, using a relatively mild, non-myeloablative preparative regimen. We conditioned recipient swine with whole-body and thymic irradiation, and we depleted their T-cells by CD3 immunotoxin-treatment. Infusion of either bone marrow cells or cytokine-mobilized peripheral blood stem cells from leukocyte antigen-matched animals resulted in stable mixed chimerism, as detected by flow cytometry in the peripheral blood, thymus, and bone marrow, without any clinical evidence of graft-versus-host disease (GvHD). Long-term acceptance of donor skin and consistent rejection of third-party skin indicated that the recipients had developed donor-specific tolerance.
Huang
C A
CA
Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02129, USA.
Fuchimoto
Y
Y
Scheier-Dolberg
R
R
Murphy
M C
MC
Neville
D M
DM
Sachs
D H
DH
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D002678:Chimera / Q000276:immunology*; D004334:Drug Administration Schedule; D005434:Flow Cytometry; D006085:Graft Survival / Q000187:drug effects / Q000528:radiation effects; D018380:Hematopoietic Stem Cell Transplantation; D007108:Immune Tolerance / Q000276:immunology*; D000922:Immunotoxins / Q000008:administration & dosage / Q000009:adverse effects; D007958:Leukocyte Count / Q000187:drug effects / Q000528:radiation effects; D008212:Lymphocyte Depletion; D010976:Platelet Count / Q000187:drug effects / Q000528:radiation effects; D016038:Skin Transplantation / Q000276:immunology; D013552:Swine; D013556:Swine, Miniature; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000528:radiation effects; D019172:Transplantation Conditioning / Q000379:methods*; D014916:Whole-Body Irradiation
D017252:CD3 Complex; D000922:Immunotoxins