Cutting edge: administration of anti-CD40 ligand and donor bone marrow leads to hemopoietic chimerism and donor-specific tolerance without cytoreductive conditioning.
Transplantation tolerance, defined as allograft acceptance by an immunocompetent recipient in the absence of long-term immunosuppression, has remained an elusive goal in clinical transplantation. Robust experimental tolerance induction strategies have in common methods to induce mixed hemopoietic chimerism. To date, however, chimerism induction across allogeneic barriers has required recipient conditioning with irradiation or cytoablative agents. In this paper we show that B6 recipients of fully allogeneic BALB/c skin grafts treated with repeated doses of donor bone marrow and anti-CD40 ligand (CD40L) develop durable (>300 days), readily detectable (6-12%) multilineage hemopoietic chimerism, indefinite allograft acceptance (>300 days), and donor-specific tolerance to secondary skin grafts. Analysis of the TCR repertoire of treated mice indicates that the underlying mechanisms of tolerance are in part mediated by deletion of donor-reactive T cells. These data demonstrate that durable hemopoietic chimerism and robust transplantation tolerance can be achieved without cytotoxic conditioning using a potentially clinically applicable regimen.
Durham
M M
MM
Carlos and Marguerite Mason Transplantation Biology Research Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA.
Bingaman
A W
AW
Adams
A B
AB
Ha
J
J
Waitze
S Y
SY
Pearson
T C
TC
Larsen
C P
CP
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D007106:Immune Sera / Q000008:administration & dosage*; D007108:Immune Tolerance / Q000235:genetics; D007274:Injections, Intraperitoneal; D008024:Ligands; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011828:Radiation Chimera / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology; D019172:Transplantation Conditioning
D019013:CD40 Antigens; D007106:Immune Sera; D008024:Ligands; D008562:Membrane Glycoproteins; D023201:CD40 Ligand