Induction of transplantation tolerance by combining non-myeloablative conditioning with delivery of alloantigen by T cells.
The observation that bone marrow derived hematopoietic cells are potent inducers of tolerance has generated interest in trying to establish transplantation tolerance by inducing a state of hematopoietic chimerism through allogeneic bone marrow transplantation. However, this approach is associated with serious complications that limit its utility for tolerance induction. Here we describe the development of a novel approach that allows for tolerance induction without the need for an allogeneic bone marrow transplant by combining non-myeloablative host conditioning with delivery of donor alloantigen by adoptively transferred T cells. CBA/Ca mice were administered 2.5 Gy whole body irradiation (WBI). The following day the mice received K(b) disparate T cells from MHC class I transgenic CBK donor mice, as well as rapamycin on days 0-13 and anti-CD40L monoclonal antibody on days 0-5, 8, 11 and 14 relative to T cell transfer. Mice treated using this approach were rendered specifically tolerant to CBK skin allografts through a mechanism involving central and peripheral deletion of alloreactive T cells. These data suggest robust tolerance can be established without the need for bone marrow transplantation using clinically relevant non-myeloablative conditioning combined with antigen delivery by T cells.
Tian
Chaorui
C
Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, 221 Longwood Avenue LM303, Boston, MA 02115, USA.
Yuan
Xueli
X
Bagley
Jessamyn
J
Blazar
Bruce R
BR
Sayegh
Mohamed H
MH
Iacomini
John
J
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D046528:Chimerism; D005260:Female; D006085:Graft Survival / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D020123:Sirolimus / Q000494:pharmacology*; D016038:Skin Transplantation / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*; D014916:Whole-Body Irradiation
D007166:Immunosuppressive Agents; D007519:Isoantigens; D020123:Sirolimus