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 Kb 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.
Bibliographical noteFunding Information:
We wish to thank members of the Iacomini and Sayegh laboratories for their helpful suggestions. C.T. is supported by an American Society of Transplantation (AST)/Roche Basic Science Faculty Development Grant. This work was supported by National Institutes of Health Grants P01 AI041521 and P01 AI056299 to M.H.S; R01 AI043619, R01 AI053666 and R01 AI070601 to J.I.; and R01 HL63452 and P01 AI056299 to BRB. Support for this work was also provided to M.H.S. by The Juvenile Diabetes Research Foundation Center Grant on Immunological Tolerance in Type I Diabetes, and to J.I. by the American Diabetes Association 7-04-RA-45.
- Negative selection
- Non-myeloablative conditioning
- T cells