Low-dose radiation plus rapamycin promotes long-term bone marrow chimerism.
BACKGROUND
The ability to achieve significant donor engraftment without fully myeloablative conditioning has revolutionized allogeneic stem cell transplantation. These nonmyeloablative approaches may allow extension of this potentially curative modality to an increasing number of patients including those with non-malignant diseases. Although a number of regimens have been explored, the optimal means of conditioning has not been determined.


METHODS
We previously demonstrated that rapamycin (RAPA) has the ability to promote T-cell tolerance even in the presence of costimulation. In the current study, we examine the ability of rapamycin or the calcineurin inhibitor cyclosporine A (CSA) to promote chimerism in a murine haploidentical bone marrow transplantation model. Mice were conditioned with 300 cGy and received either RAPA at 3 mg/kg/day IP, CSA at 20 mg/kg/day IP, or no immunosuppression starting on the day before the transplant and continued for 4 weeks.


RESULTS
There was no apparent toxicity, and animals maintained normal blood counts throughout. More importantly, long-term macrochimerism was observed only in the RAPA-treated group.


CONCLUSIONS
These results establish a simple, nontoxic, irradiation-based regimen that facilitates engraftment without ablation. This strategy may prove useful in nonmalignant disorders such as hemoglobinopathies in which moderate levels of donor chimerism could prove curative.
Powell
Jonathan D
JD
Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Fitzhugh
Courtney
C
Kang
Elizabeth M
EM
Hsieh
Mathew
M
Schwartz
Ronald H
RH
Tisdale
John F
JF
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D020123:Sirolimus / Q000627:therapeutic use*; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods
D007166:Immunosuppressive Agents; D020123:Sirolimus