title: Sirolimus and post transplant Cy synergistically maintain mixed chimerism in a mismatched murine model.
abstract: Because of the toxicity associated with myeloablative conditioning, nonmyeloablative regimens are increasingly being used in vulnerable patient populations. For patients with sickle cell disease, stable mixed chimerism has proven sufficient to reverse the phenotype. Because the vast majority of patients do not have an HLA-matched sibling, a safe nonmyeloablative regimen that could be applied to the haploidentical setting would be ideal. We employed a mismatched mouse model using BALB/c donors and C57BL/6 recipients. Recipient mice were conditioned with 200 cGy TBI and sirolimus or CSA with or without post transplant Cy (PT-Cy). Our data show that when sirolimus or PT-Cy alone is given to C57BL/6 recipients, donor cells are not detected. However, when sirolimus is administered for 15 or 31 days starting 1 day before or up to 6 days after transplant with PT-Cy, all mice maintain stable mixed chimerism. In contrast, conventional therapy employing CSA with or without PT-Cy does not result in stable mixed chimerism. Lastly, mice with stable mixed chimerism after sirolimus display decreased reactivity to donor Ag both in vitro and in vivo. These data identify a novel strategy for inducing mixed chimerism for the treatment of nonmalignant hematologic diseases.
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute/National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Fitzhugh
authors.forename: R P
authors.initials: RP
authors.lastname: Weitzel
authors.forename: M M
authors.initials: MM
authors.lastname: Hsieh
authors.forename: O A
authors.initials: OA
authors.lastname: Phang
authors.forename: C
authors.initials: C
authors.lastname: Madison
authors.forename: L
authors.initials: L
authors.lastname: Luznik
authors.forename: J D
authors.initials: JD
authors.lastname: Powell
authors.forename: J F
authors.initials: JF
authors.lastname: Tisdale
mesh_terms: D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D020123:Sirolimus / Q000494:pharmacology*; D016038:Skin Transplantation / Q000379:methods*; D018183:Transplantation Chimera
chemical_list: D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D020123:Sirolimus