title: Postgrafting immunosuppression with sirolimus and cyclosporine facilitates stable mixed hematopoietic chimerism in dogs given sublethal total body irradiation before marrow transplantation from DLA-identical littermates.
abstract: We studied the value of postgrafting immunosuppression with sirolimus (SRL) and cyclosporine (CSP) in enhancing engraftment of dog leukocyte antigen-identical littermate marrow after nonmyeloablative conditioning in a canine model. Dogs received either 2 Gy (n=7) or 1 Gy (n=5) total body irradiation (TBI), followed by postgrafting immunosuppression with SRL and CSP. In the first cohort, all 7 dogs showed rapid initial engraftment. One engrafted dog died on day 21 due to hemorrhagic pneumonitis. Durable engraftment was seen in 5 of 6 remaining dogs, with a median follow-up of >48 (range, >32 to >56) weeks. The sixth dog rejected the marrow graft (as assessed by variable number of tandem repeats) at 11 weeks; however, a subsequent skin graft from the same marrow donor did not undergo acute cellular rejection, suggesting donor-specific tolerance. In the second cohort, all 5 dogs rejected the marrow graft at a median of 9 weeks (range, 3-11 weeks). We conclude that SRL/CSP is as effective as a previously studied combination of mycophenolate mofetil and CSP at establishing durable marrow engraftment after sublethal conditioning.
authors.affiliation: Program in Transplantation Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Hogan
authors.forename: Marie-Térèse
authors.initials: MT
authors.lastname: Little
authors.forename: Eustacia
authors.initials: E
authors.lastname: Zellmer
authors.forename: Anke
authors.initials: A
authors.lastname: Friedetzky
authors.forename: Razvan
authors.initials: R
authors.lastname: Diaconescu
authors.forename: Serina
authors.initials: S
authors.lastname: Gisburne
authors.forename: Richard
authors.initials: R
authors.lastname: Lee
authors.forename: Christian
authors.initials: C
authors.lastname: Kuhr
authors.forename: Rainer
authors.initials: R
authors.lastname: Storb
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects; D006649:Histocompatibility Antigens; D007165:Immunosuppression Therapy / Q000379:methods*; D007700:Kinetics; D007962:Leukocytes / Q000166:cytology; D008111:Liver Function Tests; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D018183:Transplantation Chimera / Q000254:growth & development*; D016896:Treatment Outcome; D014916:Whole-Body Irradiation
chemical_list: D006649:Histocompatibility Antigens; D016572:Cyclosporine; D020123:Sirolimus