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.
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.
Hogan
William J
WJ
Program in Transplantation Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Little
Marie-Térèse
MT
Zellmer
Eustacia
E
Friedetzky
Anke
A
Diaconescu
Razvan
R
Gisburne
Serina
S
Lee
Richard
R
Kuhr
Christian
C
Storb
Rainer
R
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
D006649:Histocompatibility Antigens; D016572:Cyclosporine; D020123:Sirolimus