Sirolimus promotes tolerance for donor and recipient antigens after MHC class II disparate bone marrow transplantation in rats.
OBJECTIVE
Mixed chimerism after allogeneic bone marrow transplantation (BMT) promotes immunologic tolerance. Graft-vs-host disease (GvHD) can occur when immunosuppressive control of the graft fails. Here we evaluate the influence of concurrent immunosuppression after irradiation-based induction therapy on development of tolerance and GvHD.


METHODS
Conditioning was performed by different doses of total body irradiation (TBI) in a major histocompatibility complex (MHC) class II disparate rat BMT model. Animals received subsequent immunosuppression with either cyclosporine A (CsA) or sirolimus. Nonresponsiveness toward donor and recipient antigens was demonstrated by development of mixed chimerism and/or GvHD.


RESULTS
Administration of 10 Gy of TBI prior to BMT alone was associated with severe GvHD. Induction therapy with 8 Gy of TBI alone led to graft rejection in the long-term. Two weeks of immunosuppression with CsA after 8 Gy of TBI resulted in transient chimerism, but was finally associated with a combination of fatal GvHD and graft rejection. Six gray of TBI with CsA treatment for 14 or 28 days caused only mild GvHD, but did not lead to stable chimerism. In contrast, treatment with sirolimus was associated with stable chimerism after 8 Gy of TBI (14-day course) and 6 Gy of TBI (28-day course) accompanied by a low incidence of GvHD.


CONCLUSIONS
In contrast to CsA, sirolimus facilitates development of tolerance after MHC class II disparate BMT and irradiation-based conditioning, with a low risk of GvHD. Therefore, sirolimus has promising characteristics for inclusion in immunosuppressive protocols.
Jäger
Mark D
MD
Department of Surgery, Hannover Medical School, Hannover, Germany.
Liu
Jian Y
JY
Timrott
Kai F
KF
Popp
Felix C
FC
Stoeltzing
Oliver
O
Lang
Sven A
SA
Piso
Pompiliu
P
Geissler
Edward K
EK
Schlitt
Hans J
HJ
Dahlke
Marc H
MH
D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D016572:Cyclosporine; D006084:Graft Rejection / Q000209:etiology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006650:Histocompatibility Testing; D007108:Immune Tolerance / Q000187:drug effects*; D007165:Immunosuppression Therapy / Q000379:methods; D051381:Rats; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods; D014181:Transplantation Immunology / Q000187:drug effects*; D014916:Whole-Body Irradiation
D000949:Histocompatibility Antigens Class II; D016572:Cyclosporine; D020123:Sirolimus