Short-term immunosuppression facilitates induction of mixed chimerism and tolerance after bone marrow transplantation without cytoreductive conditioning.
BACKGROUND
Induction of mixed chimerism and tolerance usually requires cytoreduction or transplantation of high numbers of bone marrow cells (BMC). However, such protocols have only a suboptimal success rate and, more importantly, equivalent numbers of BMC cannot be routinely obtained in the clinical setting. The authors therefore evaluated whether a short-course of immunosuppression (IS) given in addition to co-stimulation blockade would facilitate chimerism induction and allow reduction of the minimally required number of BMC without cytoreduction.


METHODS
B6 mice received 200, 100, or 50 x 10 unseparated BMC from Balb/c donors plus an anti-CD40L monoclonal antibody (mAb) and CTLA4Ig (without irradiation or cytotoxic drugs). Some groups were treated additionally with IS (rapamycin, methylprednisolone, and mycophenolate mofetil for 4 weeks after bone marrow transplantation), donor-specific transfusion (DST), or anti-OX40L mAb, as indicated.


RESULTS
IS led to long-term multilineage chimerism in 9 of 10 mice receiving 200 x 10 BMC (without IS, 1 of 4; P<0.05), in all mice (n=10) receiving 100 x 10 (without IS, 6 of 9; P<0.05), and notably in 9 of 10 mice treated with 50 x 10 BMC (without IS, 4 of 10; P<0.05). With transient IS, donor skin grafts were accepted longer than 170 days in 9 of 10 mice receiving 200 x 10 (without IS, 0 of 5 mice; P<0.05), all mice receiving 100 x 10 (without IS, 6 of 9; P<0.05), and 6 of 11 mice receiving 50 x 10 BMC (without IS, 4 of 10). The use of DST or anti-OX40L mAb had no beneficial effect.


CONCLUSIONS
Transient IS significantly improves rates of chimerism and donor skin graft survival, and allows lasting mixed chimerism after transplantation of only 50 x 10 BMC. Thus, IS might help in the further development of noncytoreductive chimerism protocols.
Blaha
Peter
P
Division of Transplantation, Department of Surgery, Vienna General Hospital, Medical University of Vienna, Vienna, Austria.
Bigenzahn
Sinda
S
Koporc
Zvonimir
Z
Sykes
Megan
M
Muehlbacher
Ferdinand
F
Wekerle
Thomas
T
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D016026:Bone Marrow Transplantation / Q000276:immunology*; D006085:Graft Survival / Q000502:physiology*; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D007165:Immunosuppression Therapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000276:immunology*; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D000069594:Abatacept