title: Short-term immunosuppression facilitates induction of mixed chimerism and tolerance after bone marrow transplantation without cytoreductive conditioning.
abstract: 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.
authors.affiliation: Division of Transplantation, Department of Surgery, Vienna General Hospital, Medical University of Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Blaha
authors.forename: Sinda
authors.initials: S
authors.lastname: Bigenzahn
authors.forename: Zvonimir
authors.initials: Z
authors.lastname: Koporc
authors.forename: Megan
authors.initials: M
authors.lastname: Sykes
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Muehlbacher
authors.forename: Thomas
authors.initials: T
authors.lastname: Wekerle
mesh_terms: 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
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D000069594:Abatacept