Combined immunosuppression of mycophenolate mofetil and FK506 for myoblast transplantation in mdx mice.
BACKGROUND
Overcoming adverse effects of immunosuppressors can be achieved by combining different drugs, thus allowing a dosage reduction. Myoblast transplantation is a potential therapy for Duchenne muscular dystrophy. Our research group previously established that FK506 (tacrolimus) is an effective immunosuppressive drug for myoblast transplantation in mice and monkeys.


METHODS
In the present study, a reduced dose of FK506 at 1.0 mg/kg/day was used in combination with mycophenolate mofetil (MMF; 80 mg/kg/day) as an immunosuppressive protocol for myoblast transplantation. Graft success was evaluated by quantifying the number of dystrophin-positive fibers per muscle section that were injected with normal cells.


RESULTS
MMF used alone could not prevent immune rejection of the transplanted myoblasts. MMF given in combination with FK506 immediately after transplantation reduced the success of myoblast transplantation by about 50%. A low dose of FK506 combined with MMF after the establishment of the graft (3 weeks) maintained graft success and controlled immune infiltration compared with a low dose of FK506 alone. However, lymphocyte infiltration was observed at longer term using a low dose of FK506 combined with MMF.


CONCLUSIONS
The diminution of graft success when combining FK506 and MMF by the time of myoblast transplantation could be attributed to the inhibition of myoblast fusion by MMF. The use of MMF and FK506 after the establishment of the graft did not reduce graft success, however, this combination was not effective at controlling long-term immune rejection in comparison with the optimal dose of FK506 alone.
Camirand
G
G
Unité de Recherche en Génétique humaine, Centre Hospitalier de l'Université Laval, Université Laval, 2705 boul. Laurier, RC-9300, Ste-Foy (Qc) Canada G1V 4G2.
Caron
N J
NJ
Asselin
I
I
Tremblay
J P
JP
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002459:Cell Fusion; D017690:Cell Transplantation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D007107:Immune System / Q000473:pathology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000166:cytology* / Q000473:pathology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use*; D016559:Tacrolimus / Q000008:administration & dosage / Q000627:therapeutic use*
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus