Engraftment versus immunosuppression: cost-benefit analysis of immunosuppression after intrahepatic murine islet transplantation.
OBJECTIVE
Immunosuppression (IS) in islet transplantation (Tx) is a double-edged sword: it prevents immunoreaction but has the potential to impair islet engraftment. The aim of this study was to identify in murine animal models the IS platform with the best balance between these two opposite effects.


METHODS
To study the impact of IS on islet engraftment diabetic C57BL/6 mice were transplanted with 350 syngeneic islets through the portal vein and treated once-daily with either rapamycin (RAPA; 0.1-0.5-1 mg/kg ip), tacrolimus (FK506; 0.1-0.5-1 mg/kg ip), mycophenolate mofetil (MMF; 60-120-300 mg/kg oral) or vehicle for 14 days. Islet function was evaluated by measuring not-fasting glycemia and by performing an IVGTT on days 15 and 30 post-Tx.


RESULTS
RAPA ≥0.5 mg/Kg, FK506 ≥0.5 mg/Kg, and MMF ≥120 mg/kg had detrimental effects on islet engraftment but not on the function of islets already engrafted in the liver. The effect on engraftment was irreversible and persisted even after IS withdrawal. The lower dose of IS that did not affect engraftment was tested for preventing rejection in the full mismatch allogeneic Tx BALB/c to C57BL/6 model. RAPA and/or FK506 were inefficient in preventing rejection, even when anti-IL2R mAb was added to the IS regimen. On the other hand, MMF alone or in association with FK506 significantly prolonged the time to islet rejection.


CONCLUSIONS
IS showed profound dose-dependent deleterious effects on islet cell engraftment. The MMF/FK506 combination proved the best balance with less toxicity at the time of engraftment and more efficacy in controlling graft rejection.
1 Diabetes Research Institute (OSR-DRI), San Raffaele Scientific Institute, Via Olgettina 60, Milan, Italy. 2 Department of Surgery, University of Pavia, Pavia, Italy. 3 Address correspondence to: Lorenzo Piemonti, Diabetes Research Institute (OSR-DRI), San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy.
Simona
S
Marzorati
Raffaella
R
Melzi
Antonio
A
Citro
Elisa
E
Cantarelli
Alessia
A
Mercalli
Marina
M
Scavini
Lorenzo
L
Piemonti
D000818:Animals; D003362:Cost-Benefit Analysis; D003921:Diabetes Mellitus, Experimental / Q000191:economics / Q000628:therapy*; D006084:Graft Rejection / Q000191:economics / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007108:Immune Tolerance / Q000187:drug effects*; D007165:Immunosuppression Therapy / Q000191:economics* / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016381:Islets of Langerhans Transplantation / Q000191:economics* / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011182:Postoperative Care / Q000191:economics / Q000379:methods
D007166:Immunosuppressive Agents; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid