Background: For patients with end-stage renal disease secondary to type 1 diabetes mellitus, islet and kidney co-transplantation can be an ideal transplant option. However, a novel immunosuppressive regimen that effectively suppress both renal and islet allograft rejection without toxicities on the islet allograft needs to be established. In the current study, we tested CD40 blockade with rapamycin for islet/kidney co-transplantation and compared with the conventional immunosuppression with rabbit anti-thymocyte globulin (ATG)/tacrolimus/rapamycin in cynomolgus monkeys.

Methods: Kidney and islet (via portal vein) co-transplantation was performed in MHC mismatched cynomolgus monkeys. Two recipients received ATG i.v. on days, -2, -1, 0 and 1 (3, 6, 10, and 10 mg/kg), and were maintained by daily tacrolimus (FK; 10-15 ng/ml) and rapamycin (Rapa; 10-20 ng/ml) i.m.. Five recipients were treated with anti-CD40 mAb (2C10R4: CD40; 20 mg/kg i.v. on days 0, 2, 5, 7, and 9, and 10 mg/kg weekly thereafter) and rapamycin. Anti-inflammatory therapies including anti-IL-6R mAb on days 0 and 5, and anti-TNF alpha mAb on days 0, 3, 7, and 10 were given in both groups. Graft survival, graft histology and allo-immune responses (IFN-gamma ELIspot assay and anti-donor Ab formation) were assessed.

Results: Conventional immunosuppression with ATG/tacrolimus/rapamycin resulted in poor islet engraftment and CMV pneumonia on days 19 and 26, despite normal kidney function. In the anti-CD40 mAb/rapamycin group, although one recipient (M5113) showed limited islet function and another (M5813) lost islet and kidney allografts on days 94 and 98 due to antibody mediated rejection, remaining three recipients survived long-term without rejection of both islet and kidney allografts (Table 1).

Conclusion: Conventional immunosuppression with ATG/tacrolimus/rapamycin that has been used for clinical islet tranplantation resulted in over-immunosuppression in NHPs. The combination of anti-CD40 mAb and rapamycin can be a reliable immunosuppressive regimen to control allo-immunity towards both kidney and islet allografts.

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