A Multi-Modal Approach to Islet and Pancreas Transplantation With Calcineurin-Sparing Immunosuppression Maintains Long-Term Insulin Independence in Patients With Type I Diabetes

Abstract

Long-term success in beta-cell replacement remains limited by the toxic effects of calcineurin inhibitors (CNI) on beta-cells and renal function. We report a multi-modal approach including islet and pancreas-after-islet (PAI) transplant utilizing calcineurin-sparing immunosuppression. Ten consecutive non-uremic patients with Type 1 diabetes underwent islet transplant with immunosuppression based on belatacept (BELA; n = 5) or efalizumab (EFA; n = 5). Following islet failure, patients were considered for repeat islet infusion and/or PAI transplant. 70% of patients (four EFA, three BELA) maintained insulin independence at 10 years post-islet transplant, including four patients receiving a single islet infusion and three patients undergoing PAI transplant. 60% remain insulin independent at mean follow-up of 13.3 ± 1.1 years, including one patient 9 years after discontinuing all immunosuppression for adverse events, suggesting operational tolerance. All patients who underwent repeat islet transplant experienced graft failure. Overall, patients demonstrated preserved renal function, with a mild decrease in GFR from 76.5 ± 23.1 mL/min to 50.2 ± 27.1 mL/min (p = 0.192). Patients undergoing PAI showed the greatest degree of renal impairment following initiation of CNI (56% ± 18.7% decrease in GFR). In our series, repeat islet transplant is ineffective at maintaining long-term insulin independence. PAI results in durable insulin independence but is associated with impaired renal function secondary to CNI dependence.

Keywords: immune tolerance; immunosuppression; insulin independence; islet transplant; pancreas transplant.

FIGURE 1

Islet and Pancreas-After-Islet (PAI) outcomes for patients receiving CNI-sparing immunosuppression based on Belatacept (BELA) or Efalizumab (EFA). (A) Summary of beta cell replacement outcomes from time of transplant; (B) Summary of beta cell replacement outcomes by graft function status.

FIGURE 2

(A) Glycemic control measured by HbA1c (%); (B) Renal function measured by GFR (mL/min); (C) Change in GFR for patients with preserved islet function; (D) Renal function by GFR and stage of kidney disease from time of transplant.

FIGURE 3

(A) Treg expansion in first year post-transplant (adapted from Posselt, et. al., 2010); (B) Operational tolerance in patient EFA-4 following withdrawal of immunosuppression; (C) EFA4 cytokine production in mixed lymphocyte reaction to donor-specific (black) and third-party (gray) antigen. EFA4 demonstrated no reactivity to donor or third-party antigen in the first 12 months post-transplant, which returned by 24 months.