Relevance of cytotoxic alloreactivity under different immunosuppressive regimens in clinical islet cell transplantation

Islet or beta cell transplantation provides a promising cure for type 1 diabetes patients, but insulin-independency decreases frequently over time. Immunosuppressive regimens are implemented attempting to cope with both auto- and alloimmunity after transplantation. We analysed the influence of different immunotherapies on autoreactive and alloreactive T cell patterns and transplant outcome. Patients receiving three different immunosuppressive regimens were analysed. All patients received anti-thymocyte globulin induction therapy. Twenty-one patients received tacrolimus-mycophenolate mofetil maintenance immunosuppression, whereas the other patients received tacrolimus-sirolimus (SIR, n = 5) or SIR only (n = 5). Cellular autoreactivity and alloreactivity (CTL precursor frequency) were measured ex vivo. Clinical outcome in the first 6 months after transplantation was correlated with immunological parameters. C-peptide levels were significantly different between the three groups studied (P = 0.01). We confirm that C-peptide production was correlated negatively with pretransplant cellular autoreactivity and low graft size (P = 0.001, P = 0.007 respectively). Combining all three therapies, cellular autoimmunity after transplantation was not associated with delayed insulin-independence or C-peptide production. In combined tacrolimus-SIR and SIR-treated patients, CTL alloreactivity was associated with less insulin independence and C-peptide production (P = 0.03). The percentage of donors to whom high CTLp frequencies were measured was lower in insulin-independent recipients (P = 0.03). In this cohort of islet cell graft recipients, clinical outcome in the first 6 months after transplantation correlates with the applied immunosuppressive regimen. An association exists between insulin-independence and lower incidence of CTL alloreactivity towards donor human leucocyte antigen. This observational study demonstrates the usefulness of monitoring T cell reactivity against islet allografts to correlate immune function with graft survival.