Recent progress in islet transplantation for brittle Type 1 Diabetes Mellitus (T1DM) has made this procedure a feasible, minimally invasive approach to avoid severe hypoglycemia and secondary complications, improving glucose control with variable insulin-independence and improved quality of life (1–4). Long-term results have shown immunosuppression-related side-effects and progressive decline in islet graft function, most of the patients requiring reintroduction of various levels of insulin therapy within 4–5 years posttransplant (1,5–7).
Donor bone marrow cell (BMC) transplantation following myelo- or lympho-ablative conditioning has been shown to induce recipient chimerism and graft tolerance in solid organ transplantation, with reduction or discontinuation of immunosuppression (8). Similar results were seen in experimental islet transplant models, after minimal or nonablative regimens (9). In animal and clinical studies, infusion of high doses of donor CD34+hematopoietic stem cells (HSC) using minimal or nonablative conditioning resulted in successful engraftment, reduced adverse events, immunomodulation and increased allograft survival (10–15).
In this study, we attempted to induce recipient chimerism and graft tolerance in islet transplant recipients with brittle T1DM by infusing high doses of donor HSC without ablative conditioning to prevent graft rejection and eliminate life-long immunosuppression. An ‘Edmonton-like’ immunosuppression was given, with a single-dose of tumor necrosis factor-α (TNFα) monoclonal antibody (Infliximab) at induction to limit early posttransplant inflammation and maximize single-donor islet engraftment (1,4,16,17). Immunosuppression was weaned per protocol starting 12 months posttransplant to evaluate islet survival and chimerism (18–21). Clinical status, islet function, glucose control, immune reactivity and chimerism were monitored to evaluate efficacy and safety of the protocol.