Long-term islet allograft survival in nonobese diabetic mice treated with tacrolimus, rapamycin, and anti-interleukin-2 antibody

Background. Nonobese diabetic (NOD) mice develop autoimmune diabetes with features similar to those observed in the human disease. The concurrence of allorecognition and recurrence of autoimmunity might explain why most of the treatments successful in preventing islet allograft destruction in other non-autoimmune combinations often fail in NOD recipients. To assess the value of the NOD mouse model for the evaluation of treatments relevant to clinical islet transplantation, the authors have tested the effect of a protocol closely resembling the one successfully used in the Edmonton clinical trial on the survival of islet allografts in NOD mice. Methods. C57BL/6 islets were transplanted under the kidney capsule of spontaneously diabetic NOD mice. Treatment consisted of a combination of rapamycin, tacrolimus, and anti-interleukin (IL)-2 monoclonal antibody. Control groups received each treatment alone, a combination of two agents, or no treatment. Results. Untreated animals invariably lost their graft within 13 days. Administration of rapamycin and tacrolimus significantly prolonged graft survival, with two of seven animals bearing a functional graft longer than 100 days. Addition of anti-IL-2 antibody therapy further improved graft survival, with six of eight grafts functioning longer than 100 days and two of eight grafts functioning longer than 200 days. Conclusions. In view of the limited success obtained with other treatments in this model, the dramatic prolongation of graft survival observed in the authors' study, by using a therapy that mimics one successfully used in clinical trials, seems to validate the NOD mouse as a meaningful model for the study of therapeutic interventions for the prevention of islet graft loss.