PROGRESSIVE ISLET GRAFT FAILURE OCCURS SIGNIFICANTLY EARLIER IN AUTOANTIBODY-POSITIVE THAN IN AUTOANTIBODY-NEGATIVE IDDM RECIPIENTS OF INTRAHEPATIC ISLET ALLOGRAFTS

Alloimmunity has been uncovered to be a cause of graft loss representi ng a major barrier for clinical islet transplantation, and several stu dies are designed to evaluate new strategies for immunosuppression to prevent alloimmunity, In contrast, the significance for autoimmune des truction of transplanted beta-cells has remained somewhat controversia l, Recently, two case reports based on histological findings have sugg ested recurrent autoimmune insulitis despite immunosuppressive therapy both in clinical pancreas and in islet transplantation. In the presen t study, in 23 islet-grafted patients with IDDM: receiving standard im munosuppressive therapy, we demonstrate that progressive impairment of islet graft function occurs significantly earlier in those individual s positive for autoantibodies as a typical stigma of diabetes-associat ed autoimmunity that is well established in the prediabetic periods of IDDM, Intraportal infusion of allogeneic islets was performed in 23 C -peptide-negative IDDM patients, according to the clinical transplanta tion categories defined as islet after kidney (IAK) or simultaneous is let and kidney (SIK), Complete islet graft failure was defined as the Ist day of permanent C-peptide negativity in the serum (<0.2 ng/ml) an d C-peptide negativity in the urine (<2 mu g/dl). The median observati on period following islet transplantation was 12 months (range 1-50) w ith a cumulative follow-up of 336 months, Islet cell antibodies (ICAs) and GAD65 antibodies were monitored before and regularly after islet transplantation. Kaplan-Meier survival analysis and log-rank statistic s revealed a significant (P < 0.05) difference in cumulative islet gra ft survival depending on the presence of islet cell and/or GAD65 antib odies. These results strongly suggest that recurrent autoimmunity dire cted to transplanted beta-cells contributes to islet graft failure des pite sustained immunosuppression, For successful clinical islet transp lantation in the future, new immunosuppressive therapies are needed to prevent both alloimmunity and autoimmunity.