Modulation of humoral islet autoimmunity by pancreas allotransplantation influences allograft outcome in patients with type 1 diabetes

Pancreas transplantation in patients with type 1 diabetes presents allogene ic beta-cell autoantigens to the immune system long after the initial beta- cell destruction that leads to diabetes has occurred. The aims of this stud y were to determine whether re-exposure to beta-cell autoantigen through tr ansplantation affect; the humoral autoimmune response and whether its modul ation correlates with graft outcome. Antibodies to the major autoantigens G AD (GADA) and protein tyrosine phosphatase IA-2 (IA-2A) mere measured befor e and after transplantation in patients with type 1 diabetes who received p ancreas and kidney allografts, In the 110 cases studied, pancreas graft sur vival was not significantly associated with the presence of GADA or IA-2A b efore transplantation. In the 75 patients with sequential follow-up samples up to 11.2 years after transplantation, autoantibodies were persistently u ndetectable in 44 cases (59%) and remained at stable detectable levels in 1 3 cases (17%). Substantial changes in antibody levels were found in 18 case s (24%), of which 13 cases (17%) had declining levels and 5 cases (7%) had marked increments after transplantation, Rising GADA and IA-2A levels in th ese five patients were predominantly of the IgG1 subclass, with progressive spreading of epitope reactivity. Pancreas graft function was lost 0.7-2.3 years after rising autoantibody levels in four of these five patients, and a significantly lower pancreas graft, survival was found in patients with m ajor rises in either GADA or IA-2A levels (P < 0.0001 vs. the remainder) an d in patients having persistently high levels of IA-2A (P = 0.002 vs. stabl e antibody-negative patients), Kidney graft; survival was not associated wi th islet autoantibody status. In conclusion, a minority of patients receivi ng pancreas allografts under generalized immunosuppression show a stimulati on of islet autoantibody reactivity characteristic of that found in preclin ical type 1 diabetes, which is almost invariably followed by graft function failure and resumption of insulin therapy.