Glutamic acid decarboxylase antibodies are more frequent than islet cell antibodies in islet transplanted IDDM patients and persist or occur despite immunosuppression

Abstract

Pancreatic islet grafts transplanted into patients with autoimmune diabetes are potentially threatened by two immune responses, allograft rejection and the recurrence of autoimmune insulitis. In the present study we investigated the humoral autoimmune response directed to islet autoantigens by studying islet cell antibodies and glutamic acid decarboxylase (GAD 65) antibodies in twenty-one insulin-dependent diabetes-mellitus (IDDM) patients undergoing intraportal islet allotransplantation. Islet transplantation was performed according to the following recipient categories: Islet after kidney transplantation (n=10), simultaneous islet and kidney transplantation (n=6) and islet transplant alone (n=5). GAD 65 antibodies were detected in a radioligand GAD 65 antibody assay using recombinant, in vitro translated, human 35S-methionin labelled GAD 65 as tracer. Islet cell antibodies were determined by indirect immunofluorescence technique on human pancreas. In six out of twenty-one patients we observed GAD 65 antibodies before islet transplantation and the GAD 65 antibodies persisted despite immunosuppression. In contrast only two subjects were concordantly islet cell antibody positive and the titre decreased post transplantation. In addition we observed occurrence of GAD 65 antibodies in five subjects that were shown to be antibody negative before islet transplantation with three of them subsequently becoming positive for islet cell antibodies. The remaining ten patients were GAD 65 antibody and islet cell antibody negative before islet transplantation and remained negative thereafter. Interestingly none of the patients was exclusively positive for islet cell antibodies without being positive for GAD 65 antibodies. In summary we have demonstrated in twenty-one islet grafted individuals that humoral autoimmunity to islet antigens can persist or occur despite immunosuppression. Islet cell antibodies appear to be less frequent (5 out of 21, 23%) compared to GAD 65 antibodies (11 out of 21, 52%) suggesting that they are more affected by immunosuppressive therapy. We conclude that GAD 65 antibodies are a useful tool to further evaluate a possible link between persistent autoimmunity and early or late graft failure after islet transplantation.

Alloantibody and Autoantibody Monitoring Predicts Islet Transplantation Outcome in Human Type 1 Diabetes

“…The present study also strengthens the evidence for posttransplant autoantibody increases (defined as serum conversion, spreading, or increasing titers) that predict future islet pancreatic transplant failure (5,16–19). The addition of ZnT8A to GADA and IA-2A in the screening panel appear useful because there were five patients in whom ZnT8A was the only antibody to appear or increase.…”

“…Monitoring of humoral immunity is easier and has now been validated for both alloimmunity (12–14) and islet autoimmunity (15). It is largely accepted that preformed pretransplant autoimmune antibodies only weakly predict posttransplant outcome (5,16–19), whereas preformed alloreactive antibodies are an important negative predictor of islet transplant outcome (20). On the other hand, the relevance of posttransplant de novo autoantibodies (19) and de novo donor-specific alloantibodies (DSA) (11,20–22) to islet transplant outcome is still unclear.…”

Diabetes Mellitus and Closed-Loop Insulin Delivery

“…This is typically an auto-immune condition which may, however, be provoked by an environmental factor such as an infection or toxin (Giannoukakis et al, 1999;Imagawa et al, 1999;Jaeger et a/., 1999;Knip, 1998;Moriwaki et al, 1999;Mysliwiec etal., 1999;Pickup and Williams, 1997;Shimada et al, 1999;Signore et al, 1999). Autoantibodies are produced against targets including islet cell components, insulin and enzymes such as glutamic acid decarboxylase and tyrosine phosphatases.…”

Development of immune response to tissue‐restricted self‐antigens in simultaneous kidney‐pancreas transplant recipients with acute rejection

“…Several pancreas‐specific self‐antigens (PSAgs) have been identified, and immune responses to these antigens have been associated with increased incidence of diabetes in children and adults . It has been reported that intraportal islet allotransplantation can result in de novo development of Abs to glutamic acid decarboxylase (GAD) and islet cell Abs (ICA), suggesting that Abs to PSAgs may be involved in early or late islet allograft dysfunction . A recent prospective study demonstrated that persistence and recurrence of Abs to GAD and ICA occur after SKP Tx, but their roles in allograft dysfunction remain unknown .…”