Auto- and alloimmune reactivity to human islet allografts transplanted into type 1 diabetic patients.

Abstract

Allogeneic islet transplantation can restore an insulin-independent state in C-peptide-negative type 1 diabetic patients. We recently reported three cases of surviving islet allografts that were implanted in type 1 diabetic patients under maintenance immune suppression for a previous kidney graft. The present study compares islet graft-specific cellular auto- and alloreactivity in peripheral blood from those three recipients and from four patients with failing islet allografts measured over a period of 6 months after portal islet implantation. The three cases that remained C-peptide-positive for >1 year exhibited no signs of alloreactivity, and their autoreactivity to islet autoantigens was only marginally increased. In contrast, rapid failure (<3 weeks) in three other cases was accompanied by increases in precursor frequencies of graft-specific alloreactive T-cells; in one of them, the alloreactivity was preceded by a sharply increased autoreactivity to several islet autoantigens. One recipient had a delayed loss of islet graft function (33 weeks); he did not exhibit signs of graft-specific alloimmunity, but developed a delayed increase in autoreactivity. The parallel between metabolic outcome of human beta-cell allografts and cellular auto- and alloreactivity in peripheral blood suggests a causal relationship. The present study therefore demonstrates that T-cell reactivities in peripheral blood can be used to monitor immune mechanisms, which influence survival of beta-cell allografts in diabetic patients.

Islet isolation for allotransplantation: variables associated with successful islet yield and graft function

“…Other factors such as the inflammatory reaction during engraftment [21], the metabolic condition [22] or the allo-and auto-response of recipients [23,24] have also been shown to influence in vivo function of transplanted islets. Islet quality may, therefore, represent another prerequisite for successful transplantation.…”

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

“…As argued above, immunotherapies directed against T-cells have been shown to benefit beta-cell preservation [4,6,10]. It is conceivable that further understanding of the role of autoreactive T-cells, as well as elucidating the regulatory processes and identification of regulatory ('suppressive') T-cells involved in immunological control of T-cell autoimmunity, will provide more specific targets from selective immunotherapy.…”

“…In the context of islet transplantation in Type 1 diabetes patients, T-cell studies have been essential to determine the nature of islet graft failure (Fig. 4) [10]. Slow progressive loss of islet graft function was associated with recurrent (or pre-existent) T-cell autoimmunity, while rapid islet graft destruction was correlated with activation of alloreactive T-cells, with or without T-cell autoreactivity.…”

“…Nonetheless, longitudinal studies on circulating auto-and alloreactive T-cells in Type 1 diabetic patients transplanted with pancreatic islet allografts provided a strong association between graft function and T-cell auto-and/or alloimmunity (Fig. 4) [10].…”

Stable transplantation results of magnetically retracted islets: a novel method

“…Advances in immunosuppression during the last 2 years in combination with improved engraftment of islets, have now made islet transplantation a realistic therapeutic option [2,7]. However, human islet transplantation continues to be hindered by a limited availability of pure viable islets.…”