Disengaging the IL-2 receptor with daclizumab enhances IL-7-mediated proliferation of CD4(+) and CD8(+) T cells.

Allograft rejection is mainly driven by the production of IL-2, which expands T cells by linking the IL-2 receptor (IL-2R) composed of three subunits: CD25, CD122 and CD132. Daclizumab, widely used in immunosuppression, is a humanized anti-CD25 antibody that disrupts IL-2 signaling by binding to CD25 and preventing the assembly of the high-affinity IL-2R. Here we show that Daclizumab, while blocking the T-cell response to IL-2, increases CD4(+) and CD8(+) T-cell proliferative response to the homeostatic cytokine IL-7. The IL-7R shares CD132 with the IL-2R and blocking of CD25 by Daclizumab results in the enhanced formation of the IL-7R that in turn allows IL-7 to bind more efficiently on the cell surface. The consequently increased IL-7R signaling boosts intracellular phosphorylated STAT5 and T-cell proliferation. In addition, treatment with Daclizumab delays the internalization of CD127 upon IL-7 treatment, retaining T-cell sensitivity to IL-7 for a prolonged time. This effect of Daclizumab highlights the redundancy of the cytokine system, which may influence T-cell proliferation in transplanted patients, and provides information to improve future immunosuppressive strategies.

Autoantibody response to islet transplantation in type 1 diabetes.

Islet allotransplantation into patients with autoimmune type 1 diabetes represents a reexposure to autoantigen. Here, measurement of antibodies to GAD and IA-2 autoantigens before and after islet transplantation in 36 patients (33 receiving islet plus kidney grafts with cyclosporin and steroid-based immunosuppression, and 3 receiving solitary islet transplants with mycophenolate but cyclosporin-free immunosuppression) demonstrated marked rises in GAD antibodies within 7 days posttransplantation in 5 patients (3 receiving islet after kidney transplants, and 2 receiving solitary islet transplants) and within 30 days in the third patient receiving solitary islet transplantation. GAD antibodies were of the IgG1 subclass, against major autoantigenic epitopes, and in cases of islet after kidney transplants, the responses were short-lived and not accompanied by HLA antibodies. Two of these patients had subsequent marked rises of IA-2 antibodies, and an additional patient had a marked rise in IgM-GAD antibodies 3 years after transplantation. Insulin independence was not achieved in patients with autoantibody elevations and was significantly less frequent in these patients. These data are consistent with a reactivation of autoimmunity that may be dependent on immunosuppression therapy and is associated with impaired graft function.

Early autoantibody responses in prediabetes are IgG1 dominated and suggest antigen-specific regulation.

The islet autoimmunity of preclinical type 1 diabetes remains poorly characterized in humans. In this paper, the IgG subclass response to the islet autoantigens insulin, glutamic acid decarboxylase, and IA-2 was studied sequentially from birth to diabetes onset or current follow-up in 26 autoantibody positive offspring of parents with diabetes. Islet autoantibody appearance was characterized by an early IgG1 peak response to one or more Ags, most commonly to insulin, at a median age of 2.2 yr (interquartile range, 2-2.9 yr). In five offspring, an acute fulminant beta-cell destruction and diabetes onset occurred during this initial Ab response. In the remainder, early Ab levels declined markedly, and Ab peaks against other beta cell Ags arose sequentially over several years suggesting regulation and spreading of autoimmunity. Second peak Ab responses to the same Ag were observed in only two offspring, both developing diabetes at this time. Two others developed diabetes with declining Ab levels. Abs of IgG1 subclass dominated against each Ag, and other subclasses, were usually only detected during peak IgG1 responses. The IgG4 response to insulin was exceptional, being dominant over IgG1 in four offspring and in five others appeared and/or persisted after IgG1 levels declined. These Th2-associated IgG4 responses were not correlated with protection from diabetes. The presence of IgG1-restricted responses to DA2 were associated with diabetes development. These findings suggest that type 1 diabetes has an early acute destructive phase of beta cell autoimmunity, which may be regulated and which spreads chronically until diabetes onset.