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Type 1 diabetes presents clinically with overt hyperglycemia resulting from progressive immune-mediated destruction of pancreatic [3-cells and associated metabolic dysfunction. Combined genetic and immunological studies now highlight deficiencies in both the interleukin-2 (IL-2) receptor and its downstream signaling pathway as a central defect in the pathogenesis of type 1 diabetes. Prior intervention studies in animal models indicate that augmenting IL-2 signaling can prevent and reverse disease, with protection conferred primarily by restoration of regulatory T-cell (Treg) function. In this article, we will focus on studies of type 1 diabetes noting deficient IL-2 signaling and build what we believe forms the molecular framework for their contribution to the disease. This activity results in the identification of a series of potentially novel therapeutic targets that could restore proper immune regulation in type 1 diabetes by augmenting the IL-2 pathway. Diabetes 61:14-22, 2012, INTERLEUKIN-2 AND THE INTERLEUKIN-2 RECEPTOR Physiological role and function. Understanding the role of interleukin (IL)-2 in the etiology of type 1 diabetes requires knowledge of the regulation of--as well as [...]

OBJECTIVE -- Interest continues to grow regarding the therapeutic potential for umbilical cord blood therapies to modulate autoimmune disease. We conducted an open-label phase I study using autologous umbilical cord [...]

Type 1 diabetes is by characterized the autoimmune destruction of β-cells, resulting in a loss of insulin production and glucose control (1,2). In both humans and the nonobese diabetic (NOD) [...], OBJECTIVE--The autoimmune destruction of β-cells in type 1 diabetes results in a loss of insulin production and glucose homeostasis. As such, an immense interest exists for the development of therapies capable of attenuating this destructive process through restoration of proper immune recognition. Therefore, we investigated the ability of the immune-depleting agent antithymocyte globulin (ATG), as well as the mobilization agent granulocyte colony-stimulating factor (GCSF), to reverse overt hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes. RESEARCH DESIGN AND METHODS--Effects of each therapy were tested in pre-diabetic and diabetic female NOD mice using measurements of glycemia, regulatory T-cell (CD4+CD25+Foxp3+) frequency, insulitis, and/or β-cell area. RESULTS--Here, we show that combination therapy of murine ATG and GCSF was remarkably effective at reversing new-onset diabetes in NOD mice and more efficacious than either agent alone. This combination also afforded durable reversal from disease (>180 days postonset) in animals having pronounced hyperglycemia (i.e., up to 500 mg/dl). Additionally, glucose control improved over time in mice subject to remission from type 1 diabetes. Mechanistically, this combination therapy resulted in both immunological (increases in CD4-to-CD8 ratios and splenic regulatory T-cell frequencies) and physiological (increase in the pancreatic β-cell area, attenuation of pancreatic inflammation) benefits. CONCLUSIONS--In addition to lending further credence to the notion that combination therapies can enhance efficacy in addressing autoimmune disease, these studies also support the concept for utilizing agents designed for other clinical applications as a means to expedite efforts involving therapeutic translation.

The cause of cystic fibrosis-related diabetes (CFRD) remains unknown, but cystic fibrosis transmembrane conductance regulator (CFTR) mutations contribute directly to multiple aspects of the cystic fibrosis phenotype. We hypothesized that susceptibility to islet dysfunction in cystic fibrosis is determined by the lack of functional CFTR. To address this, glycemia was assessed in CFTR null (CFT[R.sup.-/-]), C57BL/6J, and FVB/NJ mice after streptozotocin (STZ)-induced β-cell injury. Fasting blood glucose levels were similar among age-matched non-STZ-administered animals, but they were significantly higher in CFT[R.sup.-/-] mice 4 weeks after STZ administration (288.4 ± 97.4, 168.4 ± 35.9, and 188.0 ± 42.3 mg/dl for CFT[R.sup.-/-], C57BL/ 6J, and FVB/NJ, respectively; P < 0.05). After intraperitoneal glucose administration, elevated blood glucose levels were also observed in STZ-administered CFT[R.sup.-/-] mice. STZ reduced islets among all strains; however, only CFT[R.sup.-/-] mice demonstrated a negative correlation between islet number and fasting blood glucose (P = 0.02). To determine whether a second alteration associated with cystic fibrosis (i.e., airway inflammation) could impact glucose control, animals were challenged with Aspergillus fumigatus. The A. fumigatus-sensitized CFT[R.sup.-/-] mice demonstrated similar fasting and stimulated glucose responses in comparison to nonseusitized animals. These studies suggest metabolic derangements in CFRD originate from an islet dysfunction inherent to the CFT[R.sup.-/-] state., Cystic fibrosis is a systemic disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Some of the manifestations of this disease are caused by defective [...]

CD[4.sup.+] CD[25.sup.+] T-cells appear to play a crucial role in regulating the immune response. Therefore, we evaluated the peripheral blood frequency and function of CD[4.sup.+] CD[25.sup.+] T-cells in 70 type 1 diabetic patients and 37 healthy individuals. Interestingly, a positive correlation was observed between increasing age and CD[4.sup.+]CD[25.sup.+] T-cell frequency in both subject groups. In contrast to previous studies of nonobese diabetic mice and type 1 diabetic patients, similar frequencies of CD[4.sup.+]CD[25.sup.+] and CD[4.sup.+]CD[25.sup.+Bright] T-cells were observed in healthy control subjects and type 1 diabetic patients of similar age. There was no difference between type 1 diabetic subjects of recent-onset versus those with established disease in terms of their CD[4.sup.+]CD[25.sup.+] or CD[4.sup.+]CD[25.sup.+Bright] T-cell frequency. However, type I diabetic patients were markedly defective in their ability to suppress the proliferation of autologous effector T-cells in vitro. This type 1 diabetes-associated defect in suppression was associated with reduced production of interleukin (IL)-2, γ-interferon, and transforming growth factor-β, whereas other cytokines including those of adaptive and innate immunity (IL-10, IL-1β, IL-6, IL-8, IL-12p70, and tumor necrosis factor-α) were similar in control subjects and type 1 diabetic patients. These data suggest that age strongly influences the frequency of CD[4.sup.+]CD[25.sup.+] T-cells and that function, rather than frequency, may represent the means by which these cells associate with type I diabetes in humans., Multiple and largely redundant mechanisms in the immune system are present to regulate and suppress immune reactivity against self-antigens, thereby protecting the body from autoimmune disease (1). In one example, [...]

OBJECTIVE--We conducted an open-label, phase I study using autologous umbilical cord blood (UCB) infusion to ameliorate type 1 diabetes (T1D). Having previously reported on the first 15 patients reaching 1 [...]