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Aurora, CO, United States

Kuriya G.,Nagasaki University | Uchida T.,Nagasaki University | Akazawa S.,Nagasaki University | Kobayashi M.,Nagasaki University | And 11 more authors.

Aims/hypothesis: T helper type (Th) 17 cells have been shown to play important roles in mouse models of several autoimmune diseases that have been classified as Th1 diseases. In the NOD mouse, the relevance of Th1 and Th17 is controversial, because single-cytokine-deficient NOD mice develop diabetes similarly to wild-type NOD mice. Methods: We studied the impact of IL-17/IFN-γ receptor double deficiency in NOD mice on the development of insulitis/diabetes compared with IL-17 single-deficient mice and wild-type mice by monitoring diabetes-related phenotypes. The lymphocyte phenotypes were determined by flow cytometric analysis. Results: IL-17 single-deficient NOD mice showed delayed onset of diabetes and reduced severity of insulitis, but the cumulative incidence of longstanding diabetes in the IL-17-deficient mice was similar to that in wild-type mice. The IL-17/IFN-γ receptor double-deficient NOD mice showed an apparent decline in longstanding diabetes onset, but not in insulitis compared with that in the IL-17 single-deficient mice. We also found that double-deficient NOD mice had a severe lymphopenic phenotype and preferential increase in regulatory T cells among CD4+ T cells compared with the IL-17 single-deficient mice and wild-type NOD mice. An adoptive transfer study with CD4+CD25- T cells from young non-diabetic IL-17 single-deficient NOD mice, but not those from older mice, showed significantly delayed disease onset in immune-deficient hosts compared with the corresponding wild-type mice. Conclusions/interpretation: These results indicate that IL-17/Th17 participates in the development of insulitis and that both IL-17 and IFN-γ signalling may synergistically contribute to the development of diabetes in NOD mice. © 2013 Springer-Verlag Berlin Heidelberg. Source

Frederiksen B.N.,University of Colorado at Denver | Seifert J.,University of Colorado at Denver | Kroehl M.,University of Colorado at Denver | Lamb M.M.,University of Colorado at Denver | And 3 more authors.
Pediatric Research

Background:Timing of solid food introduction in infancy has been associated with several chronic diseases. To explore potential mechanisms, we investigated the relationship between timing of solid food introduction and F 2 -isoprostanes - a marker of oxidative stress.Methods:Urinary F 2 -isoprostanes were assessed in 336 healthy children aged less than 11.5 y with 1,266 clinic visits (mean = 3.8 visits per child) in the Diabetes Autoimmunity Study in the Young. We analyzed the association between F 2 -isoprostane concentrations and infant diet exposures using linear mixed models adjusted for age, age 2, HLA-DR3/4,DQB1∗0302 genotype, first-degree relative with type 1 diabetes, maternal age, maternal education, sex, and exposure to in utero cigarette smoke.Results:Later solid food introduction was associated with lower F 2 -isoprostane concentrations in childhood (on average, 0.10 ng/mg per month of age at introduction; estimate: -0.10 (95% confidence interval (CI): -0.18, -0.02) P value = 0.02). Moreover, childhood F 2 -isoprostane concentrations were, on average, 0.24 ng/mg lower in individuals breastfed at solid food introduction (estimate: -0.24 (95% CI: -0.47, -0.01) P value = 0.04) compared with those who were not. Associations remained significant after limiting analyses to F 2 -isoprostanes after 2 y of age.Conclusion:Our results suggest a long-term protective effect of later solid food introduction and breastfeeding at solid food introduction against increased F 2 -isoprostane concentrations throughout childhood. © 2015 International Pediatric Research Foundation, Inc. Source

Stearman R.S.,University of Colorado at Denver | Cornelius A.R.,University of Colorado at Denver | Cornelius A.R.,New York University | Lu X.,University of Colorado at Denver | And 18 more authors.
American Journal of Respiratory and Critical Care Medicine

Rationale: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary artery pressure, vascular remodeling, and ultimately right ventricular heart failure. PAH can have a genetic component (heritable PAH), most often through mutations of bone morphogenetic protein receptor 2, and idiopathic and associated forms. Heritable PAH is not completely penetrant within families, with approximately 20% concurrence of inactivating bone morphogenetic protein receptor 2 mutations and delayed onset of PAH disease. Because one of the treatment options is using prostacyclin analogs, we hypothesized that prostacyclin synthase promoter sequence variants associated with increased mRNA expression may play a protective role in the bone morphogenetic protein receptor 2 unaffected carriers. Objectives: To characterize the range of prostacyclin synthase promoter variants and assess their transcriptional activities in PAHrelevant cell types. To determine the distribution of prostacyclin synthase promoter variants in PAH, unaffected carriers in heritable PAH families, and control populations. Methods: Polymerase chain reaction approaches were used to genotype prostacyclin synthase promoter variants in more than 300 individuals. Prostacyclin synthase promoter haplotypes' transcriptional activities were determined with luciferase reporter assays. Measurements and Main Results:Weidentified a comprehensive set of prostacyclin synthase promoter variants and tested their transcriptional activities in PAH-relevant cell types. We demonstrated differences of prostacyclin synthase promoter activities dependent on their haplotype. Conclusions: Prostacyclin synthase promoter sequence variants exhibit a range of transcriptional activities.We discovered a significant bias for more active prostacyclin synthase promoter variants in unaffected carriers as compared with affected patients with PAH. © 2014 by the American Thoracic Society. Source

Shah V.N.,Barbara Davis Center for Diabetes | Shah V.N.,University of Colorado at Denver | Shoskes A.,Barbara Davis Center for Diabetes | Tawfik B.,Barbara Davis Center for Diabetes | And 2 more authors.
Diabetes Technology and Therapeutics

Intensive insulin therapy (IIT) has been shown to reduce micro-And macrovascular complications in patients with type 1 diabetes mellitus (T1DM). However, IIT is associated with a significant increase in severe hypoglycemic events, resulting in increased morbidity and mortality. Optimization of glycemic control without hypoglycemia (especially nocturnal) should be the next major goal for subjects on insulin treatment. The use of insulin pumps along with continuous glucose monitors (CGMs) has made it easier but requires significant resources and patient education. Research is ongoing to close the loop by integrating the pump and the CGM using different algorithms. The currently available closed-loop system is the threshold suspend. Steps needed to achieve a near-perfect closed-loop are (1) a control-to-range system that will reduce the incidence and/or severity of hyper-And/or hypoglycemia by adjusting the insulin dose and (2) a control-to-target system, a fully automated or hybrid system that sets target glucose levels to individual needs and maintains glucose levels throughout the day using insulin (unihormonal) alone or with other hormones such as glucagon or possibly pramlintide (bihormonal). Future research is also focusing on better insulin delivery devices (pumps), more accurate CGMs, better predictive algorithms, and ultra-rapid-Acting insulin analogs to make the closed-loop system as physiological as possible. © Copyright 2014, Mary Ann Liebert, Inc. 2014. Source

Gottlieb P.A.,Barbara Davis Center for Diabetes | Delong T.,University of Colorado at Denver | Baker R.L.,University of Colorado at Denver | Fitzgerald-Miller L.,Barbara Davis Center for Diabetes | And 5 more authors.
Journal of Autoimmunity

Chromogranin A (ChgA) is a beta cell secretory granule protein and a peptide of ChgA, WE14, was recently identified as a ligand for diabetogenic CD4 T cell clones derived from the NOD mouse. In this study we compared responses of human CD4 T cells from recent onset type 1 diabetic (T1D) and control subjects to WE14 and to an enzymatically modified version of this peptide. T cell responders to antigens were detected in PBMCs from study subjects by an indirect CD4 ELISPOT assay for IFN-γ. T1D patients (n=27) were recent onset patients within one year of diagnosis, typed for HLA-DQ8. Controls (n=31) were either 1st degree relatives with no antibodies or from the HLA-matched general population cohort of DAISY/TEDDY. A second cohort of patients (n=11) and control subjects (n=11) was tested at lower peptide concentrations. We found that WE14 is recognized by T cells from diabetic subjects vs. controls in a dose dependent manner. Treatment of WE14 with transglutaminase increased reactivity to the peptide in some patients. This work suggests that ChgA is an important target antigen in human T1D subjects and that post-translational modification may play a role in its reactivity and relationship to disease. © 2013 Elsevier Ltd. Source

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