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F.47. Ingested IFN-alpha2A Prolongs the 'Honeymoon' Phase in New Onset Type 1 Diabetes Mellitus (T1D) in a Phase II Randomized Clinical Trial (RCT)
Abstracts
F.47. Ingested IFN-alpha2A Prolongs the 'Honeymoon' Phase in New Onset Type 1 Diabetes Mellitus (T1D) in a Phase II Randomized Clinical Trial (RCT) Kristina Rother2 , Rebecca Brown2 , Elizabeth Wright2 , Miriam Morales1, Carol Campbell2, David Harlan2, Philip Orlander1, Zhigang Duan2, Staley Brod1. 1University of Texas - Houston, Bellaire, TX; 2NIH, Bethesda, MD Background: The current study is the first RCTof the efficacy of ingested IFN-α2a for preservation of β-cell function in youths with recent onset T1D. Objectives: Determine in the first prospective RCT the safety and efficacy of ingested IFN-α2a for preservation of β-cell function in recent onset T1D. Methods: All patients had been diagnosed with T1D within 6 weeks. 128 patients were enrolled at the 5 participating centers, and were randomized centrally to one of the following 3 treatment arms: placebo, 5K U IFN-α or 30K U IFN-α. At screening and every 3 months thereafter, patients underwent a mixed meal study. Blood samples were obtained for glucose and c-peptide. The primary outcome was change in meal-stimulated C-peptide area under the curve (AUC) from the beginning to the end of the study. Results: Of 128 subjects enrolled in the study, 86 (67%) completed the 12 month follow-up. Subjects treated with IFN-α had less percent loss of C-peptide at 12 months relative to screening compared to placebo-treated controls (58±27%, 28 ±55%, 47±36% for Placebo, 5000 units, and 30,000 units, respectively, p = 0.020, ANOVA adjusted for age and study site). Exploratory analyses combining the 5000 and 30,000 unit IFN-α doses showed a statistically greater relative rise insulin dose in the placebo group versus the combined treatment group (placebo 1.9 ± 4.9, combined IFN-α (0.43 ± 0.83, p = 0.035, ANOVA adjusted for age and study site). Conclusion: Patients in the 5000 unit IFN-α treatment group maintained more β-cell function one year after enrollment into the study compared to individuals in the placebo group, while this effect was not observed in patients who received 30000 units IFN-α. Further studies of low-dose ingested IFN-α in new-onset T1D are needed to confirm this effect.
S107 immune response to infections and vaccinations), highsensitivity C-reactive protein (marker for inflammatory response) and erythrocyte superoxide dismutase (marker for oxidative stress) distinguishable from that of 27 demographically-matched statin-naïve controls. doi:10.1016/j.clim.2009.03.312
F.49. Neither Smad2 or Smad3 is Essential for TGF-β to Induce Foxp3+ Regulatory T Cells and Th17 Cells Song Guo Zheng1, Ling Lu1, Julie Wang1, David Brand2, David Horwitz1, Wei Shi3. 1University of Southern California, Los Angeles, CA; 2Veterans Affairs Medical Center, Memphis, TN; 3Children's Hospital Los Angeles, Los Angeles, CA TGF-β induces the development of Foxp3+ regulatory T (iTreg) and IL-17-producing (Th17) cells based on the present cytokines. However, the Smad-dependent and independent pathways that affect these Tcell responses are poorly defined. Others have reported that Smad3 is required for activity of the Foxp3 enhancer. To address this issue we have used mice deficient in Smad signaling. In naïve CD4+CD25- cells isolated from Smad3 Knock-out (KO) mice, TGF-β was able to induce TCR-activated Tcells to express Foxp3 and develop suppressive activity, although the level of Foxp3 was slightly lower than induction in wild type cells. In addition, TGF-β was also able to induce CD4+ cells from Smad2 conditional KO mice to become Foxp3+ suppressor cells. Moreover, IL-6 and TGF-β induced naïve CD4+ cells from wild type and Smad2 and 3 deficient mice to become Th17 cells. Similar to wild type mice, addition of retinoic acid (ATRA) increased iTreg differentiation and inhibited Th17 development in Smad deficient mice. These results suggest that although the combined effects of Smad2 and Smad3 may be needed for the induction of iTreg and Th17 cells, Smad-independent signaling pathways are also required for these TGF-β differentiation effects. doi:10.1016/j.clim.2009.03.313
doi:10.1016/j.clim.2009.03.311
F.48. IgG Subclass, hsCRP and eSOD Biased by Chronic Statin Exposure Dale Quest1, Kathryn McMahon1, Merne Wilson2, Thomas Wilson2, Michelle Webb2. 1Paul L. Foster School of Medicine, TTUHSC, El Paso, TX; 2University of Saskatchewan, Saskatoon, SK, Canada Statins are the most common drugs used to lower cholesterol. Statins have potential to alter immune and inflammatory responses. In this era of new infections and vaccines it will be important to predict whether statins might, either beneficially or detrimentally, bias the treated population's response to new and emerging vaccinations and infections. This observational study included 54 volunteers: 27 adults having continuous statin exposure of at least 2 years with 27 statin-naive adults. The aim was to determine whether chronic statin exposure is associated with a pattern of IgG subclass antibody production (pattern of humoral
F.50. The Receptor for Advanced Glycation End Products (RAGE) Promotes Activation of the Inflammasome in Murine Macrophages Rui Kang, Daolin Tang, Tara Loux, Nicole Schapiro, Michael Lotze, Herbert Zeh. University of Pittsburgh School of Medicine, Pittsburgh, PA Interleukin-1 β activation requires processing from an inactive precursor by the cysteine protease caspase-1. Caspase-1 forms a protein platform called the inflammasome, together with proteins of the nucleotide-binding oligomerization domain-like receptor (NLR) family such as NALP3. The receptor for advanced glycation end products (RAGE), is an evolutionarily recent type I transmembrane receptor, member of the immunoglobulin superfamily, encoded within the genedense major histocompatability Class III region, adjacent to TNF-α and several complement components. Here, we demonstrate that RAGE plays an important role in the activation of the inflammasome in macrophages. Diverse proinflammatory agents and TLR agonists such as LPS/ATP,
F.47. Ingested IFN-alpha2A Prolongs the 'Honeymoon' Phase in New Onset Type 1 Diabetes Mellitus (T1D) in a Phase II Randomized Clinical Trial (RCT) Kristina Rother2 , Rebecca Brown2 , Elizabeth Wright2 , Miriam Morales1, Carol Campbell2, David Harlan2, Philip Orlander1, Zhigang Duan2, Staley Brod1. 1University of Texas - Houston, Bellaire, TX; 2NIH, Bethesda, MD Background: The current study is the first RCTof the efficacy of ingested IFN-α2a for preservation of β-cell function in youths with recent onset T1D. Objectives: Determine in the first prospective RCT the safety and efficacy of ingested IFN-α2a for preservation of β-cell function in recent onset T1D. Methods: All patients had been diagnosed with T1D within 6 weeks. 128 patients were enrolled at the 5 participating centers, and were randomized centrally to one of the following 3 treatment arms: placebo, 5K U IFN-α or 30K U IFN-α. At screening and every 3 months thereafter, patients underwent a mixed meal study. Blood samples were obtained for glucose and c-peptide. The primary outcome was change in meal-stimulated C-peptide area under the curve (AUC) from the beginning to the end of the study. Results: Of 128 subjects enrolled in the study, 86 (67%) completed the 12 month follow-up. Subjects treated with IFN-α had less percent loss of C-peptide at 12 months relative to screening compared to placebo-treated controls (58±27%, 28 ±55%, 47±36% for Placebo, 5000 units, and 30,000 units, respectively, p = 0.020, ANOVA adjusted for age and study site). Exploratory analyses combining the 5000 and 30,000 unit IFN-α doses showed a statistically greater relative rise insulin dose in the placebo group versus the combined treatment group (placebo 1.9 ± 4.9, combined IFN-α (0.43 ± 0.83, p = 0.035, ANOVA adjusted for age and study site). Conclusion: Patients in the 5000 unit IFN-α treatment group maintained more β-cell function one year after enrollment into the study compared to individuals in the placebo group, while this effect was not observed in patients who received 30000 units IFN-α. Further studies of low-dose ingested IFN-α in new-onset T1D are needed to confirm this effect.
S107 immune response to infections and vaccinations), highsensitivity C-reactive protein (marker for inflammatory response) and erythrocyte superoxide dismutase (marker for oxidative stress) distinguishable from that of 27 demographically-matched statin-naïve controls. doi:10.1016/j.clim.2009.03.312
F.49. Neither Smad2 or Smad3 is Essential for TGF-β to Induce Foxp3+ Regulatory T Cells and Th17 Cells Song Guo Zheng1, Ling Lu1, Julie Wang1, David Brand2, David Horwitz1, Wei Shi3. 1University of Southern California, Los Angeles, CA; 2Veterans Affairs Medical Center, Memphis, TN; 3Children's Hospital Los Angeles, Los Angeles, CA TGF-β induces the development of Foxp3+ regulatory T (iTreg) and IL-17-producing (Th17) cells based on the present cytokines. However, the Smad-dependent and independent pathways that affect these Tcell responses are poorly defined. Others have reported that Smad3 is required for activity of the Foxp3 enhancer. To address this issue we have used mice deficient in Smad signaling. In naïve CD4+CD25- cells isolated from Smad3 Knock-out (KO) mice, TGF-β was able to induce TCR-activated Tcells to express Foxp3 and develop suppressive activity, although the level of Foxp3 was slightly lower than induction in wild type cells. In addition, TGF-β was also able to induce CD4+ cells from Smad2 conditional KO mice to become Foxp3+ suppressor cells. Moreover, IL-6 and TGF-β induced naïve CD4+ cells from wild type and Smad2 and 3 deficient mice to become Th17 cells. Similar to wild type mice, addition of retinoic acid (ATRA) increased iTreg differentiation and inhibited Th17 development in Smad deficient mice. These results suggest that although the combined effects of Smad2 and Smad3 may be needed for the induction of iTreg and Th17 cells, Smad-independent signaling pathways are also required for these TGF-β differentiation effects. doi:10.1016/j.clim.2009.03.313
doi:10.1016/j.clim.2009.03.311
F.48. IgG Subclass, hsCRP and eSOD Biased by Chronic Statin Exposure Dale Quest1, Kathryn McMahon1, Merne Wilson2, Thomas Wilson2, Michelle Webb2. 1Paul L. Foster School of Medicine, TTUHSC, El Paso, TX; 2University of Saskatchewan, Saskatoon, SK, Canada Statins are the most common drugs used to lower cholesterol. Statins have potential to alter immune and inflammatory responses. In this era of new infections and vaccines it will be important to predict whether statins might, either beneficially or detrimentally, bias the treated population's response to new and emerging vaccinations and infections. This observational study included 54 volunteers: 27 adults having continuous statin exposure of at least 2 years with 27 statin-naive adults. The aim was to determine whether chronic statin exposure is associated with a pattern of IgG subclass antibody production (pattern of humoral
F.50. The Receptor for Advanced Glycation End Products (RAGE) Promotes Activation of the Inflammasome in Murine Macrophages Rui Kang, Daolin Tang, Tara Loux, Nicole Schapiro, Michael Lotze, Herbert Zeh. University of Pittsburgh School of Medicine, Pittsburgh, PA Interleukin-1 β activation requires processing from an inactive precursor by the cysteine protease caspase-1. Caspase-1 forms a protein platform called the inflammasome, together with proteins of the nucleotide-binding oligomerization domain-like receptor (NLR) family such as NALP3. The receptor for advanced glycation end products (RAGE), is an evolutionarily recent type I transmembrane receptor, member of the immunoglobulin superfamily, encoded within the genedense major histocompatability Class III region, adjacent to TNF-α and several complement components. Here, we demonstrate that RAGE plays an important role in the activation of the inflammasome in macrophages. Diverse proinflammatory agents and TLR agonists such as LPS/ATP,