This competitve renewal application is for the continuation of a Trialnet Center at Yale University. The Center was originally established at Columbia University but moved with the Principal Investigator to Yale University in 8/06. The Yale Center has received IRB approval and participated in the Natural History study, oral insulin study, and GAD65 immunization study. The Center has been been very active in the anti-CD3 mAb trial, ITN027AI (Abate) that is jointly supported by the Immune Tolerance Network and TrialNet. The Center Principal Investigator is the Principal Investigator of the anti-CD3 monoclonal antibody (mAb) prevention trial and has also served as the Principal Investigator of the T cell validation-l study. The Center Principal Investigator is the Chair of the Mechanistic Outcomes Committee and has been active in that committee's activities in all TrialNet protocols. In addition to the trial performance, the Center investigators have conducted and published analyses of data from the DPT-1 and the T cell validation study-1. We propose to continue partipation in ongoing TrialNet studies and to participate in the future TrialNet Studies. We plan to be a referral site for the anti-CD3 mAb prevention trial and the metabolic control trial since our site has unique skills for these studies. Studies to date have indicated that combinations of therapies will be needed to reverse T1DM. We propose a new clinical trial with the combination of anti-CD3 mAb with the IL-1 receptor antagonist (IL-1Ra), to test the hypothesis that loss of tolerance following anti-CD3 mAb treatment is due to an inflammatory response, most likely in the islets, and mediated by IL-1. Our preclinical data support the synergy of IL-1Ra with anti-CD3 mAb. The proposed study is a 3 arm randomized placebo controlled trial to compare the effects of a combination of anti-CD3 mAb with Anakinra to anti-CD3 mAb or placebo. The primary endpoint of the trial will be the change in C-peptide responses to a mixed meal 18 mos after study entry. Affiliates from the Columbia site were not transferred to Yale in 2006, but since that time, new affiliates have been enlisted involving sites that had not previously been associated with TrialNet. These sites are in the New York region, the midwest, and Texas. We therefore anticipate that our ability to recruit for future TrialNet studies will increase by several orders of magnitude.

Public Health Relevance

Type 1 diabetes is an autoimmune disease leading to destruction of insulin production beta cells and dependency on exogenous insulin. Changing the natural history of the disease will require a number of clinical studies, optimally done at large centers so they can be completed in a safe and expeditious manner. Our proposal is to continue our work in TrialNet at Yale University. We are also proposing a new clinical trial involving IL-1RA and anti-CD3 mAb that have shown promise in preclinical studies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZDK1-GRB-R (O1))
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Leschek, Ellen W
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Yale University
Schools of Medicine
New Haven
United States
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Redondo, Maria J; Steck, Andrea K; Sosenko, Jay et al. (2018) Transcription Factor 7-Like 2 (TCF7L2) Gene Polymorphism and Progression From Single to Multiple Autoantibody Positivity in Individuals at Risk for Type 1 Diabetes. Diabetes Care 41:2480-2486
Sanda, Srinath; Type 1 Diabetes TrialNet Study Group (2018) Increasing ICA512 autoantibody titers predict development of abnormal oral glucose tolerance tests. Pediatr Diabetes 19:271-276
Yeo, Lorraine; Woodwyk, Alyssa; Sood, Sanjana et al. (2018) Autoreactive T effector memory differentiation mirrors ? cell function in type 1 diabetes. J Clin Invest 128:3460-3474
Redondo, Maria J; Geyer, Susan; Steck, Andrea K et al. (2018) A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk. Diabetes Care 41:1887-1894
Greenbaum, Carla J; Speake, Cate; Krischer, Jeffrey et al. (2018) Strength in Numbers: Opportunities for Enhancing the Development of Effective Treatments for Type 1 Diabetes-The TrialNet Experience. Diabetes 67:1216-1225
Haller, Michael J; Schatz, Desmond A; Skyler, Jay S et al. (2018) Low-Dose Anti-Thymocyte Globulin (ATG) Preserves ?-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes. Diabetes Care 41:1917-1925
Redondo, Maria J; Geyer, Susan; Steck, Andrea K et al. (2018) TCF7L2 Genetic Variants Contribute to Phenotypic Heterogeneity of Type 1 Diabetes. Diabetes Care 41:311-317
Sosenko, Jay M; Geyer, Susan; Skyler, Jay S et al. (2018) The influence of body mass index and age on C-peptide at the diagnosis of type 1 diabetes in children who participated in the diabetes prevention trial-type 1. Pediatr Diabetes 19:403-409
Ismail, Heba M; Xu, Ping; Libman, Ingrid M et al. (2018) The shape of the glucose concentration curve during an oral glucose tolerance test predicts risk for type 1 diabetes. Diabetologia 61:84-92
Culina, Slobodan; Lalanne, Ana Ines; Afonso, Georgia et al. (2018) Islet-reactive CD8+ T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors. Sci Immunol 3:

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