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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Orban, Tihamer; Beam, Craig A; Xu, Ping et al. (2014) Reduction in CD4 central memory T-cell subset in costimulation modulator abatacept-treated patients with recent-onset type 1 diabetes is associated with slower C-peptide decline. Diabetes 63:3449-57
Orban, Tihamer; Bundy, Brian; Becker, Dorothy J et al. (2014) Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment. Diabetes Care 37:1069-75
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Pescovitz, Mark D; Greenbaum, Carla J; Bundy, Brian et al. (2014) B-lymphocyte depletion with rituximab and *-cell function: two-year results. Diabetes Care 37:453-9
Kroll, Jing Lu; Beam, Craig; Li, Shaobing et al. (2013) Reactivation of latent viruses in individuals receiving rituximab for new onset type 1 diabetes. J Clin Virol 57:115-9
Krischer, Jeffrey P; Type 1 Diabetes TrialNet Study Group (2013) The use of intermediate endpoints in the design of type 1 diabetes prevention trials. Diabetologia 56:1919-24
Diabetes Research in Children Network (DirecNet) Study Group; Type 1 Diabetes TrialNet Study Group; Buckingham, Bruce A et al. (2013) The effects of inpatient hybrid closed-loop therapy initiated within 1 week of type 1 diabetes diagnosis. Diabetes Technol Ther 15:401-8
Loechelt, Brett J; Boulware, David; Green, Michael et al. (2013) Epstein-Barr and other herpesvirus infections in patients with early onset type 1 diabetes treated with daclizumab and mycophenolate mofetil. Clin Infect Dis 56:248-54

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