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)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-R (O1))
Program Officer
Leschek, Ellen W
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Fouts, Alexandra; Pyle, Laura; Yu, Liping et al. (2016) Do Electrochemiluminescence Assays Improve Prediction of Time to Type 1 Diabetes in Autoantibody-Positive TrialNet Subjects? Diabetes Care 39:1738-44
Triolo, Taylor M; Maahs, David M; Pyle, Laura et al. (2016) Effects of Frequency of Sensor-Augmented Pump Use on HbA1c and C-Peptide Levels in the First Year of Type 1 Diabetes. Diabetes Care 39:e61-2
Narsale, Aditi; Moya, Rosita; Robertson, Hannah Kathryn et al. (2016) Data on correlations between T cell subset frequencies and length of partial remission in type 1 diabetes. Data Brief 8:1348-51
Bundy, Brian N; Krischer, Jeffrey P; Type 1 Diabetes TrialNet Study Group (2016) A model-based approach to sample size estimation in recent onset type 1 diabetes. Diabetes Metab Res Rev 32:827-834
Pugliese, Alberto; Boulware, David; Yu, Liping et al. (2016) HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 Haplotype Protects Autoantibody-Positive Relatives From Type 1 Diabetes Throughout the Stages of Disease Progression. Diabetes 65:1109-19
Hao, Wei; Gitelman, Steven; DiMeglio, Linda A et al. (2016) Fall in C-Peptide During First 4 Years From Diagnosis of Type 1 Diabetes: Variable Relation to Age, HbA1c, and Insulin Dose. Diabetes Care 39:1664-70
Bingley, Polly J; Boulware, David C; Krischer, Jeffrey P et al. (2016) The implications of autoantibodies to a single islet antigen in relatives with normal glucose tolerance: development of other autoantibodies and progression to type 1 diabetes. Diabetologia 59:542-9
DiMeglio, Linda A; Cheng, Peiyao; Beck, Roy W et al. (2016) Changes in beta cell function during the proximate post-diagnosis period in persons with type 1 diabetes. Pediatr Diabetes 17:237-43
Moya, Rosita; Robertson, Hannah Kathryn; Payne, Dawson et al. (2016) A pilot study showing associations between frequency of CD4(+) memory cell subsets at diagnosis and duration of partial remission in type 1 diabetes. Clin Immunol 166-167:72-80
Durning, Sean P; Preston-Hurlburt, Paula; Clark, Paul R et al. (2016) The Receptor for Advanced Glycation Endproducts Drives T Cell Survival and Inflammation in Type 1 Diabetes Mellitus. J Immunol 197:3076-3085

Showing the most recent 10 out of 49 publications