The long-term objective of this proposal is the prevention of autoimmune mediated Type 1 diabetes mellitus (T1D). Many promising interventions must be tested in a safe and efficient manner in order to achieve this goal. A well-organized cooperative network of capable institutes, Type 1 Diabetes TrialNet, has greatly facilitated the prompt completion of many clinical trials needed to test these potential interventions. The application responds to the RFA to select the clinical centers that will form TrialNet for the next 3 to 5 years. The first goal of this proposal is to both continue and improve the infrastructure essential to completing the current TrialNet studies seeking to prevent T1D in subjects at risk for T1D and to preserve endogenous insulin secretion in subjects with new onset T1D. This section of the proposal reviews Stanford's seven-year experience as a TrialNet national center in central California. The proposal highlights Stanford's plans for extending and improving recruitment and retention activities for the next 3 to 5 years. These plans include both completing the current TrialNet studies and implementing the expected upcoming trials. Stanford is particularly excited about the soon to start TrialNet protocol, developed by Stanford, to test the glucose sensor enhanced strict glycemic control in subjects with new onset T1D. The second goal proposes a clinical study to develop and test a novel intervention using modified autologous dendritic cell therapy to preserve endogenous insulin secretion in subjects with new onset T1D in a multicenter TrialNet study. The proposal, Transgenic IL-4 expression by autologous dendritic cells in new onset Type 1 diabetes (aDC/IL-4), articulates Stanford's approach to testing this therapy in a collaborative manner with other centers in TrialNet. Studies using dendritic cells therapeutically have demonstrated no significant adverse events, so that it is now reasonable to consider this innovative approach as a possible therapy for diabetes prevention. This proposal describes both Phase 1 safety studies followed by Phase 2 efficacy studies using aDC/IL-4. Ultimately, this therapy will likely have a role in preventing T1D

Public Health Relevance

Type 1 diabetes mellitus is a serious life limiting disease that strikes predominantly in children and adolescents. The TrialNet clinical research network, the focus of the proposal, is charged with designing and conducting studies aimed at preventing or delaying the onset or progression of type 1 diabetes, both highly relevant public health goals

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK061042-11
Application #
8288829
Study Section
Special Emphasis Panel (ZDK1-GRB-R (O1))
Program Officer
Leschek, Ellen W
Project Start
2001-09-29
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
11
Fiscal Year
2012
Total Cost
$536,530
Indirect Cost
$239,333
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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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
Arif, Sefina; Leete, Pia; Nguyen, Vy et al. (2014) Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes. Diabetes 63:3835-45
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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
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
Sosenko, Jay M; Skyler, Jay S; Palmer, Jerry P et al. (2013) The prediction of type 1 diabetes by multiple autoantibody levels and their incorporation into an autoantibody risk score in relatives of type 1 diabetic patients. Diabetes Care 36:2615-20
Weinberg, Adriana; Boulware, David; Dighero, Bonnie et al. (2013) Effect of abatacept on immunogenicity of vaccines in individuals with type 1 diabetes. Vaccine 31:4791-4

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