This submission from the Children's Hospital of UPMC and the University of Pittsburgh responds to the TriaNet RFA DK-08-001. This group of investigators, with extensive experience who were a prior TrialNet center, has the resources, numerous recruited affilliates and a track record demonstrating their ability to continue TrialNet participation as a center. In order to answer the objective of the RFA, we propose a randomized controlled trial to evaluate the safety and efficacy of a new diabetes-suppressive cell vaccine, consisting of autologous monocyte-derived dendritic cells treated ex vivo with antisense phosphorothioate-modified oligonucleotides targeting the primary transcripts of the CD40, CD80 and CD86 co-stimulatory molecules (immunoregulatory DC;iDC). Phase 1 testing in patients with established Type 1 diabetes (T1D) and primates are almost completed. The hypotheses to be tested in this study are that gene-engineered autologous DC can attenuate or suppress the autoimmunity in: a) newly-diagnosed T1D, sparing residual beta cell mass, with restoration of insulin secretion as assessed by stimulated C-peptide levels, b) first degree relatives with disease predicting islet autoantibodies, to sustain insulin secretion assessed by stimulated C-peptide levels and to prevent progression to clinical T1D. Currently, other than immune suppression with considerable potential side effects, there is no other means to reverse or prevent new-onset T1D. These studies will be the first ever to employ autologous dendritic cell transfer to suppress an autoimmune disease and to possibly reverse it early in the clinical process. The strength of this proposal is the expertise and experience of the investigators,well established collaborations across centers and a novel intervention strategy

Public Health Relevance

The ultimate goal of TrialNet is to prevent the development of clinical type 1 diabetes. Failing this, even a delay in the onset of diabetes and insulin requirements has enormous benefits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK061058-11
Application #
8288864
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
$411,213
Indirect Cost
$190,314
Name
University of Pittsburgh
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
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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
Sims, Emily K; Chaudhry, Zunaira; Watkins, Renecia et al. (2016) Elevations in the Fasting Serum Proinsulin-to-C-Peptide Ratio Precede the Onset of Type 1 Diabetes. Diabetes Care 39:1519-26
Cabrera, Susanne M; Wang, Xujing; Chen, Yi-Guang et al. (2016) Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset. Eur J Immunol 46:1030-46

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