Type 1 diabetes arises in genetically predisposed individuals as a consequence of the immune-mediated destruction of the pancreatic islet insulin secreting beta cells. The onset of clinical symptoms of diabetes represents a relative endpoint in the chronic progressive decline of beta cell function, and occurs when a preponderance of beta cell mass is lost. The Diabetes Prevention Trial -Type 1 (DPT-1) and Type 1 Diabetes TrialNet have shown: 1) that multi-center cooperative research in type 1 diabetes can be efficiently coordinated on a national and international level and 2) that type 1 diabetes can be predicted with a high degree of accuracy in relatives of patients with type 1 diabetes by the presence of autoantibodies and evidence of pancreatic beta-cell dysfunction. These studies have enabled identification of a large number of patients at the very early stages of their disease prior to the onset of hyperglycemia. Evidence, both in animal models of type-1 diabetes and in human trials, has shown that it is possible to alter the course of beta cell destruction utilizing numerous interventions. Increasingly, novel immunologic agents characterized in investigations of other autoimmune disorders and in the field of organ transplantation have been proposed for the treatment of autoimmune diabetes. One such agent, the anti-CD20 drug rituximab (RituxanR, Genentech, South San Francisco and Biogen) originally developed for treatment of B-cell lymphoma, is now approved for treatment of rheumatoid arthritis, another classically T-cell mediated disease. Results of the TrialNet Rituximab new-onset intervention study, designed by the Co-PI for this study proposal Dr. Mark Pescovitz, has now provided evidence for safety and efficacy of this treatment modality in type 1 diabetes. We propose to extend and expand our participation in Type 1 Diabetes TrialNet as a Clinical Center. As the Clinical Center that proposed the use of rituximab in a new-onset intervention trail and the leader in subject recruitment for that study, IU is uniquely qualified to conduct a prevention study utilizing this agent.

Public Health Relevance

This application is in accordance with the RFA-DK-08-011 solicitation to invite sites to apply to become TrialNet Clinical Centers. Centers will carry out the TrialNet Natural History Study and prevention and new-onset intervention studies while overseeing a network of Affiliate Centers and additional clinical sites that will recruit and follow individuals with T1D and those at risk for development of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01DK085505-04S1
Application #
8616831
Study Section
Special Emphasis Panel (ZDK1-GRB-R (O1))
Program Officer
Leschek, Ellen W
Project Start
2009-09-30
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$11,642
Indirect Cost
$4,179
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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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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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
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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

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