Abstract

This proposal will test the hypothesis that a specific native sequence of insulin including the dominant insulin peptide, amino acids B9 to B23, is essential for disease development for the NOD mouse. Within islets of NOD mice, T cells reacting with insulin comprise up to 50 percent of islet-specific T lymphocytes and are present as early as four weeks of age. The majority of these insulin reactive T cells (more than 90 percent) recognize an immunodominant T cell epitope of a peptide termed B2 or B:9-23 (amino acids 9 to 23 of the insulin B chain). Recently, it has been shown that the majority of T cells reacting with peptide B:9-23 express a shared T cell receptor alpha chain motif with utilization of a recently discovered V-alpha13 variant, V- alpha13.3a, and additionally express J-alpha 34 or 45, with the shared J- alpha motif KLTFGKGT. Similar restriction is not apparent in the T cell receptor beta chains of these clones.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055969-02
Application #
2906421
Study Section
Special Emphasis Panel (ZAI1-PTM-I (S1))
Program Officer
Akolkar, Beena
Project Start
1998-09-30
Project End
2001-09-29
Budget Start
1999-09-30
Budget End
2000-09-29
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045

  Publications

Aydintug, M Kemal; Zhang, Li; Wang, Chao et al. (2014) ?? T cells recognize the insulin B:9-23 peptide antigen when it is dimerized through thiol oxidation. Mol Immunol 60:116-28
Nakayama, Maki; Castoe, Todd; Sosinowski, Tomasz et al. (2012) Germline TRAV5D-4 T-cell receptor sequence targets a primary insulin peptide of NOD mice. Diabetes 61:857-65
Crawford, Frances; Stadinski, Brian; Jin, Niyun et al. (2011) Specificity and detection of insulin-reactive CD4+ T cells in type 1 diabetes in the nonobese diabetic (NOD) mouse. Proc Natl Acad Sci U S A 108:16729-34
Michels, Aaron W; Ostrov, David A; Zhang, Li et al. (2011) Structure-based selection of small molecules to alter allele-specific MHC class II antigen presentation. J Immunol 187:5921-30
Michels, Aaron W; Eisenbarth, George S (2011) Immune intervention in type 1 diabetes. Semin Immunol 23:214-9
Eisenbarth, George S (2010) Banting Lecture 2009: An unfinished journey: molecular pathogenesis to prevention of type 1A diabetes. Diabetes 59:759-74
Stadinski, Brian D; Zhang, Li; Crawford, Frances et al. (2010) Diabetogenic T cells recognize insulin bound to IAg7 in an unexpected, weakly binding register. Proc Natl Acad Sci U S A 107:10978-83
Martin-Pagola, A; Pileggi, A; Zahr, E et al. (2009) Insulin2 gene (Ins2) transcription by NOD bone marrow-derived cells does not influence autoimmune diabetes development in NOD-Ins2 knockout mice. Scand J Immunol 70:439-46
Babaya, Naru; Yu, Liping; Miao, Dongmei et al. (2009) Comparison of insulin autoantibody: polyethylene glycol and micro-IAA 1-day and 7-day assays. Diabetes Metab Res Rev 25:665-70
Zhang, Li; Jasinski, Jean M; Kobayashi, Masakazu et al. (2009) Analysis of T cell receptor beta chains that combine with dominant conserved TRAV5D-4*04 anti-insulin B:9-23 alpha chains. J Autoimmun 33:42-9

Showing the most recent 10 out of 62 publications