Abstract

The goal of the proposed project is to investigate mechanisms of pathogenesis and immunoregulation in autoimmune type 1 diabetes through the use of a T cell receptor transgenic (TCR-Tg) mouse expressing the alpha and beta chain genes from the T cell receptor of an islet specific, diabetogenic T cell clone, BDC-6.9. The T cell clone, BDC-6.9, is similar to another clone in our panel, BDC-2.5, in that it was derived from spleen cells of an NOD mouse, reacts with an antigen in the beta granule membrane, and rapidly induces disease when administered to young NOD mice or to NOD-scid recipients. The BDC-6.9 clone, unlike BDC-2.5, responds to islet antigen only from NOD or NOD-related mice and we have identified a microsatellite marker which is closely linked to the BDC-6.9 antigen on chromosome six. We have taken advantage of these findings to produce an NOD congenic (NOD.C6) mouse that lacks the BDC-6.9 autoantigen.
Our aims under this project are to (1) characterize the properties of the 6.9 TCR-Tg mouse on the NOD background with respect to T cell function and disease incidence, (2) breed and characterize the 6.9 TCR-Tg mouse on the NOD.C6 congenic mouse lacking the target antigen, and (3) define the antigen for the BDC-6.9 antigen through analysis of differential gene expression in islets from NOD and NOD.C6 mice.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK050561-05A2
Application #
6430324
Study Section
Special Emphasis Panel (ZRG1-IMS (01))
Program Officer
Akolkar, Beena
Project Start
1996-09-01
Project End
2004-11-30
Budget Start
2002-02-01
Budget End
2002-11-30
Support Year
5
Fiscal Year
2002
Total Cost
$205,001
Indirect Cost

  Institution

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

  Publications

Delong, Thomas; Baker, Rocky L; He, Jing et al. (2012) Diabetogenic T-cell clones recognize an altered peptide of chromogranin A. Diabetes 61:3239-46
Baker, Rocky L; Mallevaey, Thierry; Gapin, Laurent et al. (2012) T cells interact with T cells via CD40-CD154 to promote autoimmunity in type 1 diabetes. Eur J Immunol 42:672-80
Delong, Thomas; Baker, Rocky L; Reisdorph, Nichole et al. (2011) Islet amyloid polypeptide is a target antigen for diabetogenic CD4+ T cells. Diabetes 60:2325-30
Haskins, Kathryn; Cooke, Anne (2011) CD4 T cells and their antigens in the pathogenesis of autoimmune diabetes. Curr Opin Immunol 23:739-45
Stadinski, Brian D; Delong, Thomas; Reisdorph, Nichole et al. (2010) Chromogranin A is an autoantigen in type 1 diabetes. Nat Immunol 11:225-31
Tonkin, Daniel R; Haskins, Kathryn (2009) Regulatory T cells enter the pancreas during suppression of type 1 diabetes and inhibit effector T cells and macrophages in a TGF-beta-dependent manner. Eur J Immunol 39:1313-22
He, Jing; Haskins, Kathryn (2008) Pathogenicity of T helper 2 T-cell clones from T-cell receptor transgenic non-obese diabetic mice is determined by tumour necrosis factor-alpha. Immunology 123:108-17
Tonkin, Daniel R; He, Jing; Barbour, Gene et al. (2008) Regulatory T cells prevent transfer of type 1 diabetes in NOD mice only when their antigen is present in vivo. J Immunol 181:4516-22
Cantor, Joseph; Haskins, Kathryn (2007) Recruitment and activation of macrophages by pathogenic CD4 T cells in type 1 diabetes: evidence for involvement of CCR8 and CCL1. J Immunol 179:5760-7
Cantor, Joseph; Haskins, Kathryn (2005) Effector function of diabetogenic CD4 Th1 T cell clones: a central role for TNF-alpha. J Immunol 175:7738-45

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