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Diabetes 53:978-988, 2004
© 2004 by the American Diabetes Association, Inc.

T-Cell Receptor Transgenic Response to an Endogenous Polymorphic Autoantigen Determines Susceptibility to Diabetes

Mary E. Pauza1,2, Cathleen M. Dobbs3,4, Jing He3,4, Tricia Patterson1, Steven Wagner1, Brian S. Anobile3,4, Brenda J. Bradley3,4, David Lo5, and Kathryn Haskins3,4

1 Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois
2 Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, Illinois
3 Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado
4 National Jewish Medical and Research Center, Denver, Colorado
5 Digital Gene Technologies, La Jolla, California

We have produced a T-cell receptor (TCR) transgenic NOD mouse, 6.9TCR/NOD, in which the expression of both diabetogenic T-cells and naturally occurring autoantigen were simultaneously controlled. The parent T-cell clone, BDC-6.9, and T-cells from 6.9TCR/NOD mice recognize a currently unidentified antigen present in NOD but not in BALB/c islet cells. A gene that codes for the antigen, or a protein that regulates the antigen, was previously mapped to a locus on chromosome 6. We have developed transgenic mice bearing the TCR {alpha}- and ß-chains from the BDC-6.9 T-cell clone on a NOD congenic background in which the antigen locus on chromosome 6 of the NOD mouse is replaced by a segment from BALB/c. These NOD.C6 congenic mice lack the NOD islet cell antigen to which the BDC-6.9 T-cell clone responds. Diabetes in both male and female 6.9TCR/NOD mice is dramatically accelerated, but in 6.9TCR/NOD.C6 mice lacking the NOD islet cell autoantigen, we have not observed diabetes for up to 1 year of age. Thus, the generation of 6.9TCR transgenic mice provides a model of autoimmune diabetes whereby controlled expression of an endogenous polymorphic autoantigen effectively determines disease development.

Address correspondence and reprint requests to Kathryn Haskins, Department of Immunology, UCHSC/NJMRC, 1400 Jackson St., K802, Denver, CO 80206. E-mail: katie.haskins{at}uchsc.edu


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Copyright © 2004 by the American Diabetes Association.