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Diabetes 54:2727-2733, 2005
© 2005 by the American Diabetes Association, Inc.

LEW.1WR1 Rats Develop Autoimmune Diabetes Spontaneously and in Response to Environmental Perturbation

John P. Mordes1, Dennis L. Guberski2, Jean H. Leif1, Bruce A. Woda3, Joan F. Flanagan2, Dale L. Greiner1, Edward H. Kislauskis2, and Rebecca S. Tirabassi2

1 Diabetes Division, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
2 BioMedical Research Models, Worcester, Massachusetts
3 Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts

We describe a new rat model of autoimmune diabetes that arose in a major histocompatibility complex congenic LEW rat. Spontaneous diabetes in LEW.1WR1 rats (RT1u/u/a) occurs with a cumulative frequency of ~2% at a median age of 59 days. The disease is characterized by hyperglycemia, glycosuria, ketonuria, and polyuria. Both sexes are affected, and islets of acutely diabetic rats are devoid of ß-cells, whereas {alpha}- and {delta}-cell populations are spared. The peripheral lymphoid phenotype is normal, including the fraction of ART2+ regulatory T-cells. We tested the hypothesis that the expression of diabetes would be increased by immunological perturbation of innate or adaptive immunity. Treatment of young rats with depleting anti-ART2.1 monoclonal antibody increased the frequency of diabetes to 50%. Treatment with the toll-like receptor 3 ligand polyinosinic:polycytidylic acid increased the frequency of diabetes to 100%. All diabetic rats exhibited end-stage islets. The LEW.1WR1 rat is also susceptible to collagen-induced arthritis but is free of spontaneous thyroiditis. The LEW.1WR1 rat provides a new model for studying autoimmune diabetes and arthritis in an animal with a genetic predisposition to both disorders that can be amplified by environmental perturbation.

Address correspondence and reprint requests to Dennis L. Guberski, BioMedical Research Models, 67 Millbrook St., Suite 422, Worcester, MA 01606. E-mail: dguberski{at}biomere.com

Abbreviations: IFA, incomplete Freund’s adjuvant; mAb, monoclonal antibody; MHC, major histocompatibility complex; PE, phycoerythrin; poly I:C, polyinosinic:polycytidylic acid; TCR, T-cell receptor; TLR, toll-like receptor; Tregs, regulatory T-cells


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Copyright © 2005 by the American Diabetes Association.