Infection With Viruses From Several Families Triggers Autoimmune Diabetes in LEW.1WR1 Rats

Prevention of Diabetes by Maternal Immunization

  1. Rebecca S. Tirabassi1,
  2. Dennis L. Guberski1,
  3. Elizabeth P. Blankenhorn2,
  4. Jean H. Leif3,
  5. Bruce A. Woda4,
  6. Zhijun Liu5,
  7. Donald Winans1,
  8. Dale L. Greiner3 and
  9. John P. Mordes5
  1. 1BioMedical Research Models, Worcester, Massachusetts;
  2. 2Department of Microbiology and Immunology, Center for Immunogenetics and Inflammatory Diseases, Drexel University College of Medicine, Philadelphia, Pennsylvania;
  3. 3Division of Diabetes, University of Massachusetts Medical School, Worcester, Massachusetts;
  4. 4Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts;
  5. 5Division of Endocrinology and Metabolism, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
  1. Corresponding author: Dennis L. Guberski, dguberski{at}biomere.com.

Abstract

OBJECTIVE The contribution of antecedent viral infection to the development of type 1 diabetes in humans is controversial. Using a newer rat model of the disease, we sought to 1) identify viruses capable of modulating diabetes penetrance, 2) identify conditions that increase or decrease the diabetogenicity of infection, and 3) determine whether maternal immunization would prevent diabetes.

RESEARCH DESIGN AND METHODS About 2% of LEW.1WR1 rats develop spontaneous autoimmune diabetes, but disease penetrance is much higher if weanling rats are exposed to environmental perturbants including Kilham rat virus (KRV). We compared KRV with other viruses for diabetogenic activity.

RESULTS Both KRV and rat cytomegalovirus (RCMV) induced diabetes in up to 60% of LEW.1WR1 rats, whereas H-1, vaccinia, and Coxsackie B4 viruses did not. Simultaneous inoculation of KRV and RCMV induced diabetes in 100% of animals. Pretreatment of rats with an activator of innate immunity increased the diabetogenicity of KRV but not RCMV and was associated with a moderate rate of diabetes after Coxsackie B4 and vaccinia virus infection. Inoculation of LEW.1WR1 dams with both KRV and RCMV prior to pregnancy protected weanling progeny from virus-induced diabetes in a virus-specific manner.

CONCLUSIONS Exposure to viruses can affect the penetrance of autoimmune diabetes in genetically susceptible animals. The diabetogenicity of infection is virus specific and is modified by immunomodulation prior to inoculation. Maternal immunization protects weanlings from virus-induced diabetes, suggesting that modification of immune responses to infection could provide a means of preventing islet autoimmunity.

Footnotes

  • The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received February 20, 2009.
    • Accepted September 15, 2009.
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  1. Diabetes vol. 59 no. 1 110-118
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