INFECTION WITH VIRUSES FROM SEVERAL FAMILIES TRIGGERS AUTOIMMUNE DIABETES IN LEW.1WR1 RATS: Prevention of Diabetes by Maternal Immunization

  1. Rebecca S. Tirabassi, PhD.1,
  2. Dennis L. Guberski, M.S. (dguberski{at}biomere.com)1,
  3. Elizabeth P. Blankenhorn, PhD.2,
  4. Jean H. Leif, M.S.3,
  5. Bruce A. Woda, M.D.4,
  6. Zhijun Liu, PhD.5,
  7. Donald Winans, B.S.1,
  8. Dale L. Greiner, PhD.3 and
  9. John P. Mordes, M.D.5
  1. 1BioMedical Research Models, Inc., Worcester, MA
  2. 2Department of Microbiology and Immunology, Center for Immunogenetics and Inflammatory Diseases, Drexel University College of Medicine, Philadelphia, PA
  3. Divisions of 3Diabetes and
  4. 5Endocrinology and Metabolism, Department of Medicine, and
  5. 4Department of Pathology, University of Massachusetts Medical School, Worcester, MA

    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 if 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.

    Conclusion: 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

      • Received February 20, 2009.
      • Accepted September 15, 2009.

    This Article

    1. Diabetes
    1. Online-Only Appendix
    2. All Versions of this Article:
      1. db09-0255v1
      2. 59/1/110 most recent