Coxsackievirus immunization delays onset of diabetes in non‐obese diabetic mice

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Abstract
Enteroviruses may be involved in the pathogenesis of Type 1 diabetes through different mechanisms including triggering of autoimmunity. The effect of immunization with coxsackievirus B4‐E2 on diabetes incidence was studied in the non‐obese diabetic mice, an animal model for human autoimmune insulin‐dependent diabetes mellitus. The immunization delayed the onset of diabetes in the mice, and the effect was mediated at least partially by virus immunization‐activated splenocytes as demonstrated by adoptive transfer experiments. Immunization resulted in a strong humoral immune response against the immunizing virus, formalin‐inactivated coxsackievirus B4‐E2. Cell‐mediated immune response to virus antigen was characterised by interferon gamma and interleukin 10 secretion. The immunization also resulted in increased antibody levels against several beta‐cell autoantigens. By using epitope mapping we were able to show that in addition to reactivity with the known epitopes of viral proteins and tyrosine phosphatase IA‐2 or heat shock protein 60, responses to some other regions of autoantigens were enhanced. In preproinsulin, the response was restricted against an antigenic region earlier identified as DR4‐dependent epitope. This reactivity can not be explained by homologous amino acid sequences and it is possible that enterovirus immunization might change the autoantigen specific TH1/TH2 balance in non‐obese diabetic mice. In conclusion, our results suggest that coxsackievirus immunization increased humoral immune response to beta cell autoantigens and this was associated with a less destructive pathology for spontaneous diabetes in non‐obese diabetic mice. J. Med. Virol. 69:510–520, 2003.
Funding Information
  • Academy of Finland
  • the Sigrid Jusélius Foundation
  • The Finnish Diabetes Research Foundation
  • The Juvenile Diabetes Research Foundation
  • the European Community (BMH4-CT98-3952)