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How virus induces a rapid or slow onset insulin-dependent diabetes mellitus in a transgenic model.

We developed two distinct transgenic mouse models in which virus induced insulin-dependent (type 1) diabetes mellitus (IDDM). In one of these lines, the unique viral transgene was expressed in the islets of Langerhans and also in the thymus, but in the other line, expression was only in the islets. Insertion and expression of the viral (self) gene, per se, did not lead to IDDM, (incidence < 5%). By contrast, induction of an anti-self (anti-viral) CD8+ CTL response to the same virus later in life caused IDDM (incidence < 90%) in both transgenic lines, although the kinetics and requirements for CD4 help, the affinity and avidity of CD8+ CTL differed in each line. Mice not expressing the viral (self) gene in the thymus developed IDDM 10-14 days after infection. CD4+ T cells played no detectable role, since their depletion failed to alter either the kinetics or incidence of IDDM. By contrast, mice that expressed the viral gene in the thymus required significantly more time to develop IDDM. Their anti-self (viral) CD8+ CTL were of lower affinity and avidity than CD8+ CTL generated by nontransgenic controls. Disease was dependent on T cell help, since deletion of CD4+ cells completely circumvented the IDDM.

Pubmed ID: 7889411

Authors

  • von Herrath MG
  • Dockter J
  • Oldstone MB

Journal

Immunity

Publication Data

June 18, 1994

Associated Grants

  • Agency: NIA NIH HHS, Id: AG04232
  • Agency: NIAID NIH HHS, Id: AI09484
  • Agency: NINDS NIH HHS, Id: NS12428

Mesh Terms

  • Animals
  • Base Sequence
  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Cytotoxicity, Immunologic
  • DNA Primers
  • DNA, Viral
  • Diabetes Mellitus, Experimental
  • Diabetes Mellitus, Type 1
  • Gene Expression
  • Islets of Langerhans
  • Lymphocytic choriomeningitis virus
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mice, SCID
  • Mice, Transgenic
  • Molecular Sequence Data
  • RNA, Viral
  • Thymus Gland
  • Time Factors