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

MG von Herrath, J Dockter, MBA Oldstone - Immunity, 1994 - cell.com
MG von Herrath, J Dockter, MBA Oldstone
Immunity, 1994cell.com
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< gO%) in both transgenic …
Summary
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< gO%) 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 lo-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 aff inity 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.
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