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Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
When immunological tolerance breaks down, autoimmune destruction of
insulin-producing 
cells in the pancreas can cause insulin-dependent
diabetes mellitus. We previously showed that transgenic nonobese
diabetic (NOD) mice expressing IL-4 in the pancreas (NOD-IL-4 mice)
were protected from insulitis and diabetes. Here we have characterized
the avoidance of pathological autoimmunity in these mice. The absence
of disease did not result from a lack of T cell priming, because T
cells responding to dominant islet Ags were present. These islet
Ag-specific T cells displayed a Th2 phenotype, indicating that Th2
responses could account for the observed tolerance. Interestingly,
islet Ag-specific Th1 T cells were present and found to be functional,
because neutralization of the Th2 effector cytokines IL-4 and IL-10
resulted in diabetes. Histological examination revealed that NOD-IL-4
splenocytes inhibited diabetogenic T cells in cotransfer experiments by
limiting insulitis and delaying diabetes. Neutralization of IL-4 in
this system abrogated the ability of NOD-IL-4 splenocytes to delay the
onset of diabetes. These results indicate that IL-4 expressed in the
islets does not prevent the generation of pathogenic islet responses
but induces islet Ag-specific Th2 T cells that block the action of
diabetogenic T cells in the pancreas.
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