T cells from NOD mice display an age-dependent, TCR-inducible prolifer
ative hyporesponsiveness that may be causal to IDDM. Exogenous IL-4 co
mpletely restores this hyporesponsiveness in vitro and prevents IDDM i
n vivo when administered to NOD mice. We therefore tested the hypothes
is that stimulation of a Th2 response by either IL-4 or CD28 costimula
tion may block progression to IDDM. Low-dose IL-4 treatment beginning
at 2 weeks of age (pre-insulitis) protects NOD mice from insulitis, si
alitis, and thyroiditis, indicating that IL-4 modulates T cell migrati
on to these inflammatory sites. Cytokine secretion profiles of stimula
ted T cells and assays of intrapancreatic cytokine concentrations reve
aled that IL-4 treatment prevents IDDM by stabilizing a protective Th2
-mediated environment in the thymus, spleen, and pancreatic islets. Wh
ereas treatment of NOD mice with an anti-CD28 mAb between 2 to 4 weeks
of age inhibits destructive insulitis and protects against IDDM by en
hancing IL-4 production by T cells, anti-CD28 treatment between 5 to 7
weeks of age does not prevent IDDM. Simultaneous anti-IL-4 treatment
abrogates the protective effect conferred by anti-CD28 treatment. Our
data demonstrate that stimulation of a Th2-cell-enriched environment i
n the pancreas during the inductive phase of disease development block
s progression to IDDM in NOD mice.