CYTOKINE-MEDIATED AND COSTIMULATION-MEDIATED THERAPY OF IDDM

Citation
Mj. Cameron et al., CYTOKINE-MEDIATED AND COSTIMULATION-MEDIATED THERAPY OF IDDM, Critical reviews in immunology, 17(5-6), 1997, pp. 537-544
Citations number
58
ISSN journal
10408401
Volume
17
Issue
5-6
Year of publication
1997
Pages
537 - 544
Database
ISI
SICI code
1040-8401(1997)17:5-6<537:CACTOI>2.0.ZU;2-B
Abstract
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.