Cytokine- and costimulation-mediated therapy of IDDM

Crit Rev Immunol. 1997;17(5-6):537-44.


T cells from NOD mice display an age-dependent, TCR-inducible proliferative hyporesponsiveness that may be causal to IDDM. Exogenous IL-4 completely restores this hyporesponsiveness in vitro and prevents IDDM in vivo when administered to NOD mice. We therefore tested the hypothesis that stimulation of a Th2 response by either IL-4 or CD28 costimulation may block progression to IDDM. Low-dose IL-4 treatment beginning at 2 weeks of age (pre-insulitis) protects NOD mice from insulitis, sialitis, and thyroiditis, indicating that IL-4 modulates T cell migration to these inflammatory sites. Cytokine secretion profiles of stimulated T cells and assays of intrapancreatic cytokine concentrations revealed that IL-4 treatment prevents IDDM by stabilizing a protective Th2-mediated environment in the thymus, spleen, and pancreatic islets. Whereas treatment of NOD mice with an anti-CD28 mAb between 2 to 4 weeks of age inhibits destructive insulitis and protects against IDDM by enhancing 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 in the pancreas during the inductive phase of disease development blocks progression to IDDM in NOD mice.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • CD28 Antigens / immunology*
  • CD28 Antigens / pharmacology
  • Cell Division
  • Chemokines, CC / immunology
  • Cytokines / immunology
  • Cytokines / pharmacology
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / prevention & control*
  • Disease Models, Animal
  • Humans
  • Interleukin-4 / immunology
  • Interleukin-4 / pharmacology*
  • Mice
  • Mice, Inbred NOD
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • Th2 Cells / immunology


  • Antibodies, Monoclonal
  • CD28 Antigens
  • Chemokines, CC
  • Cytokines
  • Interleukin-4