Cytokine- and costimulation-mediated therapy of IDDM.
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.
Cameron
M J
MJ
John P. Robarts Research Institute, University of Western Ontario, London, Canada.
Arreaza
G A
GA
Delovitch
T L
TL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology* / Q000494:pharmacology; D002455:Cell Division; D019742:Chemokines, CC / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D019742:Chemokines, CC; D016207:Cytokines; D015847:Interleukin-4