Gamma interferon paradoxically inhibits the development of diabetes in the NOD mouse.
Gamma interferon (IFN-gamma) has been thought to play an important role in the pathogenesis of diabetes. This report determines if rIFN-gamma administration to NOD mice paradoxically inhibits the development of diabetes. Injections of recombinant rIFN-gamma of 5 x 10(3), 20 x 10(3), and 100 x 10(3) units, dose dependently inhibited the development of diabetes. The maximal rIFN-gamma dose decreased the incidence of diabetes from 74% in control animals to 42%. 100x10(3) unit rIFN-gamma dose significantly decreased insulitis score, and increased islet number. The development of diabetes in irradiated NOD mice was slower in animals injected with spleen cells from rIFN-gamma treated than from saline treated NOD mice suggesting that rIFN-gamma decreases anti-islet effector cell activity. The susceptibility to apoptosis was increased in splenic cells of rIFN-gamma treated mice. The expressions of the co-stimulatory molecules B7-2 and ICAM-1 were significantly increased in spleen cells of rIFN-gamma treated mice while the expression of MHC class I was decreased. In vitro studies demonstrated that NOD mouse mononuclear spleen cells preincubated with rIFN-gamma and subsequently cocultured with responder cells, potently inhibited responder T-cell proliferative responses. rIFN-gamma administration decreased IL-12 and IL-2 mRNA expression in spleen cells while increasing IL-1 expression. In conclusion, rIFN-gamma inhibits the diabetic process in NOD mice by decreasing anti-islet effector activity and in turn decreasing insulitis and islet destruction. The suppression of Th1 cell related cytokines and/or augmentation of the macrophage cytokine IL-1 may play a role in the diabetes sparing effect of rIFN-gamma.
Sobel
Douglas O
DO
Georgetown University Medical Center, Division of Pediatric Endocrinology and Metabolism, 3800 Reservoir Road N.W., 2 PHC, Washington, DC 20007-2197, USA.
Han
Jaeseok
J
Williams
Joy
J
Yoon
Ji-Won
JW
Jun
Hee-Sook
HS
Ahvazi
Behrouz
B
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D051940:B7-2 Antigen; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects; D003920:Diabetes Mellitus / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D005805:Genes, MHC Class I; D007371:Interferon-gamma / Q000008:administration & dosage / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D015815:Cell Adhesion Molecules; D016207:Cytokines; D008562:Membrane Glycoproteins; D007371:Interferon-gamma