Interferon-alpha initiates type 1 diabetes in nonobese diabetic mice.
With the goal of identifying changes in gene expression in CD4(+) T cells during the development of diabetes in the nonobese diabetic (NOD) mouse, we used DNA microarrays to analyze gene expression in CD4(+) T cells from the pancreatic draining lymph nodes of NOD/BDC 2.5 T cell receptor transgenic and WT NOD mice at different ages. At 4 and 6 weeks of age, we found up-regulation of a number of genes that are known to be induced by IFN-alpha. IFN-alpha levels and IFN-alpha-producing plasmacytoid dendritic cells were increased in the PLNs of 3- to 4-week-old NOD mice. Moreover, blockade of IFN-alpha receptor 1 in NOD mice by a neutralizing antibody at 2-3 weeks of age significantly delayed the onset and decreased the incidence of type 1 diabetes, increased the relative number of immature dendritic cells in the PLNs, and enhanced the ability of spleen CD4(+) T cells to produce IL-4 and IL-10. These findings demonstrate that IFN-alpha in the PLNs is an essential initiator in the pathogenesis of type 1 diabetes in NOD mice.
Li
Qing
Q
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Xu
Baohui
B
Michie
Sara A
SA
Rubins
Kathleen H
KH
Schreriber
Robert D
RD
McDevitt
Hugh O
HO
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000473:pathology; D020869:Gene Expression Profiling; D016898:Interferon-alpha / Q000032:analysis / Q000494:pharmacology / Q000502:physiology*; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010179:Pancreas / Q000166:cytology / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
D016898:Interferon-alpha; D016753:Interleukin-10; D053633:Receptor, Interferon alpha-beta; D015847:Interleukin-4