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Diabetes 54:1415-1422, 2005
© 2005 by the American Diabetes Association, Inc.
Autoimmune Diabetes Onset Results From Qualitative Rather Than Quantitative Age-Dependent Changes in Pathogenic T-Cells
1 Institut National de la Santé et de la Recherche Médicale (INSERM) U580, Paris, France
2 Faculté de Medicine, René Descartes Paris 5, Paris, France
3 Sir William Dunn School of Pathology, Oxford, U.K
Diabetogenic T-cells can be detected in pre-diabetic nonobese diabetic (NOD) mice after transfer in NOD-SCID recipients. Here we demonstrate that 6-week-old pre-diabetic NOD mice, >2 months before disease onset, already harbor pathogenic T-cells in equal numbers to overtly diabetic animals. The delay in diabetes appearance is explained by the presence of regulatory CD4+CD25+ T-cells that control diabetogenic effectors and that are, in our hands, transforming growth factor (TGF)-ß–dependent. Our present results suggest, however, that diabetes onset is only partly explained by a decline in this regulatory T-cell activity. Another major factor appears to be the progressive resistance of diabetogenic cells to TGF-ß–dependent mediated inhibition. We propose that progression to overt disease correlates with the pathogenic T-cell’s escape from TGF-ß–dependent T-cell–mediated regulation.
Address correspondence and reprint requests to Pr. Lucienne Chatenoud, INSERM U580, Hôpital Necker, 161 rue de Sèvres, 75015 Paris, France. E-mail: chatenoud{at}necker.fr
Abbreviations:
APC, antigen-presenting cell; GITR, glucocorticoid-induced tumor necrosis factor receptor; IFN-
, -interferon; IL, interleukin; TGF, transforming growth factor
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