Increased serum levels of IL-15 are reported in type 1 diabetes (T1D). Here we report elevated serum soluble IL-15R? levels in human T1D. To investigate the role of IL-15/IL-15R? in the pathogenesis of T1D, we generated double transgenic mice with pancreatic ?-cell expression of IL-15 and IL-15R?. The mice developed hyperglycemia, marked mononuclear cell infiltration, ?-cell destruction, and anti-insulin autoantibodies that mimic early human T1D. The diabetes in this model was reversed by inhibiting IL-15 signaling with anti-IL2/IL15R? (anti-CD122), which blocks IL-15 transpresentation. Furthermore, the diabetes could be reversed by administration of the Janus kinase 2/3 inhibitor tofacitinib, which blocks IL-15 signaling. In an alternative diabetes model, nonobese diabetic mice, IL15/IL-15R? expression was increased in islet cells in the prediabetic stage, and inhibition of IL-15 signaling with anti-CD122 at the prediabetic stage delayed diabetes development. In support of the view that these observations reflect the conditions in humans, we demonstrated pancreatic islet expression of both IL-15 and IL-15R? in human T1D. Taken together our data suggest that disordered IL-15 and IL-15R? may be involved in T1D pathogenesis and the IL-15/IL15R? system and its signaling pathway may be rational therapeutic targets for early T1D.
Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15R? / Chen, J.; Feigenbaum, L.; Awasthi, P.; Butcher, D. O.; Anver, M. R.; Golubeva, Y. G.; Bamford, R.; Zhang, X.; S, t. Claire M. B.; Thomas, C. J.; Discepolo, V.; Jabri, B.; Waldmann, T. A.. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - 110:33(2013), pp. 13534-13539. [10.1073/pnas.1312911110]
Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15R?
Zhang X.;Discepolo V.;
2013
Abstract
Increased serum levels of IL-15 are reported in type 1 diabetes (T1D). Here we report elevated serum soluble IL-15R? levels in human T1D. To investigate the role of IL-15/IL-15R? in the pathogenesis of T1D, we generated double transgenic mice with pancreatic ?-cell expression of IL-15 and IL-15R?. The mice developed hyperglycemia, marked mononuclear cell infiltration, ?-cell destruction, and anti-insulin autoantibodies that mimic early human T1D. The diabetes in this model was reversed by inhibiting IL-15 signaling with anti-IL2/IL15R? (anti-CD122), which blocks IL-15 transpresentation. Furthermore, the diabetes could be reversed by administration of the Janus kinase 2/3 inhibitor tofacitinib, which blocks IL-15 signaling. In an alternative diabetes model, nonobese diabetic mice, IL15/IL-15R? expression was increased in islet cells in the prediabetic stage, and inhibition of IL-15 signaling with anti-CD122 at the prediabetic stage delayed diabetes development. In support of the view that these observations reflect the conditions in humans, we demonstrated pancreatic islet expression of both IL-15 and IL-15R? in human T1D. Taken together our data suggest that disordered IL-15 and IL-15R? may be involved in T1D pathogenesis and the IL-15/IL15R? system and its signaling pathway may be rational therapeutic targets for early T1D.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
