Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15Rα

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 33; pp. 13534 - 13539
• Main Authors: Chen, Jing, Feigenbaum, Lionel, Awasthi, Parirokh, Butcher, Donna O., Anver, Miriam R., Golubeva, Yelena G., Bamford, Richard, Zhang, Xiaojie, St. Claire, Mark B., Thomas, Craig J., Discepolo, Valentina, Jabri, Bana, Waldmann, Thomas A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13-08-2013; National Acad Sciences
• Subjects: Animals; Beta cells; Biological Sciences; Blood glucose; Diabetes; Diabetes Mellitus, Type 1 - etiology; Disease Models, Animal; Humans; Hyperglycemia; Insulin-Secreting Cells - metabolism; Interleukin-15 - antagonists & inhibitors; Interleukin-15 - blood; Interleukin-15 - metabolism; Interleukin-15 Receptor alpha Subunit - blood; Interleukin-15 Receptor alpha Subunit - metabolism; Islet cells; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Transgenic; Natural killer cells; Piperidines - pharmacology; Pyrimidines - pharmacology; Pyrroles - pharmacology; Signal Transduction - drug effects; T lymphocytes; Transgenic animals; Type 1 diabetes mellitus
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1312911110

Increased serum levels of IL-15 are reported in type 1 diabetes (T1D). Here we report elevated serum soluble IL-15Rα levels in human T1D. To investigate the role of IL-15/IL-15Rα in the pathogenesis of T1D, we generated double transgenic mice with pancreatic β-cell expression of IL-15 and IL-15Rα. The mice developed hyperglycemia, marked mononuclear cell infiltration, β-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/IL15Rβ (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-15Rα 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-15Rα in human T1D. Taken together our data suggest that disordered IL-15 and IL-15Rα may be involved in T1D pathogenesis and the IL-15/IL15Rα system and its signaling pathway may be rational therapeutic targets for early T1D.