title: Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15Rα.
abstract: 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.
authors.affiliation: Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1374, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.forename: Parirokh
authors.initials: P
authors.lastname: Awasthi
authors.forename: Donna O
authors.initials: DO
authors.lastname: Butcher
authors.forename: Miriam R
authors.initials: MR
authors.lastname: Anver
authors.forename: Yelena G
authors.initials: YG
authors.lastname: Golubeva
authors.forename: Richard
authors.initials: R
authors.lastname: Bamford
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Zhang
authors.forename: Mark B
authors.initials: MB
authors.lastname: St Claire
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.forename: Valentina
authors.initials: V
authors.lastname: Discepolo
authors.forename: Bana
authors.initials: B
authors.lastname: Jabri
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology*; D004195:Disease Models, Animal; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D019409:Interleukin-15 / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D053720:Interleukin-15 Receptor alpha Subunit / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010880:Piperidines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib
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