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.

CD122 blockade restores immunological tolerance in autoimmune type 1 diabetes via multiple mechanisms

“…After the treatment, all mice were monitored for spontaneous development of diabetes until 40 weeks of age. The incidence of diabetes onset in ChMBC7-treated mice was significantly lower than that in the control group ( Figure 1B), consistent with previous reports (13)(14)(15)(16). Using the same treatment protocol, separated cohorts of mice were sacrificed at 10 weeks old, and the pancreata were excised and processed for histopathology analysis.…”

“…Using the NOD mouse strain, the primary animal model for T1D basic research and preclinical studies (8,17), we showed that a Fc-silent rat/mouse chimeric anti-CD122 mAb (clone ChMBC7) effectively suppressed T1D development, consistent with previous reports (13)(14)(15)(16). Using this engineered anti-CD122 mAb to modulate IL-2/IL-15Rβ signaling, we have investigated how T1D-associated autoimmunity at a prediabetic stage was regulated.…”

“…Several studies have reported that an in vivo treatment with an anti-mouse CD122 mAb (clone TM-β1, rat IgG2b) (18) prevented the development of diabetes in NOD mice (13)(14)(15)(16). However, the underlying mechanisms remain poorly defined.…”

“…It thus can be speculated that modulating CD122 signaling may impact the activities of all CD122-bearing cells in normal and diseased conditions. Indeed, a mAb against CD122 (clone TM-β1, rat IgG2b) has been reported to suppress diabetes development in nonobese diabetic (NOD) mice (13)(14)(15)(16), suggesting a therapeutic potential of CD122 blockade for human T1D patients. However, the underlying mechanisms remain largely undefined.…”

Trans-presentation of interleukin-15 by interleukin-15 receptor alpha is dispensable for the pathogenesis of autoimmune type 1 diabetes

“…15 Recently, we and others have shown that IL-15 plays a crucial role in the pathogenesis of autoimmune type 1 diabetes (T1D). 16,17 In this study, we investigated whether IL-15 trans-presentation plays an essential role in T1D pathogenesis. We show that IL-15Ra deficiency does not affect T1D incidence in two different mouse models and that IL-15Ra is also dispensable for antigen cross-presentation to CD8 1 T cells, and key process in activating autoreactive CD8 1 T cells.…”