Repurposed JAK1/JAK2 Inhibitor Reverses Established Autoimmune Insulitis in NOD Mice

Abstract

Recent advances in immunotherapeutics have not yet changed the routine management of autoimmune type 1 diabetes. There is an opportunity to repurpose therapeutics used to treat other diseases to treat type 1 diabetes, especially when there is evidence for overlapping mechanisms. Janus kinase (JAK) 1/JAK2 inhibitors are in development or clinical use for indications including rheumatoid arthritis. There is good evidence for activation of the JAK1/JAK2 and signal transducer and activator of transcription (STAT) 1 pathway in human type 1 diabetes and in mouse models, especially in β-cells. We tested the hypothesis that using these drugs to block the JAK-STAT pathway would prevent autoimmune diabetes. The JAK1/JAK2 inhibitor AZD1480 blocked the effect of cytokines on mouse and human β-cells by inhibiting MHC class I upregulation. This prevented the direct interaction between CD8 T cells and β-cells, and reduced immune cell infiltration into islets. NOD mice treated with AZD1480 were protected from autoimmune diabetes, and diabetes was reversed in newly diagnosed NOD mice. This provides mechanistic groundwork for repurposing clinically approved JAK1/JAK2 inhibitors for type 1 diabetes.

<b><i>JAK1</i></b> rs310241 and <b><i>JAK3</i></b> rs3008 Genotypes May Increase Susceptibility to Psoriasis: A Case Control Study

“…In population studies, various polymorphisms in the JAK2 gene have been associated with central adiposity [28], while others are linked to a reduced risk of MS [29]. Evidence from human and mouse models showed a requirement for JAK1/JAK2 and STAT1 pathway activation in β-cells in the pathogenesis of autoimmune diabetes [30][31][32]. Large-scale studies are needed to determine whether these elusive molecules and their genetic variants contribute to metabolic disease in psoriasis.…”

Type-I interferons inhibit interleukin-10 signaling and favor type 1 diabetes development in NOD mice

“…A deeper understanding of the molecular mediators of this phenomenon would be of crucial importance as some of these molecules could be targeted to control the development of diabetes. In fact, Jak1/Jak2 inhibition in vivo is effective at preventing, and reverting, established insulitis in NOD mice [36, 37]. Improving the efficacy and safety of this type of intervention would be a major advancement for type 1 diabetes patients.…”

Differential regulation of pro-inflammatory cytokine signalling by protein tyrosine phosphatases in pancreatic β-cells

“…Indeed, STAT1-deficient NOD mice and NOD mice that overexpress SOCS-1 in β-cells, a potent negative regulation of STAT1 signalling, are protected from insulitis and diabetes development (Chong et al 2004, Kim et al 2007. Inhibiting JAK1 and JAK2, which activate STAT1 in response to IFN-γ, has also been shown to protect and reverse diabetes development in the NOD mouse (Trivedi et al 2017). The insulitis reduction in these models is attributed to reduced chemokine production and MHC-I expression on β-cells (Sarkar et al 2012, Trivedi et al 2016, masking them from autoreactive immune cells.…”

“…Once activated, STAT1 dimers translocate to the nucleus and induce gamma-activated site (GAS) gene expression (Moore et al 2011), which includes chemokines, BH3-only apoptotic proteins and the major histocompatibility complex (MHC-I), important for diabetes development in the NOD mouse model (Serreze et al 1994, Hamilton-Williams et al 2003. Indeed, inhibition of STAT1 activity in NOD mice has been shown to protect from insulitis and diabetes development (Chong et al 2004, Kim et al 2007, Trivedi et al 2017.…”

“…Cytokine signalling is tightly regulated by PTPs and suppressors of cytokine signalling (SOCS) proteins. Inactivation of cytokine signalling in β-cells can reduce autoimmune diabetes (Chong et al 2004, Kim et al 2007, Moore et al 2009, Santin et al 2011, Trivedi et al 2017, therefore, understanding the key players in regulation of these pathways is important and may result in the development of therapies to protect β-cells. In this study, we characterize a novel negative regulatory function of PTPN6 in TNF-α-induced death in β-cells by JNK signalling, as well as a positive regulatory role for PTPN1 (opposite to PTPN2) in IFN-γ-induced STAT1 activation and downstream gene expression.…”