Progression of type 1 diabetes from the prediabetic stage is controlled by interferon-α signaling

Abstract

Blockade of IFN-α but not IFN-β signaling using either an antibody or a selective S1PR1 agonist, CYM-5442, prevented type 1 diabetes (T1D) in the mouse Rip-LCMV T1D model. First, treatment with antibody or CYM-5442 limited the migration of autoimmune "antiself" T cells to the external boundaries around the islets and prevented their entry into the islets so they could not be positioned to engage, kill, and thus remove insulin-producing β cells. Second, CYM-5442 induced an exhaustion signature in antiself T cells by up-regulating the negative immune regulator receptor genes Pdcd1, Lag3, Ctla4, Tigit, and Btla, thereby limiting their killing ability. By such means, insulin production was preserved and glucose regulation maintained, and a mechanism for S1PR1 immunomodulation described.type I interferon | IFN-alpha | S1PR1 | type 1 diabetes T ype 1 diabetes (T1D) is an autoimmune disorder defined by infiltration of autoreactive lymphoid cells into the islets of Langerhans that destroy insulin-producing β cells (1). By the time of clinical diagnosis, T cells have destroyed 60-80% or more of total β cells, resulting in high blood glucose levels as a result of low insulin production. Prevention of ketoacidosis and death require lifelong delivery of exogenous insulin. However, daily insulin therapy is associated with increased prevalence of debilitating pathologies of cardiovascular, central and peripheral nervous, ophthalmic, and peripheral vascular systems among others.A role for type I IFN in autoimmune disease was first reported by Notkins' laboratory (2) and pancreata removed at necropsy from humans with T1D displayed significant increases in type I IFN (3, 4). Treatment of humans having hairy cell leukemia (5) or hepatitis C virus (6) with IFN-α was associated with induction or acceleration of the diabetogenic process, and recent longitudinal studies demonstrated that a IFN-I gene signature of individuals at risk for developing T1D preceded clinical onset (7,8). Direct evidence for an association of IFN-I with T1D was shown by Stewart et al. (9) in transgenic (tg) mice and strengthened in studies with NOD mice (10, 11). Unanue and coworkers (10) found IFN-I transcriptional signatures within the islets preceded T-cell activation. McDevitt and coworkers (11) reported treatment of 2-to 3-wk-old NOD mice with antibody to IFNAR1 delayed the onset and decreased the incidence of T1D. Using the virusinduced Rip-LCMV T1D model, Zinkernagel and coworkers (12) demonstrated that genetic ablation of Ifnar could delay onset of T1D. However, the mechanism of action by type I IFN was unknown. Here, we report studies that define the species of type I IFN and mechanism involved causing T1D and therapeutic approaches to prevent diabetes by preserving β-cell function. Results and DiscussionTo uncover the pathological role(s) of IFN-I, a viral mouse model of T1D (13) was used in which several parameters mimic immunological and histopathological components of human T1D and the "self" antigen recognized by specific autoimmune T cells ca...

Cytokines in type 1 diabetes: mechanisms of action and immunotherapeutic targets

“…IFN‐α promotes the overexpression of HLA‐I molecules in human β cells and mediates their endoplasmic reticulum stress and apoptosis, which reflects the direct contribution of IFN‐α to β‐cell destruction (Figure 1). Therapies targeting IFN‐α and its signalling have been shown to suppress β‐cell dysfunction and prevent the progression from prediabetes to T1D . IFN‐α produced by pDCs augments Th1 responses in patients with T1D, whereas blockade of IFN‐α signalling prevents the entry of autoreactive T cells into islets and induces an exhaustion signature in T cells, with upregulation of genes that encode negative immune regulators ( Pdcd1 , Lag3 , Ctla4 , Tigit and Btla ), thereby limiting the diabetogenic ability of these cells (Figure 1).…”

“…77,78 Therapies targeting IFN-a and its signalling have been shown to suppress b-cell dysfunction and prevent the progression from prediabetes to T1D. [79][80][81] IFN-a produced by pDCs augments Th1 responses in patients with T1D, whereas blockade of IFN-a signalling prevents the entry of autoreactive T cells into islets and induces an exhaustion signature in T cells, with upregulation of genes that encode negative immune regulators (Pdcd1, Lag3, Ctla4, Tigit and Btla), thereby limiting the diabetogenic ability of these cells (Figure 1). 76,79 Interestingly, low-dose IFN-a seems to have a beneficial effect on the preservation of b-cell function in young patients with recent-onset T1D 82 ; this positive effect was also observed in NOD mice.…”

Macrophage IFN-I signaling promotes autoreactive T cell infiltration into islets in type 1 diabetes model

“…Type I IFN (IFN-I) are pleiotropic cytokines that induce potent antiviral programs to protect the host from microbial infections, but they also potentiate the diabetogenic process of β cell destruction (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Our recent study (8) and that of Carrero et al (11) have documented distinctive IFN-I gene signatures in islets that precede lymphocytic infiltration into the islets in 2 distinctly different experimental models of T1D. Moreover, expression of IFN-I-inducible genes in peripheral blood mononuclear cell (PBMC) samples isolated from children at risk for T1D preceded onset of autoimmunity and seroconversion in 2 independent longitudinal studies (12,13).…”

A personalised approach for identifying disease-relevant pathways in heterogeneous diseases

“…IL-1 is a pro-inflammatory cytokine that enhances the production of IL-2, encourages B cell proliferation, and increases immunoglobulin production [Borish et al, 2003;Hartemann and Bourron, 2012]; whereas IL-4 is an anti-inflammatory Th2 cytokine that inhibits autoimmunity by down-regulating the production of pro-inflammatory cytokines, such as IL-1, IL-6 and TNF-α [Borish et al, 2003;Souto et al, 2014;Qiao et al, 2016]. Through mice studies, IFNα and PD-1 signalling pathways have been established as important contributors to T1D pathogenesis from an early stage of the disease [Marro et al, 2017;Li et al, 2008;Mbongue et al, 2017;Martinov et al, 2016]. Where up-regulation of IFNα in pLN is an initiator of the pathogenesis , up-regulation of programmed cell death protein 1 (PD-1) signalling prevents T1D and promotes self-tolerance by suppressing the expansion and infiltration of autoreactive T cells in the pancreas [Granados et al, 2017;Martinov et al, 2016;Mbongue et al, 2017].…”

“…Where up-regulation of IFNα in pLN is an initiator of the pathogenesis , up-regulation of programmed cell death protein 1 (PD-1) signalling prevents T1D and promotes self-tolerance by suppressing the expansion and infiltration of autoreactive T cells in the pancreas [Granados et al, 2017;Martinov et al, 2016;Mbongue et al, 2017]. In fact, blocking IFNα signalling before clinical T1D onset has been shown to prevent β-cell apoptosis or even abort T1D progression [Marro et al, 2017]. Additionally, PD-1 pathway has been proposed as a target for novel therapy for preventing and modulating autoimmunity [Granados et al, 2017].…”