Dataset Information

Inhibition of JAK-STAT Signaling Suppresses Pathogenic Immune Responses in Medium and Large Vessel Vasculitis.

ABSTRACT: BACKGROUND:Giant cell arteritis, a chronic autoimmune disease of the aorta and its large branches, is complicated by aneurysm formation, dissection, and arterial occlusions. Arterial wall dendritic cells attract CD4+ T cells and macrophages to form prototypic granulomatous infiltrates. Vasculitic lesions contain a diverse array of effector T cells that persist despite corticosteroid therapy and sustain chronic, smoldering vasculitis. Transmural inflammation induces microvascular neoangiogenesis and results in lumen-occlusive intimal hyperplasia. We have examined whether persistent vessel wall inflammation is maintained by lesional T cells, including the newly identified tissue-resident memory T cells, and whether such T cells are sensitive to the cytokine-signaling inhibitor tofacitinib, a Janus kinase (JAK) inhibitor targeting JAK3 and JAK1. METHODS:Vascular inflammation was induced in human arteries engrafted into immunodeficient mice that were reconstituted with T cells and monocytes from patients with giant cell arteritis. Mice carrying inflamed human arteries were treated with tofacitinib or vehicle. Vasculitic arteries were examined for gene expression (reverse transcription polymerase chain reaction), protein expression (immunohistochemistry), and infiltrating cell populations (flow cytometry). RESULTS:Tofacitinib effectively suppressed innate and adaptive immunity in the vessel wall. Lesional T cells responded to tofacitinib with reduced proliferation rates (<10%) and minimal production of the effector molecules interferon-?, interleukin-17, and interleukin-21. Tofacitinib disrupted adventitial microvascular angiogenesis, reduced outgrowth of hyperplastic intima, and minimized CD4+CD103+ tissue-resident memory T cells. CONCLUSIONS:Cytokine signaling dependent on JAK3 and JAK1 is critically important in chronic inflammation of medium and large arteries. The JAK inhibitor tofacitinib effectively suppresses tissue-resident memory T cells and inhibits core vasculitogenic effector pathways.

SUBMITTER: Zhang H

PROVIDER: S-EPMC5930040 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inhibition of JAK-STAT Signaling Suppresses Pathogenic Immune Responses in Medium and Large Vessel Vasculitis.

Zhang Hui H Watanabe Ryu R Berry Gerald J GJ Tian Lu L Goronzy Jörg J JJ Weyand Cornelia M CM

Circulation 20171218 18

<h4>Background</h4>Giant cell arteritis, a chronic autoimmune disease of the aorta and its large branches, is complicated by aneurysm formation, dissection, and arterial occlusions. Arterial wall dendritic cells attract CD4<sup>+</sup> T cells and macrophages to form prototypic granulomatous infiltrates. Vasculitic lesions contain a diverse array of effector T cells that persist despite corticosteroid therapy and sustain chronic, smoldering vasculitis. Transmural inflammation induces microvascul ...[more]

PMID: 29254929

Similar Datasets

Project description:BACKGROUND:In giant cell arteritis, vessel-wall infiltrating CD4 T cells and macrophages form tissue-destructive granulomatous infiltrates, and the artery responds with a maladaptive response to injury, leading to intramural neoangiogenesis, intimal hyperplasia, and luminal occlusion. Lesion-residing T cells receive local signals, which represent potential therapeutic targets. OBJECTIVES:The authors examined how CD28 signaling affects vasculitis induction and maintenance, and which pathogenic processes rely on CD28-mediated T-cell activation. METHODS:Vasculitis was induced by transferring peripheral blood mononuclear cells from giant cell arteritis patients into immunodeficient NSG mice engrafted with human arteries. Human artery-NSG chimeras were treated with anti-CD28 domain antibody or control antibody. Treatment effects and immunosuppressive mechanisms were examined in vivo and in vitro applying tissue transcriptome analysis, immunohistochemistry, flow cytometry, and immunometabolic analysis. RESULTS:Blocking CD28-dependent signaling markedly reduced tissue-infiltrating T cells and effectively suppressed vasculitis. Mechanistic studies implicated CD28 in activating AKT signaling, T-cell proliferation and differentiation of IFN-? and IL-21-producing effector T cells. Blocking CD28 was immunosuppressive by disrupting T-cell metabolic fitness; specifically, the ability to utilize glucose. Expression of the glucose transporter Glut1 and of glycolytic enzymes as well as mitochondrial oxygen consumption were all highly sensitive to CD28 blockade. Also, induction and maintenance of CD4+CD103+ tissue-resident memory T cells, needed to replenish the vasculitic infiltrates, depended on CD28 signaling. CD28 blockade effectively suppressed vasculitis-associated remodeling of the vessel wall. CONCLUSIONS:CD28 stimulation provides a metabolic signal required for pathogenic effector functions in medium and large vessel vasculitis. Disease-associated glycolytic activity in wall-residing T-cell populations can be therapeutically targeted by blocking CD28 signaling.

Dataset Information

Inhibition of JAK-STAT Signaling Suppresses Pathogenic Immune Responses in Medium and Large Vessel Vasculitis.

Publications

Inhibition of JAK-STAT Signaling Suppresses Pathogenic Immune Responses in Medium and Large Vessel Vasculitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets