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

Circulation. 2018 May 1;137(18):1934-1948. doi: 10.1161/CIRCULATIONAHA.117.030423. Epub 2017 Dec 18.

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-γ, 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.

Keywords: Janus kinases; STAT transcription factors; T-lymphocytes; cytokines; giant cell arteritis; inflammation; vasculitis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptive Immunity / drug effects
  • Adoptive Transfer
  • Aged
  • Animals
  • Cell Proliferation / drug effects
  • Cytokines / immunology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation / drug effects
  • Giant Cell Arteritis / enzymology
  • Giant Cell Arteritis / immunology
  • Giant Cell Arteritis / pathology
  • Giant Cell Arteritis / prevention & control*
  • Heterografts
  • Humans
  • Immunity, Innate / drug effects
  • Immunologic Memory / drug effects
  • Janus Kinase 1 / antagonists & inhibitors
  • Janus Kinase 1 / metabolism
  • Janus Kinase 3 / antagonists & inhibitors
  • Janus Kinase 3 / metabolism
  • Janus Kinase Inhibitors / pharmacology*
  • Janus Kinases / antagonists & inhibitors*
  • Janus Kinases / metabolism
  • Lymphocyte Activation / drug effects
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Middle Aged
  • Neointima
  • Neovascularization, Pathologic
  • Piperidines / pharmacology*
  • Pyrimidines / pharmacology*
  • Pyrroles / pharmacology*
  • STAT Transcription Factors / metabolism*
  • Signal Transduction / drug effects
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / enzymology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / transplantation
  • Temporal Arteries / drug effects*
  • Temporal Arteries / enzymology
  • Temporal Arteries / immunology
  • Temporal Arteries / transplantation
  • Vascular Remodeling / drug effects

Substances

  • Cytokines
  • Janus Kinase Inhibitors
  • Piperidines
  • Pyrimidines
  • Pyrroles
  • STAT Transcription Factors
  • tofacitinib
  • JAK1 protein, human
  • JAK3 protein, human
  • Janus Kinase 1
  • Janus Kinase 3
  • Janus Kinases