Inhibition of JAK-STAT Signaling Suppresses Pathogenic Immune Responses in Medium and Large Vessel Vasculitis
Giant cell arteritis (GCA), a chronic autoimmune disease of the aorta and its large branches, is complicated by aneurysm formation, dissection, and arterial occlusions. Arterial wall dendritic cells (DC) attract CD4+ T-cells and macrophages (Mo), 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 (TRM) and whether such T-cells are sensitive to the cytokine signaling inhibitor tofacitinib, a JAK inhibitor (Jakinib) targeting the Janus kinase (JAK) 3 and JAK1.Methods—
Vascular inflammation was induced in human arteries engrafted into immunodeficient mice that were reconstituted with T-cells and monocytes from GCA patients. Mice carrying inflamed human arteries were treated with tofacitinib or vehicle. Vasculitic arteries were examined for gene expression (RT-PCR), 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 IFN-γ, IL-17 and IL-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 Jakinib tofacitinib effectively suppresses tissue-resident memory T-cells and inhibits core vasculitogenic effector pathways.