tofacitinib and Neointima

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. 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).. 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. 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.

Topics: Adaptive Immunity; Adoptive Transfer; Aged; Animals; Cell Proliferation; Cytokines; Disease Models, Animal; Female; Gene Expression Regulation; Giant Cell Arteritis; Heterografts; Humans; Immunity, Innate; Immunologic Memory; Janus Kinase 1; Janus Kinase 3; Janus Kinase Inhibitors; Janus Kinases; Lymphocyte Activation; Male; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Middle Aged; Neointima; Neovascularization, Pathologic; Piperidines; Pyrimidines; Pyrroles; Signal Transduction; STAT Transcription Factors; T-Lymphocytes; Temporal Arteries; Vascular Remodeling