Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition

斑秃 细胞毒性T细胞 NKG2D公司 CD8型 免疫学 贾纳斯激酶 细胞因子 T细胞 生物 癌症研究 免疫系统 生物化学 体外
作者
Luzhou Xing,Zhijun Dai,Ali Jabbari,Jane Cerise,Claire A. Higgins,Wei Gong,Annemieke de Jong,Sivan Harel,Gina M. DeStefano,Lisa Rothman,Pallavi Singh,Lynn Petukhova,Julian Mackay‐Wiggan,Angela M. Christiano,Raphael Clynes
出处
期刊:Nature Medicine [Springer Nature]
卷期号:20 (9): 1043-1049 被引量:701
标识
DOI:10.1038/nm.3645
摘要

Cytotoxic T cells are necessary and sufficient for the development of alopecia areata in mice, while JAK inhibition promotes regrowth of hair in patients and mice with established disease. Alopecia areata (AA) is a common autoimmune disease resulting from damage of the hair follicle by T cells. The immune pathways required for autoreactive T cell activation in AA are not defined limiting clinical development of rational targeted therapies1. Genome-wide association studies (GWAS)2 implicated ligands for the NKG2D receptor (product of the KLRK1 gene) in disease pathogenesis. Here, we show that cytotoxic CD8+NKG2D+ T cells are both necessary and sufficient for the induction of AA in mouse models of disease. Global transcriptional profiling of mouse and human AA skin revealed gene expression signatures indicative of cytotoxic T cell infiltration, an interferon-γ (IFN-γ) response and upregulation of several γ-chain (γc) cytokines known to promote the activation and survival of IFN-γ–producing CD8+NKG2D+ effector T cells. Therapeutically, antibody-mediated blockade of IFN-γ, interleukin-2 (IL-2) or interleukin-15 receptor β (IL-15Rβ) prevented disease development, reducing the accumulation of CD8+NKG2D+ T cells in the skin and the dermal IFN response in a mouse model of AA. Systemically administered pharmacological inhibitors of Janus kinase (JAK) family protein tyrosine kinases, downstream effectors of the IFN-γ and γc cytokine receptors, eliminated the IFN signature and prevented the development of AA, while topical administration promoted hair regrowth and reversed established disease. Notably, three patients treated with oral ruxolitinib, an inhibitor of JAK1 and JAK2, achieved near-complete hair regrowth within 5 months of treatment, suggesting the potential clinical utility of JAK inhibition in human AA.
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