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

Luzhou Xing; Zhenpeng Dai; Ali Jabbari; Jane E Cerise; Claire A Higgins; Weijuan Gong; Annemieke de Jong; Sivan Harel; Gina M DeStefano; Lisa Rothman; Pallavi Singh; Lynn Petukhova; Julian Mackay-Wiggan; Angela M Christiano; Raphael Clynes

doi:10.1038/nm.3645

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

Journal article

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

Luzhou Xing, Zhenpeng Dai, Ali Jabbari, Jane E Cerise, Claire A Higgins, Weijuan Gong, Annemieke de Jong, Sivan Harel, Gina M DeStefano, Lisa Rothman, …

Nature medicine, Vol.20(9), pp.1043-1049

09/2014

DOI: 10.1038/nm.3645

PMCID: PMC4362521

PMID: 25129481

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Abstract

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 therapies. Genome-wide association studies (GWAS) 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.

Janus Kinases - antagonists & inhibitors

T-Lymphocytes, Cytotoxic - immunology

Animals

Alopecia Areata - drug therapy

Protein Kinase Inhibitors - therapeutic use

Skin - metabolism

Humans

Gene Expression Profiling

Mice

Protein Kinase Inhibitors - pharmacology

Alopecia Areata - immunology

Mice, Inbred C3H

Details

Title: Subtitle: Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition
Creators: Luzhou Xing - 1] Department of Pathology, Columbia University, New York, New York, USA.
Zhenpeng Dai - 1] Department of Dermatology, Columbia University, New York, New York, USA.
Ali Jabbari - 1] Department of Dermatology, Columbia University, New York, New York, USA.
Jane E Cerise - 1] Department of Dermatology, Columbia University, New York, New York, USA. Department of Psychiatry, Columbia University, New York, New York, USA
Claire A Higgins - Department of Dermatology, Columbia University, New York, New York, USA
Weijuan Gong - Department of Dermatology, Columbia University, New York, New York, USA
Annemieke de Jong - Department of Dermatology, Columbia University, New York, New York, USA
Sivan Harel - Department of Dermatology, Columbia University, New York, New York, USA
Gina M DeStefano - 1] Department of Dermatology, Columbia University, New York, New York, USA. Department of Epidemiology, Columbia University, New York, New York, USA
Lisa Rothman - Department of Dermatology, Columbia University, New York, New York, USA
Pallavi Singh - Department of Dermatology, Columbia University, New York, New York, USA
Lynn Petukhova - Department of Dermatology, Columbia University, New York, New York, USA
Julian Mackay-Wiggan - Department of Dermatology, Columbia University, New York, New York, USA
Angela M Christiano - 1] Department of Dermatology, Columbia University, New York, New York, USA. Department of Genetics and Development, Columbia University, New York, New York, USA.
Raphael Clynes - 1] Department of Pathology, Columbia University, New York, New York, USA. Department of Dermatology, Columbia University, New York, New York, USA. Department of Medicine, Columbia University, New York, New York, USA.
Resource Type: Journal article
Publication Details: Nature medicine, Vol.20(9), pp.1043-1049
DOI: 10.1038/nm.3645
PMID: 25129481
PMCID: PMC4362521
NLM abbreviation: Nat Med
ISSN: 1078-8956
eISSN: 1546-170X
Publisher: United States
Grant note: R01 AR056016 / NIAMS NIH HHS P30AR044535 / NIAMS NIH HHS R21 AR061881 / NIAMS NIH HHS R21AR061881 / NIAMS NIH HHS T32 GM007088 / NIGMS NIH HHS R01AR056016 / NIAMS NIH HHS T32 GM082771 / NIGMS NIH HHS P30 AR044535 / NIAMS NIH HHS T32GM082271 / NIGMS NIH HHS U01 AR067173 / NIAMS NIH HHS S10RR027050 / NCRR NIH HHS
Language: English
Date published: 09/2014
Academic Unit: Dermatology
Record Identifier: 9984025317702771

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