Imperial College London
Alternate

DrClaireHiggins

Faculty of Engineering, Department of Bioengineering

Reader in Tissue Regeneration
 
 
 
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Contact

 

c.higgins Website

 
 
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Location

 

Uren 319Sir Michael Uren HubWhite City Campus

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Summary

 

Publications

Citation

BibTex format

@article{Xing:2014:10.1038/nm.3645,
author = {Xing, L and Dai, Z and Jabbari, A and Cerise, JE and Higgins, CA and Gong, W and de, Jong A and Harel, S and DeStefano, GM and Rothman, L and Singh, P and Petukhova, L and Mackay-Wiggan, J and Christiano, AM and Clynes, R},
doi = {10.1038/nm.3645},
journal = {Nature Medicine},
pages = {1043--1049},
title = {Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition},
url = {http://dx.doi.org/10.1038/nm.3645},
volume = {20},
year = {2014}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Xing,L
AU  - Dai,Z
AU  - Jabbari,A
AU  - Cerise,JE
AU  - Higgins,CA
AU  - Gong,W
AU  - de,Jong A
AU  - Harel,S
AU  - DeStefano,GM
AU  - Rothman,L
AU  - Singh,P
AU  - Petukhova,L
AU  - Mackay-Wiggan,J
AU  - Christiano,AM
AU  - Clynes,R
DO  - 10.1038/nm.3645
EP  - 1049
PY  - 2014///
SN  - 1078-8956
SP  - 1043
TI  - Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition
T2  - Nature Medicine
UR  - http://dx.doi.org/10.1038/nm.3645
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000341404000017&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://www.nature.com/articles/nm.3645
VL  - 20
ER  -
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