title: CXCR3 Blockade Inhibits T Cell Migration into the Skin and Prevents Development of Alopecia Areata.
abstract: Alopecia areata (AA) is an autoimmune disease of the hair follicle that results in hair loss of varying severity. Recently, we showed that IFN-γ-producing NKG2D(+)CD8(+) T cells actively infiltrate the hair follicle and are responsible for its destruction in C3H/HeJ AA mice. Our transcriptional profiling of human and mouse alopecic skin showed that the IFN pathway is the dominant signaling pathway involved in AA. We showed that IFN-inducible chemokines (CXCL9/10/11) are markedly upregulated in the skin of AA lesions, and further, that the IFN-inducible chemokine receptor, CXCR3, is upregulated on alopecic effector T cells. To demonstrate whether CXCL9/10/11 chemokines were required for development of AA, we treated mice with blocking Abs to CXCR3, which prevented the development of AA in the graft model, inhibiting the accumulation of NKG2D(+)CD8(+) T cells in the skin and cutaneous lymph nodes. These data demonstrate proof of concept that interfering with the Tc1 response in AA via blockade of IFN-inducible chemokines can prevent the onset of AA. CXCR3 blockade could be approached clinically in human AA with either biologic or small-molecule inhibition, the latter being particularly intriguing as a topical therapeutic.
authors.affiliation: Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032;
authors.forename: Zhenpeng
authors.initials: Z
authors.lastname: Dai
authors.affiliation: Department of Pathology, Columbia University, New York, NY 10032; and.
authors.forename: Luzhou
authors.initials: L
authors.lastname: Xing
authors.affiliation: Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032;
authors.forename: Jane
authors.identifier: 0000-0001-8568-1383
authors.initials: J
authors.lastname: Cerise
authors.affiliation: Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032;
authors.forename: Eddy Hsi Chun
authors.identifier: 0000-0001-7785-1442
authors.initials: EH
authors.lastname: Wang
authors.affiliation: Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032;
authors.forename: Ali
authors.initials: A
authors.lastname: Jabbari
authors.affiliation: Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032;
authors.forename: Annemieke
authors.identifier: 0000-0001-6707-6585
authors.initials: A
authors.lastname: de Jong
authors.affiliation: Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032;
authors.forename: Lynn
authors.initials: L
authors.lastname: Petukhova
authors.affiliation: Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032; Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032 amc65@cumc.columbia.edu.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Christiano
authors.affiliation: Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032;
authors.forename: Raphael
authors.identifier: 0000-0002-7963-8482
authors.initials: R
authors.lastname: Clynes
mesh_terms: D000506:Alopecia Areata / Q000276:immunology*; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008809:Mice, Inbred C3H; D016133:Polymerase Chain Reaction; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D012867:Skin / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D054367:Receptors, CXCR3