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 (HF) that results in hair loss of varying severity. Recently, we showed that IFN-γ-producing NKG2D+CD8+ T cells actively infiltrate the HF, 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 antibodies 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.

Alopecia areata: a review of disease pathogenesis

“…As mentioned above, IFN‐γ and tumour necrosis factor‐α are the first cytokines produced and released around HFs by either NK cells or activated T cells. IFN‐γ induces expression of MHC‐I, NKG2D and chemokines such as CXCLs, all of which could perpetuate a vicious cycle of inflammation . IFN‐γ is so important in the disease process that IFN‐γ gene knockout C3H/HeJ mice have shown resistance to AA induction, and antibodies against IFN‐γ have resulted in prevention of hair loss in this mouse model …”

“…Three of the IFN‐γ‐induced chemokines in AA are CXCL9, CXCL10 and CXCL11 . They play a critical role in immune response development and maintenance by attracting immune cells.…”

Integrative analysis of rare copy number variants and gene expression data in alopecia areata implicates an aetiological role for autophagy

“…These findings prompted us to initiate functional immunological and pharmacological studies that demonstrated IFNγ‐producing CD8+NKG2D cytotoxic T cells are both necessary and sufficient to induce AA in a mouse model of the disease. Finally, we showed that targeting these cells with topical or systemic JAK inhibitors induces hair regrowth in patients with long‐standing moderate‐to‐severe AA . Our GWAS were highly fruitful and represented an unusual example of GWAS candidate genes and functional studies that led to new targeted treatment approaches …”

Alopecia areata

“…Increased expression of IFN-response genes (including CXCL9 (which encodes CXC-chemokine ligand 9) , CXCL10, and CXCL11 ) was found in several human and mouse transcriptome studies 2,58,189,190 . Monoclonal antibodies against these cytokines seem to be effective in mouse models, paving the way for additional clinical approaches to treating patients 191 . Patients with alopecia areata had significant increase in IL12 and IL23 in their skin compared with normal patients who were treated with ustekinumab, a human monoclonal antibody which is targeted to these cytokines.…”