Research ArticleAutoimmunity

Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo

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Science Translational Medicine  18 Jul 2018:
Vol. 10, Issue 450, eaam7710
DOI: 10.1126/scitranslmed.aam7710

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Forcing memory T cells to forget

In vitiligo, autoreactive T cells attack melanocytes, leading to white spots on the skin. Depigmentation typically recurs upon cessation of treatment, so new therapies are needed for permanent patient relief. Richmond and colleagues reasoned that targeting tissue-resident memory T cells may allow for durable therapy. They observed that T cells from patient lesional samples expressed the receptor for IL-15, an important survival cytokine. T cells in a mouse model of vitiligo also expressed the IL-15 receptor, and blocking IL-15 signaling with an antibody was able to reverse disease symptoms. A clinical trial to test this therapy is now in the works.

Abstract

Vitiligo is an autoimmune disease of the skin mediated by CD8+ T cells that kill melanocytes and create white spots. Skin lesions in vitiligo frequently return after discontinuing conventional treatments, supporting the hypothesis that autoimmune memory is formed at these locations. We found that lesional T cells in mice and humans with vitiligo display a resident memory (TRM) phenotype, similar to those that provide rapid, localized protection against reinfection from skin and mucosal-tropic viruses. Interleukin-15 (IL-15)–deficient mice reportedly have impaired TRM formation, and IL-15 promotes TRM function ex vivo. We found that both human and mouse TRM express the CD122 subunit of the IL-15 receptor and that keratinocytes up-regulate CD215, the subunit required to display the cytokine on their surface to promote activation of T cells. Targeting IL-15 signaling with an anti-CD122 antibody reverses disease in mice with established vitiligo. Short-term treatment with anti-CD122 inhibits TRM production of interferon-γ (IFNγ), and long-term treatment depletes TRM from skin lesions. Short-term treatment with anti-CD122 can provide durable repigmentation when administered either systemically or locally in the skin. On the basis of these data, we propose that targeting CD122 may be a highly effective and even durable treatment strategy for vitiligo and other tissue-specific autoimmune diseases involving TRM.

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