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

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 (T) 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 T formation, and IL-15 promotes T function ex vivo. We found that both human and mouse T 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 T production of interferon-γ (IFNγ), and long-term treatment depletes T 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 T.

Skin‐resident memory T cells as a potential new therapeutic target in vitiligo and melanoma

“…Moreover, in human melanoma, local IL‐15 levels strongly correlated with tumor‐resident CD8 + T‐cell numbers, and high IL‐15 levels were associated with a more favorable prognosis (Edwards et al, ). IL‐15 seems to be essential in retaining T cells within the tumor microenvironment, indicating that IL‐15 is worthy of further investigation, as supported by the murine vitiligo data discussed previously (Richmond, Strassner, Zapata, et al, ).…”

“…T RM cell formation has been shown to be highly dependent on IL‐15, and IL‐15 promoted T RM cell function ex vivo (Adachi et al, ; Mackay et al, ). A subsequent study therefore looked at IL‐15 signaling as a therapeutic target for vitiligo (Richmond, Strassner, Zapata, et al, ). Treatment with anti‐CD122 antibody, a subunit of the IL‐15 receptor on human and mouse T RM cells, was shown to reverse disease in mice with established vitiligo (Figure ).…”

Mouse Model for Human Vitiligo

“…Pmel‐1 CD8 + T cells are recruited into the skin as early as 1 week after vitiligo induction (unpublished observation), but infiltration peaks at 5 to 7 weeks after induction. We have found that Pmel‐1 CD8 + T cells remain in the skin until the end of natural life as resident memory CD8 + T cells (Richmond et al., ). Between 10 and 12 weeks after vitiligo induction some wild‐type SCF mice spontaneously repigment, and the reasons behind this are unknown.…”

“…Spots of depigmentation appear as early as 3 to 4 weeks and continue to develop in severity over time. SCF mice reach a plateau of vitiligo around 7 to 8 weeks, after which the disease stabilizes, and the majority of Pmel‐1 adopt a resident memory phenotype defined as CD103 + CD69 + CD44 + CD62L – (Richmond et al., ).…”

Vitiligo as a skin memory disease: The need for early intervention with immunomodulating agents and a maintenance therapy to target resident memory T cells

“…Factors that induce upregulation of CD69 expression include TNF‐α and type I interferons . As an example, strategies targeting IL‐15 could be promising to inhibit the generation of T RM ; however, it is still unknown whether a targeted antibody can efficiently deplete T RM cells located into the skin, as recently shown with the use of an antibody directed against CD122, the β subunit of the IL‐15 receptor expressed on T RM cells . However, human data are still lacking to confirm these results obtained in a mouse model of depigmentation.…”