Vitiligo is a chronic autoimmune skin disease that is characterized by loss of pigment from areas of the skin, resulting in white spots or patches. It affects over 1% of the world’s population irrespective of gender or race. The disease frequently starts at a young age – half get it before the age of 20, and most before the age of 30. Therefore, people can struggle with its effects for many, many years. In a few people, the patches get better on their own, though in most the white patches linger for life. The disease can have a profound psychological, emotional, and social impact on many people who are affected.
There is significant unmet need for the treatment of vitiligo. Currently, there are no FDA-approved medical treatments available that improve the disease, however existing “off-label” treatments can be effective. These treatments reverse the disease by stimulating brown spots to appear around hair follicles within the affected skin, which then increase in number and size until the white spot disappears. However, in most cases when treatments are stopped the disease relapses, meaning that the white spots reappear at the same location they were before treatment.
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One recurring question that kept coming up in the clinic was, “Why do the white spots keep coming back in the same locations when the treatments are stopped?” It seemed that an “autoimmune memory” was forming in the skin when the white spots appeared, so that the spots “knew” where to return when treatment is stopped. Four independent laboratories across the world discovered that a specific type of autoimmune cells, called resident memory T cells (TRM), are the source of this remaining disease memory in the skin. TRM form within the skin of vitiligo patients immediately when white spots appear and remain at that location for a long period of time afterward. It was thought that if these cells could be removed from the skin, the disease would get better and this improvement would be long-lasting, since the autoimmune memory would be removed from them.
Studies have shown that cytokine protein interleukin-15 (IL-15) is important for the maintenance of TRM. Using a mouse model of vitiligo, Harris and colleagues demonstrated that blocking the signaling of the IL-15 cytokine with an antibody treatment removed the TRM from the mouse skin and resulted in significant improvement in their skin. Short-term treatment of the mice resulted in long-term improvement, suggesting that this treatment strategy might provide lasting benefits for those with vitiligo.
(a) Vitiligo progression occurs through a positive-feedback loop that requires continued T cell recruitment. Melanocyte-reactive CD8+ T cells produce IFN-γ upon encounter of melanocyte antigen, which induces local keratinocytes to produce CXCL9 and CXCL10, leading to additional recruitment through the CXCR3 chemokine receptor. (b) Established vitiligo lesions are maintained by melanocyte-reactive, Trm cells, which remain long-lived in skin through IL-15-dependent survival signals. Emerging drugs capable of interrupting vitiligo pathogenesis are labeled in orange. Abbreviations: TCR, T cell receptor; Trm, resident memory T.
Villaris Therapeutics is developing a novel humanized anti IL-15R antibody to target depletion of TRM for the effective and durable treatment of vitiligo and other tissue-specific autoimmune diseases that involve these cells.
Antibody Blockade of IL-15 Signaling has the Potential to Durably Reverse Vitiligo
Jillian M. Richmond, James P. Strassner, Lucio Zapata Jr., Madhuri Garg, Rebecca L. Riding, Maggi A. Refat, Xueli Fan, Vincent Azzolino, Andrea Tovar-Garza, Naoya Tsurushita, Amit G. Pandya, J. Yun Tso, John E. Harris
Sci. Transl. Med. 2018; 10, eaam7710
Mouse Model for Human Vitiligo
Riding RL, Richmond JM, Harris JE
Curr Protoc Immunol. 2019; 124, e63
The Role of Memory T Cells in Vitiligo
Riding RL and Harris JE
J Immunol 2019; 11-19
Richmond J, Strassner JP, Rashighi M, Agarwal P, Garg M, Essien KI, Pell LS, and Harris JE. Resident memory and recirculating memory T cells cooperate to maintain disease in a mouse model of vitiligo. J. Invest. Dermatol. (2019) 139:769-778.