Mouse Model for Human Vitiligo

Abstract

Vitiligo is an autoimmune skin disease in which the pigment‐producing melanocytes are destroyed by autoreactive CD8+ T cells. As a result, patients develop disfiguring white spots on the skin. This article discusses the first mouse model of vitiligo that develops epidermal depigmentation, similar to disease in human patients. To achieve epidermal depigmentation, mice are genetically engineered to retain melanocytes in the skin epidermis. Induction of disease occurs by adoptive transfer of melanocyte‐specific CD8+ T cells into recipient mice and the subsequent activation of these T cells using a viral vector. Depigmentation of the epidermis occurs within 5 to 7 weeks in a patchy pattern similar to patients with vitiligo. This article describes the methods of vitiligo induction, quantification of lesion progression and regression, processing of the skin for detailed analysis, and how to use this model to inform clinical studies. © 2018 by John Wiley & Sons, Inc.

The Role of Memory CD8+ T Cells in Vitiligo

“…Likewise, gene expression analysis of vitiligo lesional skin revealed an IFN-g-specific gene signature and no upregulation of IL-17 transcripts (53-57). These human studies point to IFN-g as the central cytokine in disease, and mechanistic studies in mice support this hypothesis (53,58). The IFN-g signature in mice parallels that seen in human patient skin.…”

“…In a mouse model of vitiligo (53,58), transferred naive melanocyte-specific CD8 + T cells are activated and recruited to the skin through expression of CXCR3 ligands. T EM traffic to the skin and kill epidermal melanocytes, which leads to patchy white depigmentation on the tail, ears, nose, and footpads (53).…”

Type-1 cytokines regulate matrix metalloprotease-9 production and E-cadherin disruption to promote melanocyte loss in vitiligo

“…after infiltration of melanocyte-specific CD8 T cells are available (52) and could be used to fully validate a strategy to inhibit melanocyte detachment through targeting of MMP-9. Showing that the use of a MMP-9 inhibitor alone or in combination with immunomodulating agents could either prevent depigmentation or induce repigmentation would be of great interest before going to clinical trials.…”

Resident Memory and Recirculating Memory T Cells Cooperate to Maintain Disease in a Mouse Model of Vitiligo

“…To begin to answer these questions, we sought to define autoreactive Tcm in our vitiligo mouse model, which was adapted from previous studies of melanoma-associated vitiligo models (Gregg et al, 2010;Overwijk et al, 1998Overwijk et al, , 2003. Our model uses the adoptive transfer of TCR transgenic T cells recognizing the human melanocyte antigen premelanosome protein (PMEL) into recipient mice with epidermal melanocytes (Agarwal et al, 2015;Harris et al, 2012;Rashighi et al, 2014;Richmond et al, 2017aRichmond et al, , 2017bRichmond et al, , 2018Riding et al, 2018). These T cells (also called PMEL) like their antigenic target accumulate in the epidermis, kill mouse melanocytes, and induce patchy epidermal depigmentation that mirrors human disease (Alikhan et al, 2011;Frisoli and Harris, 2017;Richmond and Harris, 2017;Rodrigues et al, 2017).…”