Targeting the IFN-γ pathway for the treatment of autoimmune vitiligo
Our lab is interested in the autoimmune mechanisms that drive depigmentation in vitiligo, with the goal of developing new treatments and translating them to the clinic. Vitiligo is a disfiguring autoimmune disease of the skin that results in patchy loss of pigment. It afflicts 0.5-2% of the population without preference for race or gender. Melanocyte-specific, autoreactive CD8 T cells have been implicated in the pathogenesis of vitiligo in humans, and a role for IFN-γ is suspected based on increased expression in active lesions.
Observations in the clinic reveal that depigmentation begins as small macules in a seemingly random pattern within the skin, which then grow into patches that coalesce into even larger patches. We became interested in why this pattern occurs, as opposed to a more even, diffuse pattern of depigmentation. We hypothesize that if we could understand the differences between depigmented and normal skin, we could identify targets for intervening with the process to prevent and treat disease.
These clinical observations, with the knowledge that IFN-γ is expressed within lesions, led us to hypothesize that IFN-γ driven, skin-derived signals are responsible for the recruitment of T cells to active sites of involvement. In order to test this hypothesis, we developed a mouse model of vitiligo with epidermal depigmentation that recapitulates human disease clinically and histologically, characteristics of human vitiligo not observed in other currently available models.
Using this mouse model, we discovered that IFN-γ is expressed within involved skin during depigmentation, consistent with observations in human disease. Blocking the effects of IFN-γ with neutralizing antibody effectively abrogated disease. In addition, blocking IFN-γ prevented autoreactive CD8 T cell accumulation within the skin, while systemic numbers in the lymph nodes, spleen and blood were not affected. Preliminary data suggest that IFN-γ-dependent chemokines expressed by stromal cells within the skin are responsible for the recruitment of autoreactive T cells to sites of involvement. We are interested in targeting the IFN-γ-chemokine axis for treatment of vitiligo, and ongoing projects in the lab are focused on this goal.