IL-27 and downstream mechanisms in Alopecia Areata

PROJECT SUMMARY Alopecia areata (AA) is a common autoimmune disease in which the hair follicle is the target of attack and results clinically in hair loss. Despite the associated high lifetime risk of approximately 2% and its substantive psychosocial impact, no FDA approved treatments exist for AA. The lack of effective options for the population that suffers from this disfiguring disease with significant psychosocial ramifications represents a significant unmet medical need. The absence of approved treatments is in part due to an incomplete understanding of the unbalanced equilibrium between pathogenic immune responses and immunoregulatory mechanisms that prevent autoimmunity in AA. Although many cytokines, pathways, and cell types have been hypothesized to prevent immune attack of the hair follicle, it is unknown what factors participate in regulating autoimmune responses in vivo. Identifying these critical immunoregulatory participants may not only deepen our understanding of AA pathogenesis, but may reveal anti-inflammatory pathways that may be exploited to develop novel approaches to treatment. IL-27 is a cytokine with immunoregulatory properties that has been studied in various autoimmune, infectious, and tumor models. The receptor for IL-27 is expressed by a wide array of immune cell types as well as epithelial and endothelial cells, supporting its potential to modulate the immune system and critical cell types that interact with the immune system. In particular, IL-27 has been shown to dampen conventional T cell responses, increase the number of regulatory T cells, and induce naïve and previously activated CD4 and CD8 T cells to produce IL-10, a well-known cytokine with anti-inflammatory effects in most contexts. Our preliminary data indicate that overexpression of IL-27 can substantially prevent the development of murine AA, and further analysis revealed regulatory T cells and IL-10 as potential downstream candidates participating in disease suppression. We propose to study the mechanisms of AA suppression of exogenous IL-27 and its downstream effects on regulating immune responses to the hair follicle and preventing the development of AA. We have adopted and further developed a spontaneous AA mouse model to robustly develop disease in an inducible, controlled, and well-characterized manner by adoptive transfer of activated pathogenic T cells. Combining our AA model with newly developed genetic tools will allow us to dissect the mechanisms by which IL-27 may be used to ablate AA pathogenesis and has the potential to reveal novel therapeutic strategies.