IL-27 and downstream mechanisms in Alopecia Areata

项目摘要 斑秃（AA）是一种常见的自身免疫性疾病，毛囊是攻击的目标 并在临床上导致脱发。尽管相关的高终身风险约为2%， 心理社会影响，没有FDA批准的AA治疗方法。民众缺乏有效的选择 患有这种具有显著心理社会后果的毁容疾病的人， 医疗需求。 缺乏批准的治疗方法部分是由于对不平衡的 病原性免疫应答和免疫调节机制之间的平衡， AA的自身免疫性尽管许多细胞因子、途径和细胞类型已经被假设可以预防 毛囊的免疫攻击，它是未知的因素参与调节自身免疫反应， vivo.识别这些关键的免疫调节参与者不仅可以加深我们对AA的理解， 发病机制，但可能揭示抗炎途径，可用于开发新的方法， 治疗 IL-27是一种具有免疫调节特性的细胞因子， 感染和肿瘤模型。IL-27的受体也由多种免疫细胞类型表达 作为上皮细胞和内皮细胞，支持其调节免疫系统和关键细胞的潜力， 与免疫系统相互作用的类型。特别是，IL-27已经显示出抑制常规T细胞增殖， 反应，增加调节性T细胞的数量，并诱导幼稚和先前活化的CD 4和CD 8 T细胞产生IL-10，一种在大多数情况下具有抗炎作用的众所周知的细胞因子。我们 初步数据表明IL-27的过表达可以基本上防止鼠AA的发展， 进一步的分析显示，调节性T细胞和IL-10是潜在的下游候选者， 疾病抑制 本研究拟探讨AA抑制外源性IL-27及其下游信号转导的机制， 调节毛囊的免疫反应和预防AA的发展。我们有 采用并进一步开发了自发AA小鼠模型， 通过过继转移活化的病原性T细胞，以受控和充分表征的方式。结合我们 使用新开发的遗传工具的AA模型将使我们能够剖析IL-27可能被 用于消除AA发病机制，并有可能揭示新的治疗策略。

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.