IL-27 and downstream mechanisms in Alopecia Areata

斑秃中的 IL-27 及其下游机制

基本信息

批准号：
10297577
负责人：
Ali Jabbari
金额：
$ 33.99万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10297577
关键词：
20 year old Address Adopted Adoptive Transfer Affect Alopecia Areata Anti-Inflammatory Agents Antigen-Presenting Cells Antiinflammatory Effect Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity Automobile Driving Blocking Antibodies Bone Marrow CD8-Positive T-Lymphocytes CD8B1 gene Cells Cellular biology Clinical Data Dependovirus Development Disease Endothelial Cells Epithelial Epithelial Cells Equilibrium FDA approved Familiarity Foundations Gene Expression Genetic Goals Hair Hair follicle structure Immune Immune Targeting Immune response Immune system Infiltration Inflammatory Interleukin-10 Knowledge Lead Ligands Ligation MHC Class I Genes MHC Class II Genes Maintenance Mediating Medical Modeling Molecular Mus Organ Outcome Participant Pathogenesis Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Phenotype Population Production Property Quality of life Regulatory T-Lymphocyte Research Role Signal Pathway Signal Transduction Site Skin T cell differentiation T cell response T-Lymphocyte Therapeutic Agents Therapeutic Uses Tissues United States Up-Regulation Work autoimmune pathogenesis autoreactive T cell base cell type cytokine draining lymph node effector T cell immunoregulation improved in vivo interleukin-10 receptor lifetime risk mortality mouse model new therapeutic target novel strategies novel therapeutic intervention overexpression preservation prevent psychosocial receptor self esteem side effect tool transcriptomics tumor

项目摘要

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.

项目概要斑秃 (AA) 是一种常见的自身免疫性疾病，其中毛囊是攻击目标尽管其相关的终生风险高达约 2%，并且具有实质性脱发，但临床上仍会导致脱发。社会心理影响，目前尚无 FDA 批准的 AA 治疗方法。缺乏针对人群的有效选择。患有这种具有重大社会心理影响的毁容疾病的人代表了一个重大的未得到满足的问题医疗需要。缺乏批准的治疗方法部分是由于对不平衡的理解不完全致病性免疫反应与预防的免疫调节机制之间的平衡尽管许多细胞因子、途径和细胞类型已被用来预防 AA 中的自身免疫。毛囊的免疫攻击，目前尚不清楚哪些因素参与调节自身免疫反应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，已在多种自身免疫、 IL-27 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特别是，IL-27 已被证明可以抑制传统 T 细胞。反应，增加调节性 T 细胞的数量，并诱导幼稚的和先前激活的 CD4 和 CD8 T 细胞产生 IL-10，这是一种众所周知的细胞因子，在大多数情况下具有抗炎作用。初步数据表明IL-27的过度表达可以显着阻止小鼠AA的发展，进一步的分析表明调节性 T 细胞和 IL-10 作为潜在的下游候选者参与疾病抑制。我们拟研究AA抑制外源IL-27及其下游的机制我们有调节毛囊免疫反应和预防 AA 发展的作用。采用并进一步开发了自发 AA 小鼠模型，以在可诱导的、通过结合我们的活性致病性 T 细胞的过继转移，以受控且充分表征的方式。使用新开发的遗传工具的 AA 模型将使我们能够剖析 IL-27 的机制用于消除 AA 发病机制，并有可能揭示新的治疗策略。