Psoriatic Regulatory T cell Dysfunction

银屑病调节性 T 细胞功能障碍

• 批准号: 8683592
• 负责人: Kevin D Cooper
• 金额: $ 5.36万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8683592
• 关键词: Accounting; Aftercare; Allogenic; Antigen-Presenting Cells; Autoimmune Process; Award; Biological Assay; Biological Models; Biopsy; Blocking Antibodies; Blood; Blood Vessels; CCR5 gene; CCR6 gene; CD4 Positive T Lymphocytes; Cell Proliferation; Cell physiology; Cells; Cellular Immunology; Characteristics; Chemotaxis; Chronic; Coculture Techniques; Commit; Complex; Conditioned Culture Media; Cutaneous; Cytokine Signaling; Data; Defect; Defensins; Dendritic Cells; Dermal; Development; Disease; Drug effect disorder; Effectiveness; Effector Cell; Equilibrium; Eragrostis; Etanercept; Event; Exhibits; Exposure to; Failure; Functional disorder; Funding; Future; Human; Hyperplasia; IL7R gene; Immune System Diseases; Immune response; In Vitro; Infection; Inflammation; Inflammatory; Interferon-alpha; Interferons; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-17; Interleukin-2; Interleukin-6; Intervention; Job' s Syndrome; Lesion; Location; Lymphocyte; Maintenance; Manuscripts; Measures; Mediating; Memory; Messenger RNA; Modeling; Molecular Target; Monitor; Mus; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Play; Population; Predisposition; Proliferating; Proteins; Psoriasis; Psoriatic Arthritis; Publishing; Reaction; Reagent; Recombinants; Refractory; Regulation; Regulatory Element; Regulatory T-Lymphocyte; Relative (related person); Reporting; Research; Response Elements; Rest; Retinoids; Role; STAT1 gene; STAT3 gene; STAT4 gene; Serum-Free Culture Media; Side; Signal Transduction; Skin; Small Interfering RNA; Suspension substance; Suspensions; System; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Thymidine; Time; Tissues; Translating; Trauma; Tretinoin; Umbilical Cord Blood; base; cadmium ion; cell type; chemokine; clinical efficacy; cytokine; design; high throughput analysis; human disease; improved; inhibitor/antagonist; insight; interleukin-12 receptor; interleukin-12 subunit p40; interleukin-22; interleukin-23; keratinocyte; lymphocyte proliferation; novel therapeutic intervention; novel therapeutics; overexpression; peripheral blood; prevent; programs; public health relevance; receptor; response; skin disorder; therapeutic target

DESCRIPTION (provided by applicant): Psoriasis presents a unique opportunity to dissect the interplay between protective regulatory T cells, and pathogenic Th1 and Th17 type T cells. Findings in psoriasis of Treg dysfunction in combination with high IL-6 levels and the capacity of this cytokine to inhibit regulatory T cell function and stimulate Th17 differentiation may explain observed alterations in psoriatic T cell response. Based upon our observations that a) IL-6 is produced at high levels in critical T cell microenvironments in psoriatic skin, b) that IL-6 can inhibit suppression of effector cell proliferation by human T regulatory cells, and c) that psoriatic T cells exhibit hyper-responsive phosphorylation of STAT3, it is critical to test whether IL-6 and and/or other STAT3-activating cytokines favor escape for Tmem/eff cells from suppression. Thus we will I.) Determine whether the psoriatic lesional milieu can create functionally decreased psoriatic Treg activity via effector T cells becoming refractive to suppression by psoriatic regulatory T cells. On the Treg side, our published and preliminary data demonstrate that psoriatic Tregs are functionally less effective, are insufficient numerically to functionally suppress in developed psoriatic lesions, have decreased numbers of CCR5+ Tregs, decreased chemotaxis to Rantes and Mip1a, decreased CD73, and increased IFI27 (ISG12). Furthermore, over-expressed psoriatic STAT3-associated signaling cytokines such as IL-6, IL-23, and IL-22, in combination with IL- 1 and TGFb, can divert the differentiation of Tregs from precursors away from a regulatory phenotype and toward a pathogenic Th17 cell pathway, or even cause trans-differentiative re-programming of committed Tregs into IFNg-, IL-17-,or TNF-producing Teff cells. Therefore, we will also II.) Determine whether the psoriatic lesional milieu can a) induce the abnormal profile of psoriatic Treg cells, b) divert differentiation away from Treg development toward Th17's, or c) cause trans-differentiative re-programming of Tregs into Teff cells. Designing a model that recapitulates the effector/regulatory T cells changes observed in psoriasis will allow for high throughput analysis of potential therapeutic reagents and opens new research opportunities in diseases where regulatory T cells play a role. PUBLIC HEALTH RELEVANCE: The current application proposes to dissect the interplay between protective regulatory T cells, and pathogenic Th1 and Th17 type T cells. A more comprehensive understanding of the relationship between regulatory and pathogenic effector T cells in psoriasis is necessary to gain insight into the mechanism(s) of action for drugs already in use for psoriasis, Crohn's and rheumatoid/psoriatic arthritis. Better understanding of the mechanisms for efficacious therapies will help to improve the next generation of therapeutics and identify more tailored targets for intervention.

描述（由申请人提供）： 银屑病提供了一个独特的机会来剖析保护性调节 T 细胞与致病性 Th1 和 Th17 型 T 细胞之间的相互作用。银屑病 Treg 功能障碍与高 IL-6 水平相结合以及该细胞因子抑制调节性 T 细胞功能和刺激 Th17 分化的能力的发现可能解释了观察到的银屑病 T 细胞反应的变化。根据我们的观察，a) 在银屑病皮肤的关键 T 细胞微环境中高水平产生 IL-6，b) IL-6 可以抑制人类 T 调节细胞对效应细胞增殖的抑制，以及 c) 银屑病 T 细胞表现出 STAT3 的高反应性磷酸化，因此测试 IL-6 和/或其他 STAT3 激活细胞因子是否有利于逃逸至关重要 使 Tmem/eff 细胞免受抑制。因此，我们将 I.) 确定银屑病病变环境是否可以通过效应 T 细胞对银屑病调节性 T 细胞的抑制产生功能性降低。在Treg方面，我们发表的初步数据表明，银屑病Treg在功能上效果较差，在数量上不足以对已发展的银屑病病变进行功能抑制，CCR5+Treg数量减少，对Rantes和Mip1a的趋化性减少，CD73减少，IFI27 (ISG12)增加。此外，过度表达的银屑病 STAT3 相关信号细胞因子（例如 IL-6、IL-23 和 IL-22）与 IL-1 和 TGFb 结合，可以将前体的 Tregs 分化从调节表型转向致病性 Th17 细胞途径，甚至导致定向 Tregs 转分化重编程为 产生 IFNg、IL-17 或 TNF 的 Teff 细胞。因此，我们还将 II.) 确定银屑病病变环境是否可以 a) 诱导银屑病 Treg 细胞的异常特征，b) 将分化从 Treg 发育转向 Th17，或 c) 导致 Treg 转分化重编程为 Teff 细胞。设计一个模型来概括在银屑病中观察到的效应/调节性 T 细胞的变化，将允许对潜在的治疗试剂进行高通量分析，并为调节性 T 细胞发挥作用的疾病开辟新的研究机会。 公共卫生相关性： 当前的申请旨在剖析保护性调节 T 细胞与致病性 Th1 和 Th17 型 T 细胞之间的相互作用。有必要更全面地了解银屑病中调节性效应 T 细胞和致病性效应 T 细胞之间的关系，以深入了解已用于治疗银屑病、克罗恩病和类风湿/银屑病关节炎的药物的作用机制。更好地了解有效治疗的机制将有助于改进下一代治疗方法并确定更适合的干预目标。