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性T细胞和致病性Th 1和Th 17型T细胞之间的相互作用。银屑病中Treg功能障碍与高IL-6水平以及这种细胞因子抑制调节性T细胞功能和刺激Th 17分化的能力的组合的发现可以解释观察到的银屑病T细胞应答的改变。基于我们的观察，a）在银屑病皮肤中的关键T细胞微环境中以高水平产生IL-6，B）IL-6可以抑制人T调节细胞对效应细胞增殖的抑制，和c）银屑病T细胞表现出STAT 3的超应答磷酸化，测试IL-6和/或其它STAT 3激活细胞因子是否有利于TcR/eff细胞逃避抑制是关键的。我们将（）确定银屑病皮损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的银屑病Treg活性。在Treg方面，我们已发表的和初步的数据表明，银屑病TcR在功能上不太有效，在数量上不足以在发展的银屑病病变中进行功能性抑制，CCR 5 + TcR数量减少，对Rantes和Mip 1a的趋化性降低，CD 73减少，IFI 27（ISG 12）增加。此外，过度表达的银屑病STAT 3相关信号细胞因子如IL-6、IL-23和IL-22与IL- 1和TGF β的组合可以使Teff从前体的分化远离调节表型并朝向致病性Th 17细胞途径，或者甚至引起定向Teff向产生IFNg、IL-17或TNF的Teff细胞的转分化重编程。所以我们也要二）。确定银屑病皮损环境是否可以a）诱导银屑病Treg细胞的异常分布，B）将分化从Treg发育转向Th 17，或c）引起Teff向Teff细胞的转分化重编程。设计一个模型，概括银屑病中观察到的效应/调节性T细胞的变化，将允许潜在的治疗试剂的高通量分析，并开辟了新的研究机会，在疾病中的调节性T细胞发挥作用。 公共卫生相关性： 本申请提出剖析保护性调节性T细胞与致病性Th 1和Th 17型T细胞之间的相互作用。更全面地了解银屑病中调节性和致病性效应T细胞之间的关系对于深入了解已用于银屑病、克罗恩病和类风湿/银屑病关节炎的药物的作用机制是必要的。更好地理解有效疗法的机制将有助于改进下一代疗法，并确定更适合的干预靶点。