Psoriatic Regulatory T cell Dysfunction

银屑病调节性 T 细胞功能障碍

• 批准号: 8501377
• 负责人: Kevin D Cooper
• 金额: $ 32.22万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501377
• 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）： 牛皮癣提供了一个独特的机会，可以剖析保护性调节性T细胞之间的相互作用，以及致病性TH1和Th17型T细胞。 Treg功能障碍与高IL-6水平的结合以及该细胞因子抑制调节性T细胞功能并刺激Th17分化的能力的结果可能解释了牛皮癣T细胞反应的改变。根据我们的观察结果，即a）a）IL-6在临界T细胞微环境中在银屑病皮肤中高水平产生，b）IL-6可以抑制人类T调节细胞抑制效应细胞的抑制，c）c）牛皮癣T细胞表现出STAT3的超响应性磷酸化，测试IL-6和/或其他STAT3激活细胞因子是否有利于抑制TMEM/EFF细胞的逃脱。因此，我们将进行。）确定银屑病病态环境是否可以通过效应T细胞在牛皮屑调节T细胞抑制抑制的功能上降低银屑病的Treg活性。在Treg方面，我们发表的和初步的数据表明，银屑病在功能上的有效性较低，在数值上不足以在功能上抑制发达的银屑病病变，CCR5+ Treg数量减少，减少了对RANTES和MIP1A的化学量，并增加了MIP1A，并增加了CD73，并且Ififi ifi27， （ISG12）。此外，过表达的银屑病STAT3相关信号传导细胞因子（例如IL-6，IL-23和IL-22）与IL-1和TGFB结合使用，可以将Treg从前体的分化从监管表型转移到监管表型，并转移致病性TH17细胞途径，甚至引起委托treg的反差重编程到IFNG-，IL-17-或产生TNF的TEFF细胞中。因此，我们还将ii ii。）确定银屑病的环境是否可以a）诱导牛皮癣细胞的异常谱，b）转移从Treg发育转移到Th17的分化，或C）导致TREG的跨分化重新编程到teff细胞。设计一个模型，该模型概括牛皮癣中观察到的效应子/调节性T细胞的变化将允许对潜在的治疗试剂进行高吞吐量分析，并在调节性T细胞起作用的疾病中为新的研究机会打开了新的研究机会。 公共卫生相关性： 当前的应用提议剖析保护性调节性T细胞以及致病性TH1和Th17型T细胞之间的相互作用。对于牛皮癣的调节和致病效应T细胞之间的关系，需要更全面地理解，以了解已经用于牛皮癣，克罗恩斯和类风湿/牛皮癣关节炎的药物的作用机制。更好地了解有效疗法的机制将有助于改善下一代的治疗疗法，并确定更多量身定制的干预靶标。