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）：