Psoriatic regulatory T cell dysfunction

银屑病调节性 T 细胞功能障碍

• 批准号: 7257309
• 负责人: Kevin D Cooper
• 金额: $ 33万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7257309
• 关键词: Acute; Address; Affect; Allergic Contact Dermatitis; Antibodies; Antigen-Presenting Cells; Antigens; Appearance; Appendix; Area; Autoimmunity; Autologous; Biological Assay; Biological Markers; Biopsy; Blood; CD4 Positive T Lymphocytes; CTLA4 gene; CTLA4-Ig; Cell Proliferation; Cells; Chronic; Clinical; Clinical Trials; Contact Dermatitis; Coupled; Cutaneous; Cyclosporins; Data; Dendritic Cells; Dermal; Disease; Doctor of Medicine; Environment; Epidermis; Eragrostis; Exhibits; Exposure to; FK506; Family; Flow Cytometry; Functional disorder; Gene Expression; Goals; Human; IL2RA gene; IL2RB gene; Individual; Inflammation; Interleukin-2; Interleukin-6; Intervention; Laboratories; Lead; Lesion; Ligands; Measures; Mediating; Medical Surveillance; Memory; Messenger RNA; Methods; Modeling; Monitor; Monoclonal Antibodies; Monoclonal Antibody HuM291; Muromonab-CD3; Mus; Normal tissue morphology; Numbers; Organ; Pathogenesis; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phase; Phenotype; Physiologic pulse; Polymerase Chain Reaction; Population; Principal Investigator; Production; Proliferating; Proteins; Psoriasis; Pulse taking; Recombinants; Recruitment Activity; Refractory; Regulation; Relative (related person); Resolution; Rest; Rheumatoid Arthritis; Role; SCID Mice; Signal Transduction; Site; Skin; Source; Surface; System; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; TFRC gene; TLR4 gene; Testing; Time; Tissues; Transplantation; Up-Regulation; Variant; alefacept; autocrine; beta-defensin-2; cell preparation; cell type; chronic autoimmune disease; concept; cytokine; day; human disease; in vivo; mRNA Expression; macrophage; monocyte; novel; peripheral blood; preconditioning; programs; research study; response; sensitizing antigen

DESCRIPTION (provided by applicant): Recent exciting evidence has emerged on a critical mechanism of effector T cell (Teff) mediated by regulatory T (Treg) cells; the data show that Treg suppression can be blocked via IL-6 produced by dendritic cells (DC) (Medzhitov). Interestingly, both Treg function and IL-6 production appear aberrant in psoriasis, and their linkage may represent a novel mechanism of chronic autoimmune disease. Treg cells can be isolated from psoriatic skin, and our preliminary data suggests that regulatory cells found in psoriatic skin are deficient in their ability to inhibit Teff proliferation. This is also true for Treg cells isolated from peripheral blood of psoriatic patients. It is clear that Teff cells in psoriasis are numerous, highly proliferative, and pathogenic, because T cell specific interventions such as cyclosporin, FK506, anti-CD4, CTLA4-Ig, Alefacept and anti-CD3 confirm that T cell activation, specifically that of memory effector T ceils (Tmem/eff), is critical for sustaining a psoriatic lesion. In order to become pathogenic, Teff cells must have escaped Treg surveillance, which normally restrains pathogenic T cell proliferation. Although numerous laboratories have noted the presence of the cytokine IL-6 in psoriatic tissue, the specific functional role of IL-6 in psoriasis pathogenesis has not been clearly defined. Our preliminary data indicates that IL-6 secretion from isolated psoriatic epidermal cell preparations is quite high in the involved tissue and is only noted in extremely low amounts in uninvolved and normal tissue. This observation, coupled with our data demonstrating a deficiency in psoriatic Treg cells and the findings by Medzhitov, leads us to the hypothesis that: Regulatory T cells in psoriasis are blocked in their ability to suppress effector T cell responses due to the excessive levels of IL-6 present in involved areas of psoriatic tissue. Because Treg cells restrain T mem/eff cells, there is high value in investigating these ceils as a target for immunomodulatory intervention in human disease. Understanding Treg regulation, function and dysfunction in psoriasis is the focus of this proposal. Since Treg cells restrain both T memory (Tmem) and T mem/eff cells, there is high value in investigating these cells as a target for immunomodulatory intervention in human disease. Lesional psoriatic epidermis possesses an elevated allo-antigen presenting capacity and an abnormal ability to stimulate autologous T cells in the absence of exogenous antigen. The responsible antigen presenting cell (APC) appears activated and to express macrophage markers. Because activated macrophages are potent sources of IL-6 it is highly likely that these cells are providing signals for intralesional T cell activation and may themselves be stimulated to activation by IL-6 in the proper psoriatic microenvironment. However, the consequences of such autocrine stimulation in the context of a regulatory T cell environment has not been examined. Further, the local production of IL-6 may provide clues to the question of why psoriatic patients are capable of clearing routine immunological challenges without excessive Teff activation leading to generalized systemic or multiorgan autoimmunity. The local effect on Treg function which is delivered by 1L-6 may be exquisitely locally suppressing the Treg function specifically in lesional psoriasis skin.

描述（由申请人提供）： 最近的令人兴奋的证据已经出现在调节t（Treg）细胞介导的效应T细胞（TEFF）的关键机制上。数据表明，Treg抑制可以通过树突状细胞（DC）（Medzhitov）产生的IL-6阻塞。有趣的是，Treg功能和IL-6产生在牛皮癣中都异常，它们的连锁可能代表了慢性自身免疫性疾病的新机制。 Treg细胞可以从银屑病皮肤中分离出来，我们的初步数据表明，在银屑病皮肤中发现的调节细胞缺乏抑制TEFF增殖的能力。对于从银屑病患者的外周血分离的Treg细胞也是如此。 It is clear that Teff cells in psoriasis are numerous, highly proliferative, and pathogenic, because T cell specific interventions such as cyclosporin, FK506, anti-CD4, CTLA4-Ig, Alefacept and anti-CD3 confirm that T cell activation, specifically that of memory effector T ceils (Tmem/eff), is critical for sustaining a psoriatic lesion.为了成为致病性，Teff细胞必须逃脱Treg监测，这通常限制致病性T细胞增殖。尽管许多实验室注意到银屑病组织中存在细胞因子IL-6，但尚未明确定义IL-6在牛皮癣发病机理中的特定功能作用。我们的初步数据表明，孤立的银屑病表皮细胞制剂中的IL-6分泌在所涉及的组织中非常高，并且仅在未参考和正常组织中以极低的量注意。这一观察结果以及我们的数据表明，银屑病细胞缺乏症状以及Medzhitov的发现，我们提出了这样一种假设：牛皮癣中的调节性T细胞因抑制效应T细胞反应的能力而被阻断，因为它们由于psoriatic组织中所涉及的IL-6的过度水平而导致的效应T细胞反应。由于Treg细胞限制了T MEM/EFF细胞，因此研究这些天花板是对人类疾病的免疫调节干预的靶标具有很高的价值。了解牛皮癣的Treg调节，功能和功能障碍是该提案的重点。由于Treg细胞限制了T记忆（TMEM）和T MEM/EFF细胞，因此研究这些细胞作为对人类疾病的免疫调节干预的靶标具有很高的价值。在没有外源性抗原的情况下，病情的银屑病表皮具有升高的同种抗原表现能力和异常刺激自体T细胞的能力。负责的抗原呈递细胞（APC）似乎被激活并表达巨噬细胞标记。由于活化的巨噬细胞是IL-6的有效来源，因此这些细胞很有可能为病情内T细胞激活提供信号，并且本身可能会在适当的银屑病微环境中刺激IL-6激活。但是，在调节性T细胞环境的背景下，这种自分泌刺激的后果尚未进行检查。此外，IL-6的局部产生可能会为为什么银屑病患者能够消除常规免疫学挑战而不会过多的TEFF激活导致全身性或多GAN自身免疫性的问题提供线索。由1L-6传递的Treg功能的局部影响可能会在局部局部抑制特异性牛皮癣皮肤中的Treg功能。