Mechanisms of immune homeostasis and regulation of intraocular inflammation

免疫稳态机制和眼内炎症调节

• 批准号: 8339763
• 负责人: Charles E Egwuagu
• 金额: $ 21.31万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8339763
• 关键词: Acute; Address; Age; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; Biological Assay; Blood; Bone Marrow; Bone Marrow Cells; Brain; CD4 Positive T Lymphocytes; Cells; Chromatin; Chronic; Competence; Cytokine Gene; Disease; Disease Progression; Disease remission; Ensure; Equilibrium; Eye; GRB10 gene; Gene Silencing; Genetic; Histone Deacetylation; Homeostasis; Hypermethylation; Immune; Immune response; Immunization; Infiltration; Inflammation; Inflammatory; Interferons; Interleukin-10; Interleukin-17; Interleukin-4; Location; Lymphocyte; Mediating; Modeling; Monitor; Multiple Sclerosis; Mus; Optical Coherence Tomography; Organ; Pathology; Peripheral; Play; Recurrence; Regulation; Residual state; Rest; Retina; Retinal; Role; STAT3 gene; Signal Transduction; Stromal Cells; T memory cell; T-Cell Activation; T-Lymphocyte; TNFSF5 gene; Thymus Gland; Time; Tissues; Uveitis; autoreactive T cell; interest; mouse model; osteopontin; pathogen; therapeutic target

Several organ-specific autoimmune diseases such as uveitis and multiple sclerosis are mediated by autoreactive CD4+ T cells and are characterized by unpredictable repetitive cycles of explosive inflammatory attacks, which can subside spontaneously (without treatment). Between attacks, there can be little or no evidence of inflammation in the eyes or brain. In this study, we established a long-term mouse model of chronic uveitis and used this model to address the age-old question of where the autoreactive memory T cells that mediate the repeated cycles of remission and recurrent autoimmune disease reside during remissions of inflammation. We induced experimental autoimmune disease (EAU) in mice by immunization with IRBP/CFA and monitored progression of the disease over a period of 6 months by funduscopy, histophathology, optical coherence tomography (OCT) and eletroretinography (ERG). Peak EAU characterized by massive infiltration of Th1/Th17 cells in retina was observed 21 days after disease induction but by day-30 post-immunization the disease went into remission with very few cells detectable in blood or retina. We utilized the very sensitive antigen-induced CD154 expression assay to trace the location of autoreactive T-cells that persist in peripheral tissues over time, starting 30 to 225 days post-immunization. We show that several months after inception of acute uveitis that residual autoreactive memory T-cells specific to retinal autoantigen, IRBP, relocated to bone marrow (BM). The IRBP-specific memory T-cells (IL-7RαHiLy6CHiCD4+) resided in BM in resting state but upon re-stimulation converted to IL-17-/IFN-γ-expressing effectors (IL-7RαLowLy6CLowCD4+). We further show that recruitment into and retention of IRBP-specific memory T-cells in BM required induction of α4β1 and osteopontin expression by STAT3-dependent mechanism. We adoptively transferred uveitis to nave mice using BM cells from WT mice with chronic uveitis but not with BM cells from IRBP-immunized STAT3-deficient (CD4-STAT3KO) mice. Identifying BM as survival-niche for T-cells that cause uveitis, suggests that BM stromal cells that provide survival signals to autoreactive memory T-cells and STAT3-dependent mechanisms that mediate their relocation into BM, are attractive therapeutic targets that can be exploited to selectively deplete memory T-cells that drive chronic inflammation.

一些器官特异性自身免疫性疾病，如葡萄膜炎和多发性硬化症，是由自身反应性CD4+ T细胞介导的，其特征是不可预测的重复性炎症发作周期，可自发消退（无需治疗）。在两次发作之间，眼睛或大脑几乎没有炎症的迹象。在这项研究中，我们建立了慢性葡萄膜炎的长期小鼠模型，并使用该模型来解决一个古老的问题，即在炎症缓解期间，介导缓解和复发性自身免疫性疾病的重复周期的自身反应记忆T细胞驻留在哪里。我们通过IRBP/CFA免疫小鼠诱导实验性自身免疫性疾病（EAU），并在6个月内通过眼底检查、组织病理学、光学相干断层扫描（OCT）和视网膜电图（ERG）监测疾病的进展。在疾病诱导后21天观察到以大量Th1/Th17细胞浸润为特征的EAU峰值，但在免疫后第30天，疾病进入缓解期，血液或视网膜中检测到的细胞很少。我们利用非常敏感的抗原诱导CD154表达测定来追踪免疫后30至225天持续存在于外周组织中的自身反应性t细胞的位置。我们发现，急性葡萄膜炎发病几个月后，视网膜自身抗原（IRBP）残留的自身反应性记忆t细胞迁移到骨髓（BM）。irbp特异性记忆t细胞（IL-7RαHiLy6CHiCD4+）在静息状态下驻留在BM中，但在重新刺激后转化为表达IL-17-/IFN-&#947；-的效应细胞（IL-7RαLowLy6CLowCD4+）。我们进一步表明，BM中irbp特异性记忆t细胞的募集和保留需要通过stat3依赖机制诱导&#945；4&#946；1和骨桥蛋白的表达。我们采用来自患有慢性葡萄膜炎的WT小鼠的骨髓细胞，而不是来自irbp免疫的stat3缺陷（CD4-STAT3KO）小鼠的骨髓细胞，将葡萄膜炎转移到正常小鼠。将BM确定为引起葡萄膜炎的t细胞的生存利基，表明BM基质细胞向自身反应性记忆t细胞提供生存信号，并介导其重新定位到BM的stat3依赖机制是有吸引力的治疗靶点，可以被利用来选择性地消耗驱动慢性炎症的记忆t细胞。