T-cell mediated RGC damage in glaucoma

T 细胞介导的青光眼 RGC 损伤

• 批准号: 10564648
• 负责人: MARKUS H. KUEHN
• 金额: $ 53.15万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10564648
• 关键词: Affect; Age; Alleles; Animal Disease Models; Animal Model; Animals; B-Lymphocytes; Biological Assay; Blindness; Blood specimen; CD3 Antigens; CD4 Positive T Lymphocytes; Cell Death; Cell Fraction; Cessation of life; Chronic; Clinical Research; Cytoprotection; Data; Development; Disease; Excision; Exhibits; Extravasation; Eye; Eye diseases; Frequencies; Functional disorder; Future; Gene Deletion; Gene Expression Profile; Genetic Transcription; Glaucoma; Goals; Human; Immune response; Immunohistochemistry; Individual; Inflammation; Inflammatory; Knock-out; Knockout Mice; Mature T-Lymphocyte; Mediating; Medical; Methods; Modeling; Molecular; Mus; Pathology; Patients; Peripheral Blood Mononuclear Cell; Persons; Physiologic Intraocular Pressure; Population; Primary Open Angle Glaucoma; Process; Production; Publishing; Quality of life; Retina; Retinal Ganglion Cells; Rodent Model; Role; T cell therapy; T-Lymphocyte; TNF gene; Testing; Therapeutic; Time; Transgenic Mice; Treatment Protocols; Vision; Work; axonal degeneration; cell injury; cell mediated immune response; cell type; comparison control; cytotoxic; design; expectation; experience; human disease; immunomodulatory therapies; immunoregulation; improved; in vitro Assay; in vivo; innovation; insight; lymph nodes; mouse model; myocilin; normotensive; novel; novel therapeutic intervention; peripheral blood; preservation; retinal damage; single nucleus RNA-sequencing; translational impact

Abstract: Primary open angle glaucoma (POAG) is a potentially blinding ocular disease that affects 60 million people world-wide. Reduction of IOP is currently the only glaucoma treatment, but fails to preserve vision in a significant fraction of patients, suggesting that other –currently untreated- factors contribute to the disease. Therefore, there is a critical need to identify these additional pathomechanisms to aid the development of new therapeutic approaches that directly support survival and function of retinal ganglion cells (RGC). Our recently published studies have demonstrated that adoptive transfer of T-cells from glaucomatous mice into normal recipients causes RGC loss in the recipients. We have also demonstrated that the absence of T- and B-cells profoundly protects RGC in a mouse glaucoma model. Preliminary data included in this application demonstrates that peripheral blood mononuclear cells (PBMC) of glaucoma patients contain a higher fraction of CD4 cells synthesizing TNFα and exhibit a higher activation state than those of controls. We further demonstrate that glaucoma PBMC have a heightened propensity to damage RGC in an ex vivo assay when compared to controls. Together, these findings strongly suggest that T-cell mediated damage is one of the mechanisms contributing to RGC loss in both animal models and in human patients. This project is designed with the long-term goal to determine whether modulation of immune responses provides vision saving benefits to glaucoma patients. The objective of this application is to establish which subtype of CD4 T-cells mediates damage in the glaucoma retina and to determine the functional significance of CD4 cell derived TNFα. To test our novel hypothesis we will employ a transgenic mouse model of myocilin-associated spontaneous glaucoma that we previously developed (Tg-MYOCY437H) containing an inducible Tnf knockout allele. We have also developed a novel in vitro assay allowing the quantitation of the cytotoxic activity of patient PBMC targeted toward RGC. Finally we propose to determine the activities T cells extravasated in the glaucoma retina, as well as those in lymph nodes and PBMC by establishing detailed gene transcription profiles. Experimental proof that CD4 T-cell mediated mechanisms contribute to vision loss in patients would establish new targets for the medical treatment of glaucoma. These in turn will pave a way for future clinical studies with the ultimate aim of preserving the sight and improving the quality of life of patients with primary open angle glaucoma.

摘要： 原发性开角型青光眼是一种潜在的致盲性眼病， 全球百万人。降低IOP是目前唯一的青光眼治疗方法，但未能 在很大一部分患者中保留视力，这表明其他-目前未经治疗- 这些因素导致了这种疾病。因此，迫切需要确定这些额外的 病理机制，以帮助开发新的治疗方法，直接支持 视网膜神经节细胞（RGC）的存活和功能。 我们最近发表的研究表明，过继转移的T细胞从 正常受体中的RGC丢失。我们还 证明了T细胞和B细胞的缺乏深刻地保护了小鼠青光眼中的RGC。 模型本申请中包含的初步数据表明，外周血 青光眼患者的单个核细胞（PBMC）含有较高比例的CD 4细胞 合成TNFα，并表现出比对照组更高的活化状态。我们进一步 证明青光眼PBMC在离体培养中具有更高的损伤RGC的倾向， 与对照相比，总之，这些发现强烈表明，T细胞 介导的损伤是两种动物模型中导致RGC丢失的机制之一 和人类患者。 本项目设计的长期目标是确定是否调节免疫 这些反应为青光眼患者提供了视力挽救益处。本申请的目的 目的是确定哪种CD 4 T细胞亚型介导青光眼视网膜损伤， 确定CD 4细胞源性TNFα的功能意义。为了验证我们的新假设， 将采用一种肌球蛋白相关的自发性青光眼转基因小鼠模型， 先前开发的（Tg-MYOCY 437 H）含有可诱导的Tnf敲除等位基因。我们还 开发了一种新的体外试验，允许定量患者的细胞毒活性 PBMC靶向RGC。最后，我们建议确定T细胞外渗的活动， 在青光眼视网膜，以及淋巴结和PBMC中，通过建立详细的 基因转录谱。 实验证明CD 4 T细胞介导的机制导致患者视力丧失 将为青光眼的医学治疗建立新的目标。这反过来又会使 未来临床研究的最终目的是保护视力和改善视力。 原发性开角型青光眼患者的生活质量