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.

抽象的： 原发性开角青光眼（POAG）是一种潜在的眼镜疾病，影响60 全球百万人。 IOP的减少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，这表明其他尚未治疗的患者 因素导致该疾病。因此，迫切需要确定这些额外 病理机制有助于开发直接支持的新治疗方法 残留神经节细胞（RGC）的生存和功能。 我们最近发表的研究表明，T细胞从 青光眼小鼠进入正常的接受者会导致受体中的RGC丢失。我们也有 证明缺乏T-和B细胞可深刻保护小鼠青光眼中的RGC 模型。本应用程序中包含的初步数据表明外周血 青光眼患者的单核细胞（PBMC）含有更高的CD4细胞 比对照组合的TNFα合成并表现出更高的激活态。我们进一步 证明青光眼PBMC在离体中损坏RGC的倾向增强 与对照组相比，测定。这些发现共同表明T细胞 介导的损伤是两种动物模型中导致RGC损失的机制之一 和人类患者。 该项目的设计具有长期目标，以确定是否调节免疫 反应为青光眼患者提供了省视力益处。此应用的目的 是确定哪种CD4 T细胞的亚型介导了视网膜青光眼的损伤和 确定CD4细胞得出的TNFα的功能显着性。为了检验我们的新假设我们 我们将采用与肌动蛋白相关的赞助子糖果的转基因小鼠模型，我们 先前开发的（TG-Myocy437h）包含诱导型TNF敲除等位基因。我们也有 开发了一种新型的体外测定，允许定量患者的细胞毒性活性 PBMC针对RGC。最后，我们建议确定活性T细胞渗入 在视网膜的青光眼以及淋巴结和PBMC中的视网膜中 基因转录曲线。 CD4 T细胞介导的机制导致患者视力丧失的实验证明 将建立新目标的青光眼治疗。这些反过来将铺平一个 未来临床研究的方式，最终目的是保留视线并改善 初级开角性青光眼患者的生活质量。