T-cell mediated RGC damage in glaucoma

摘要： 原发性开角型青光眼(POAG)是一种潜在的致盲疾病，影响60% 全世界有一百万人。降低眼压是目前唯一的青光眼治疗方法，但未能奏效 相当大一部分患者保持视力，这表明另一些目前未治疗的患者 导致这种疾病的因素有很多。因此，迫切需要确定这些额外的 帮助开发直接支持的新治疗方法的病理机制 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，T细胞的过继转移 青光眼小鼠变成正常受者会导致受者RGC丢失。我们还有 证明T和B细胞的缺失对小鼠青光眼的RGC有深远的保护作用 模特。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)中含有较高比例的CD4细胞 合成肿瘤坏死因子α，表现出比对照组更高的激活状态。我们进一步 证明青光眼PBMC在体外有更高的损伤RGC的倾向 与对照组比较时的化验结果。综上所述，这些发现强烈表明T细胞 在两种动物模型中，介导性损伤是导致RGC丢失的机制之一 在人类病人身上也是如此。 该项目的设计具有长远的目标，以确定免疫调节是否 RESPONSE为青光眼患者提供了挽救视力的好处。本应用程序的目标是 是确定哪种亚型的CD4T细胞介导了青光眼视网膜的损伤，并 确定CD_4细胞来源的肿瘤坏死因子α的功能意义。为了检验我们的新假设，我们 将使用一种转基因小鼠的霉菌素相关的自发性青光眼模型，我们 先前开发的(TG-MYOCY437H)含有可诱导的肿瘤坏死因子基因敲除等位基因。我们还有 开发了一种新的体外试验，可以定量测定患者的细胞毒活性 PBMC的目标是RGC。最后，我们建议确定渗出的T细胞的活性 在青光眼视网膜中，以及在淋巴结和PBMC中通过建立详细的 基因转录图谱。 实验证明CD4T细胞介导的机制与患者视力丧失有关 将为青光眼的医疗治疗建立新的目标。这些反过来又将为 未来临床研究的方向，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

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.