Developing Tolerization Therapies from a New T-cell Based Mouse Model of Neuromyelitis Optica

项目摘要 视神经肌萎缩症（NMO）是一种自身免疫性疾病，优先靶向视神经，脑干， 和脊髓，导致失明和瘫痪，与抗 水通道蛋白4（AQP4）。没有其他自身免疫性疾病专门针对AQP4，一种水通道 在CNS中的星形胶质细胞上表达。我们最近开发了一种NMO小鼠模型，证实了 通过证明靶向AQP4的致病性T细胞引起视神经病变， 神经炎和横肌炎。小鼠失明和瘫痪的临床表现与 在视神经和脊髓有广泛的炎症浸润有趣的是，虽然这些细胞 静脉内转移，尽管有AQP4表达，但非CNS器官中没有炎症， 与肺和肾一样，它们概括了人类的NMO疾病。 我们的小鼠模型再现了人类疾病的几个方面，这些方面可能提供对人类疾病的深入了解。 NMO免疫发病机制。关于NMO的一个永恒的问题是为什么这种疾病 优先针对脊髓和视神经，以及脑干？这不能简单地解释为 通过AQP4的表达模式，因为AQP4在整个大脑以及肺中表达， 肾脏、胃、心脏、淋巴细胞和身体的几乎每一个组织。在我们的NMO小鼠模型中，T 将抗AQP4的细胞注射到尾静脉中，但8天后，它们侵入视神经和脊髓。 脊髓，而保留所有其他AQP4表达器官，就像在人类NMO疾病。因此，理解 我们的动物模型可能有助于回答关于NMO在人类中的定位的问题。第二 关于NMO的一个紧迫问题是什么引发了CNS的攻击？在我们的小鼠模型中， 外周注射的细胞恰好在8天后引发视神经炎的发作。了解这些T 在这8天里，T细胞在做什么，它们与谁互动，这可能解释了T细胞是如何被触发的， 用NMO攻击人类关于NMO的第三个问题是，免疫系统是否可以被重新教育， 攻击AQP4？我们的动物模型表明，由于AQP4反应性T细胞足以引起疾病， 它们是耐受化治疗的理想靶点。耐受治疗，也称为无反应诱导，旨在 通过用抗原刺激T细胞受体来抑制T细胞的致病作用，但这样做 在没有共刺激的情况下，其具有诱导T细胞凋亡而不是活化的作用。我们将 使用我们的模型来开发可以直接转化为临床的耐受性治疗。研究这只老鼠 NMO的模型将产生重要的见解人类NMO疾病的发病机制，并有助于回答 一些最紧迫的问题更重要的是，我们可以利用这些信息来开发 特异性治疗永久性地关闭对AQP4的反应。

Project Summary Neuromyelitis optica (NMO) is an autoimmune disease that preferentially targets the optic nerve, brainstem and spinal cord leading to blindness and paralysis associated with a serological biomarker antibody against the aquaporin-4 (AQP4) water channel. No other autoimmune disease specifically targets AQP4, a water channel expressed on astrocytes in the CNS. We recently developed an NMO mouse model that confirmed the specificity of the immune attack on AQP4 by demonstrating that pathogenic T cells targeting AQP4 cause optic neuritis and transverse myelitis. The clinical manifestation of blindness and paralysis in the mouse correlated with extensive inflammatory infiltrates in the optic nerves and spinal cord. Interestingly, although these cells were transferred intravenously, there was no inflammation in non-CNS organs despite AQP4 expression, such as the lungs and kidneys, which recapitatules human NMO disease. Our mouse model reproduces several aspects of the human disease that may provide insight into the immunopathogenesis of NMO. One of the timeless questions about NMO is why does this disease preferentially targets the spinal cord and optic nerve, as well as the brainstem? It cannot simply be explained by the expression pattern of AQP4 because AQP4 is expressed throughout the brain, as well as the lung, kidney, stomach, heart, lymphocytes and just about every tissue in the body. In our mouse model of NMO, T cells against AQP4 are injected into the tail vein and yet 8 days later, they invade the optic nerves and spinal cord while sparing all other AQP4-expressing organs, just as in the human NMO disease. Thus, understanding our animal model may help to answer this question about the localization of NMO in humans. A second burning question about NMO is what triggers an attack of the CNS? In our mouse model, AQP4-reactive T cells injected peripherally initiate an attack of optic neuritis exactly 8 days later. Understanding what these T cells are doing and who they are interacting with during those 8 days may explain how T cells are triggered to attack in humans with NMO. The third question about NMO is can the immune system be re-educated not to attack AQP4? Our animal model suggests that since AQP4-reactive T cells are sufficient to cause the disease, they are an ideal target for tolerization therapy. Tolerization therapy, also known as anergy induction, is aimed at suppressing the pathogenic effects of T cells by stimulating their T cell receptors with antigen, but doing so in the absence of co-stimulation, which has the effect of inducing T cell apoptosis instead of activation. We will use our model to develop a tolerization therapy that can be directly translated to the clinic. Studying this mouse model of NMO will yield important insights into the pathogenesis of human NMO disease and help to answer some of the most pressing questions in the field. More importantly, we can use this information to develop specific treatments to switch off the reaction to AQP4, permanently.