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

利用基于新 T 细胞的视神经脊髓炎小鼠模型开发耐受疗法

基本信息

批准号：
10396470
负责人：
Michael Levy
金额：
$ 39.62万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-25 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396470
关键词：
Adoptive Transfer Anatomy Animal Model Antibodies Antigen-Presenting Cells Antigens Antimetabolites Apoptosis Astrocytes Autoimmune Diseases Biological Markers Blindness Blood Brain Brain Stem Cells Clinic Clinical Complement Consequentialism Demyelinations Disease Dose Engineering Epitopes Exhibits Experimental Autoimmune Encephalomyelitis Experimental Models Goals Heart Human Immune Immune response Immune system Immunologics Individual Inflammation Inflammatory Inflammatory Infiltrate Intravenous Invaded Kidney Lesion Lung Lymphocyte Mediating Modeling Multiple Sclerosis Mus Nervous System Trauma Neuraxis Neurologic Dysfunctions Neuromyelitis Optica Optic Nerve Optic Neuritis Organ PTPRC gene Paralysed Pathogenesis Pathogenicity Pathway interactions Patients Pattern Peptides Peripheral Positioning Attribute Reaction Relapse Role Sampling Serology Signal Transduction Specificity Spinal Cord Stomach T cell therapy T-Cell Receptor T-Lymphocyte Tail Testing Time Tissues Translating Transverse Myelitis Variant Veins Work anergy aquaporin 4 base body system human disease immunoreaction inflammatory milieu insight mortality mouse model novel novel therapeutic intervention novel therapeutics prevent recruit targeted treatment water channel

项目摘要

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.

项目摘要视神经脊髓炎(NMO)是一种自身免疫性疾病，首发于视神经、脑干。和脊髓导致失明和瘫痪与一种抗水通道蛋白4(AQP4)水通道。没有其他自身免疫性疾病专门针对水通道AQP4 表达于中枢神经系统的星形胶质细胞。我们最近开发了一种NMO小鼠模型，证实了针对AQP4的致病T细胞导致视神经病变的免疫攻击的特异性神经炎和横贯性脊髓炎。小鼠致盲和瘫痪的相关临床表现视神经和脊髓有广泛的炎性浸润物。有趣的是，尽管这些细胞静脉转移，尽管AQP4表达，但非中枢器官没有炎症反应，如就像肺和肾一样，它们概括了人类的NMO疾病。我们的小鼠模型复制了人类疾病的几个方面，这可能为深入了解 NMO的免疫发病机制。关于NMO的一个永恒的问题是，为什么这种疾病优先攻击脊髓和视神经，以及脑干？这不能简单地解释通过AQP4的表达模式，因为AQP4在大脑和肺中都有表达，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，T小鼠模型中针对AQP4的细胞被注射到尾静脉，但8天后，它们侵入视神经和脊髓脊髓，同时保留所有其他表达AQP4的器官，就像在人类NMO疾病中一样。因此，理解我们的动物模型可能有助于回答有关NMO在人类体内定位的问题。一秒钟关于NMO的迫切问题是，是什么触发了对CNS的攻击？在我们的小鼠模型中，AQP4-反应T 外周注射的细胞恰好在8天后引发视神经炎。了解这些T 细胞在做什么以及在这8天里它们与谁相互作用可以解释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，免疫系统能否被重新教育而不是攻击AQP4？我们的动物模型表明，由于AQP4反应的T细胞足以导致这种疾病，它们是耐受治疗的理想靶点。耐受疗法，也被称为无能诱导，其目的是通过用抗原刺激T细胞受体来抑制T细胞的致病作用在没有共刺激的情况下，具有诱导T细胞凋亡而不是激活的作用。我们会使用我们的模型来开发一种可以直接移植到临床的耐受疗法。研究这只老鼠 NMO模型将对人类NMO疾病的发病机制产生重要的见解并有助于回答这是该领域最紧迫的一些问题。更重要的是，我们可以利用这些信息来开发永久关闭对AQP4反应的特定治疗。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Upregulated complement receptors correlate with Fc gamma receptor 3A-positive natural killer and natural killer-T cells in neuromyelitis optica spectrum disorder.

DOI：
10.1186/s12974-022-02661-1
发表时间：
2022-12-12
期刊：
Journal of neuroinflammation
影响因子：
9.3
作者：
通讯作者：

Review of Treatment for Central Spinal Neuropathic Pain and Its Effect on Quality of Life: Implications for Neuromyelitis Optica Spectrum Disorder.

DOI：
10.1016/j.pmn.2019.03.003
发表时间：
2019-12
期刊：
Pain management nursing : official journal of the American Society of Pain Management Nurses
影响因子：
0
作者：
M. Mealy;S. Kozachik;M. Levy
通讯作者：
M. Mealy;S. Kozachik;M. Levy

MRI Predictors of Recurrence and Outcome after Acute Transverse Myelitis of Unidentified Etiology.

病因不明的急性横贯性脊髓炎复发和结果的 MRI 预测因子。