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Regulation of Neuromyelitis Optica via Tolerance Induced by PLG Nanoparticles Encapsulating Aquaporin 4 Epitopes

通过封装水通道蛋白 4 表位的 PLG 纳米颗粒诱导的耐受性调节视神经脊髓炎

基本信息

批准号：
10088406
负责人：
STEPHEN D MILLER
金额：
$ 19.83万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-24 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10088406
关键词：
Adoptive Transfer Adrenal Cortex Hormones Affect Aftercare Allergic Allergic Disease Antibody Formation Antibody Response Antigen-Presenting Cells Antigens Autoantibodies Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity Automobile Driving Biopolymers Blindness CD8B1 gene CNS Demyelinating Autoimmune Diseases CNS autoimmune disease Celiac Disease Cells Chronic Clinical Collaborations Demyelinations Development Disease Dose Effector Cell Encapsulated Epitope spreading Epitopes Evaluation Experimental Autoimmune Encephalomyelitis FDA approved FOXP3 gene Genetic Gliadin Gluten Glycolic-Lactic Acid Polyester Human Hypersensitivity IL2RB gene Immune Immune Tolerance Immune response Immunization Immunotherapy Infusion procedures Injections Insulin-Dependent Diabetes Mellitus Interleukin-10 Intravenous infusion procedures Knockout Mice Liver MHC Class I Genes Mediating Methods Modeling Multiple Sclerosis Mus Myelin Myelin Proteins Neuromyelitis Optica Oligodendroglia Optic Nerve Optic Neuritis Paralysed Pathogenesis Pathway interactions Patients Peptides Pharmacologic Substance Phase Placebos Plant Roots Plasma Exchange Plasmapheresis Population Preparation Process Production Proteins Recombinants Regulation Regulatory T-Lymphocyte Specificity Spinal Cord Spinal Cord Demyelinating Autoimmune Diseases T-Cell Proliferation T-Lymphocyte T-Lymphocyte Epitopes Testing Therapeutic immunosuppression Tolerogen Toxin Transforming Growth Factor beta Transplantation Up-Regulation Vision anergy aquaporin 4 autoreactivity base carboxylate cytokine disorder control efficacy testing efficacy trial high reward high risk mouse model nanoparticle novel oligodendrocyte-myelin glycoprotein particle phase II trial poly(lactide)prevent programmed cell death ligand 1 programmed cell death protein 1 research clinical testing rituximab scavenger receptor side effect uptake water channel

项目摘要

PROJECT SUMMARY/ABSTRACT: Neuromyelitis optica (NMO) is an autoimmune disease of the CNS characterized by T cell and antibody responses to the water channel protein Aquaporin 4 (AQP4) and myelin oligodendrocyte protein (MOG). NMO patients often suffer from blindness and paralysis as a result of chronic damage to the optic nerves and spinal cord. Current treatments such as high dose corticosteroids, plasmapheresis and rituximab are expensive, non- curative and fail to provide durable disease control. The Miller lab has developed a method using carboxylated biodegradable nanoparticles composed of the FDA-approved biopolymer polylactide-co-glycolide (PLG) to encapsulate proteins or peptides [PLG(Ag)] for induction of T cell tolerance for treatment of autoimmune models of Multiple Sclerosis (EAE) as well as other autoimmune and allergic diseases. Following i.v. infusion, PLG(Ag) NPs are taken up by tolerogenic antigen presenting cells (APCs) in the liver and splenic marginal zone via the MARCO scavenger receptor. These APCs present the encapsulated antigen and induce tolerance by several mechanisms such as anergy induction and the activation of various subsets of Ag-specific Treg cells. Significantly, PLG NPs encapsulating gliadin are presently undergoing phase 2 clinical testing in celiac disease patients. NMO is a prime candidate autoimmune disease which may benefit from this tolerogenic therapy due to substantial evidence that the disease is primarily driven by autoimmune responses to AQP4. Therefore, we propose to test the hypothesis that tolerogenic treatment with PLG nanoparticles encapsulating AQP4 and/or its immunodominant T cell epitopes will induce specific immunotherapy of NMO via induction of anergy and AQP4-specific Tregs. Aim 1 will establish mouse models of NMO by transfer of activated T cells from AQP4 KO mice primed with either recombinant AQP4 protein (rAQP4), yielding T cells specific for multiple AQP4 epitopes, or with T cells from KO mice primed with NMO-inducing I- Ab/I-As-restricted AQP4201-220 or I-Ab-restricted AQP4135—153 epitopes to wildtype B6 or SJL recipients. As NMO patients often display autoantibodies to MOG and PLP as well as to AQP4 due, we will assess if epitope spreading leads to T cell and antibody responses to these myelin proteins in NMO mice. Aim 2 will determine the effects of tolerance induced by PLG NPs encapsulating the immunodominant AQP4201-220 and/or AQP4135- 153 T cell epitopes in rAQP4 and AQP4 peptide-induced NMO mice. Aim 3 will determine the effects of tolerance induced by PLG NPs encapsulating rAQP4 on disease initiated by transfer of rAQP4 vs. AQP4 peptide-specific T cells due to the possibility that human NMO patients recognize multiple AQP4 determinants presented by different HLA class II molecules. Tolerance induction will be assessed by clinical scoring, evaluation of demyelination and optic neuritis, and by immune criteria (T cell proliferation and cytokine production and Ab responses). It is anticipated that successful demonstration of AQP4-specific tolerance will propel the rapid clinical testing of this novel immune tolerance inducing platform for the treatment of NMO.

项目总结/摘要：视神经肌萎缩症是一种以T细胞和抗体为特征的中枢神经系统自身免疫性疾病对水通道蛋白水通道蛋白4（AQP 4）和髓鞘少突胶质细胞蛋白（MOG）的反应。NMO 由于视神经和脊髓的慢性损伤，线.目前的治疗，如高剂量皮质类固醇，血浆置换和利妥昔单抗是昂贵的，非- 治疗和未能提供持久的疾病控制。米勒实验室开发了一种方法，由FDA批准的生物聚合物聚丙交酯-共-乙交酯（PLG）组成的可生物降解的纳米颗粒，用于诱导治疗自身免疫性疾病的T细胞耐受的包封蛋白或肽[PLG（Ag）] 多发性硬化症（EAE）以及其他自身免疫性和过敏性疾病的模型。静脉输注后， PLG（Ag）NPs被肝和脾边缘的致耐受性抗原呈递细胞（APC）摄取，区通过MARCO清道夫受体。这些APC呈递包封的抗原并诱导免疫耐受通过几种机制，如无反应性诱导和激活Ag特异性 Treg细胞。值得注意的是，包封麦醇溶蛋白的PLG NP目前正在进行2期临床试验。乳糜泻患者。NMO是一种主要的候选自身免疫性疾病，可能会从中受益由于大量证据表明疾病主要由自身免疫反应驱动， AQP4。因此，我们建议检验用PLG纳米颗粒进行致耐受性治疗的假设，包封AQP 4和/或其免疫显性T细胞表位将诱导特异性免疫治疗， NMO通过诱导无反应性和AQP 4特异性T细胞。目的1建立小鼠NMO模型，从用重组AQP 4蛋白（rAQP 4）致敏的AQP 4 KO小鼠转移活化的T细胞，产生对多种AQP 4表位特异性的T细胞，或使用来自用MMO诱导的I-启动的KO小鼠的T细胞 Ab/I-As-限制性AQP 4201 -220或I-Ab-限制性AQP 4135 -153表位与野生型B6或SJL受体结合。作为NMO 患者经常显示出MOG和PLP以及AQP 4的自身抗体，我们将评估表位在NMO小鼠中，扩散导致T细胞和抗体对这些髓磷脂蛋白的应答。目标2将决定由包封免疫显性AQP 4201 -220和/或AQP 4135 - 225的PLG NP诱导的耐受性的作用 rAQP 4和AQP 4肽诱导的NMO小鼠中的153个T细胞表位。目标3将决定包封rAQP 4的PLG NPs对由rAQP 4相对于AQP 4的转移引发的疾病诱导的耐受性肽特异性T细胞，因为人类NMO患者可能识别多种AQP 4决定簇由不同的HLA II类分子呈递。将通过临床评分评估耐受诱导，评价脱髓鞘和视神经炎，并通过免疫标准（T细胞增殖和细胞因子生产和抗体应答）。预期AQP 4特异性耐受性的成功证明将推动这种新型免疫耐受诱导平台治疗NMO的快速临床试验。