Intra-Lymph Node Delivery of Tolerogenic Microparticles for Modulating Disease in a Model of Multiple Sclerosis

淋巴结内递送耐受性微粒以调节多发性硬化症模型中的疾病

• 批准号: 9760601
• 负责人: Emily A Gosselin
• 金额: $ 3.43万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-30 至 2021-01-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760601
• 关键词: Affect; Antibodies; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune Diseases; B-Lymphocytes; Biocompatible Materials; Blood; Cell Communication; Cells; Cytotoxic T-Lymphocytes; Data; Demyelinations; Dendritic Cells; Deposition; Development; Disease; Disease Progression; Disease remission; Effector Cell; Ensure; Enzyme-Linked Immunosorbent Assay; Epitope spreading; Epitopes; Experimental Autoimmune Encephalomyelitis; Feedback; Flow Cytometry; Foreign Bodies; Frequencies; Future; Goals; Helper-Inducer T-Lymphocyte; Histology; Immune; Immune Targeting; Immune Tolerance; Immune response; Immune signaling; Immune system; Immunity; Immunocompromised Host; Immunomodulators; Impairment; Inflammation; Inflammatory; Injections; Kinetics; Life; Lymph Node Tissue; Lymphocyte; Mediating; Modeling; Monitor; Multiple Sclerosis; Mus; Muscular Atrophy; Myelin; Nerve Degeneration; Neuraxis; Neurons; Onset of illness; Opportunistic Infections; Paralysed; Patients; Peptides; Phenotype; Polymers; Population; Pre-Clinical Model; Recovery; Recurrent disease; Relapse; Relapsing-Remitting Multiple Sclerosis; Research; Role; Serum; Severity of illness; Signal Transduction; Sirolimus; Site; Stains; Symptoms; T cell differentiation; T-Lymphocyte; Techniques; Testing; Time; Tissues; Training Activity; Treatment Efficacy; Treatment Protocols; Tumor-infiltrating immune cells; Work; base; biodegradable polymer; career development; cell injury; chronic pain; cytokine; design; disorder control; experience; human disease; immunoregulation; interest; lymph nodes; mouse model; multiple sclerosis treatment; next generation; overtreatment; particle; preservation; prevent; recruit; study population; therapy development; treatment response

PROJECT SUMMARY Multiple Sclerosis (MS) is a debilitating disease that occurs when the body’s immune system incorrectly recognizes myelin, the matrix that insulates neurons in the central nervous system (CNS) as foreign. Current treatments for MS aim to reduce the severity of disease, but do not treat the cause, and require continual, frequent treatments over the lifetime of the patient to maintain disease remission, though the disease ultimately will progress. Unfortunately, these existing therapy options are also non-specific – they cannot differentiate between myelin-specific inflammatory immune cells and other lymphocytes, leaving patients susceptible to opportunistic infections. Myelin-specific inflammatory cells are activated in lymph nodes (LNs), sites which coordinate immune cell interactions that control immune cell phenotypes. In the LNs, antigen presenting cells, including dendritic cells (DCs), present antigens – such as myelin in MS – to T and B cells. Depending on the signals present during this interaction, T cells can become inflammatory effector cells or regulatory cells (TREGS) that control the activity of inflammatory cells. During MS, these myelin-specific effector cells contribute to inflammation and neurodegeneration in the CNS. To overcome the limitations of current treatments, this proposal focuses on developing therapies that promote selective immune tolerance to myelin by inducing antigen-specific TREGS that can selectively control disease. To meet this goal, a direct LN injection technique will be used to deposit polymer particles co-loaded with myelin self-antigens and rapamycin, an immunomodulator, in LNs of mice induced with a relapsing-remitting model of MS. Studies have shown that the presence of Rapamycin, during the priming of a T cell can promote TREGS. Our lab has shown that a single injection of particles into LNs allows local programming of the LN microenvironment to promote TREGS, which permanently stopped and reversed disease-induced paralysis in a model of progressive MS. However, 85% of patients initially present with the relapsing-remitting form of MS, in which the immune system becomes reactive to different sections of myelin over time. This epitope spreading complicates treatment regimens, and therapies do not consistently work at all stages of disease. Thus, a relapsing-remitting model will allow for the study of epitope spreading, and how disease progresses when protection is conferred to an epitope at an earlier disease stage. Preliminary data shows that treating during the first wave of disease with a single iLN injection of particles co-loaded with rapamycin and the myelin epitope attacked during that wave can reverse disease and prevent relapse. This proposal will investigate how treatments at different stages of disease with different myelin epitopes alters disease progression and prevents relapse.

项目总结 多发性硬化症(MS)是一种当人体免疫系统错误识别髓鞘时发生的一种衰弱疾病， 将中枢神经系统(CNS)中的神经元作为异物隔绝的基质。目前对多发性硬化症的治疗旨在减少 疾病的严重程度，但不治疗病因，需要在患者的一生中持续、频繁地治疗 以维持疾病的缓解，尽管疾病最终会发展。不幸的是，这些现有的治疗方案是 同样也是非特异性的--它们无法区分髓鞘特异性炎症免疫细胞和其他淋巴细胞， 使患者容易受到机会性感染。淋巴结髓磷脂特异性炎症细胞被激活 (LNS)，协调免疫细胞相互作用的部位，控制免疫细胞表型。在LNS中，抗原呈递 包括树突状细胞(DC)在内的细胞将抗原--如MS中的髓鞘--呈递给T和B细胞。视信号而定 在这种相互作用中，T细胞可以成为炎性效应细胞或调节细胞(Treg)，控制着 炎性细胞的活性。在多发性硬化症期间，这些髓鞘特异性效应细胞有助于炎症和 中枢神经系统的神经变性。为了克服目前治疗方法的局限性，这项建议的重点是开发 通过诱导抗原特异性树突状细胞促进对髓鞘的选择性免疫耐受的治疗 疾病。为了实现这一目标，将使用直接层注入技术来沉积与髓鞘共负载的聚合物颗粒 自身抗原和免疫调节剂雷帕霉素在MS复发缓解型小鼠LNS中的作用 已经证明，在T细胞的启动过程中，雷帕霉素的存在可以促进Tregs。我们的实验室已经证明一种 单次将颗粒注入LNS允许局部编程LN微环境以促进Tregs，这 在进展性多发性硬化症模型中，永久停止和逆转疾病引起的瘫痪，然而，85%的患者 最初出现的是复发-缓解型多发性硬化症，免疫系统对不同部位产生反应 随着时间的推移髓鞘的数量。这种表位扩散使治疗方案复杂化，而且治疗方法根本不会持续有效。 疾病的各个阶段。因此，复发-缓解模型将允许研究表位传播，以及疾病是如何 当在疾病的早期阶段给予表位保护时，进展。初步数据显示，在治疗期间 一次ILN注射与雷帕霉素和髓鞘表位共载的颗粒攻击的第一波疾病 在此期间，电波可以逆转疾病，防止复发。这项提案将调查不同阶段的治疗方法 不同髓鞘表位的疾病可以改变疾病的进展并防止复发。