Leveraging nanotechnology and skin delivery to drive selective immune tolerance for Multiple Sclerosis

利用纳米技术和皮肤递送来驱动多发性硬化症的选择性免疫耐受

• 批准号: 10012971
• 负责人: Robert Smith Oakes
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012971
• 关键词: Address; Affect; Allergens; Allergy Shot; Animal Model; Antibodies; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Automobile Driving; Axon; B-Lymphocytes; Biological Assay; Biological Markers; Biological Response Modifiers; Blindness; Brain; Cells; Clinic; Clinical Data; Cues; Dangerousness; Data; Delayed Hypersensitivity; Disease; Dose; Engineering; Ensure; Environment; Experimental Autoimmune Encephalomyelitis; Family; Fluorescence; Generations; Goals; Growth; Immune; Immune Targeting; Immune Tolerance; Immune signaling; Immune system; Immunity; Immunocompromised Host; Immunologics; In Vitro; Infection; Inflammation; Inflammatory; Injections; Length; Libraries; Life; Ligands; Mentors; Molecular; Motor; Multiple Sclerosis; Myelin; Myelin Sheath; Nanotechnology; Needles; Neuraxis; Neurologic; Neurophysiology - biologic function; Onset of illness; Organ; Pain; Paralysed; Pathogen detection; Pathway interactions; Patients; Pattern; Peptides; Pharmaceutical Preparations; Phenotype; Polymers; Population; Predisposition; Quality of life; Receptor Signaling; Regulatory T-Lymphocyte; Research; Risk; Role; Self Administration; Signal Pathway; Signal Transduction; Site; Skin; Specificity; Spinal Cord; Surface; Surveys; Symptoms; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Tissues; Toll-Like Receptor Pathway; Toll-like receptors; Tracer; Treatment Efficacy; Veterans; Visual impairment; Woman; base; career; career development; cell type; curative treatments; cytotoxic; density; design; draining lymph node; effective therapy; efficacy testing; experience; extracellular; immune function; immunoregulation; improved; in vivo; in vivo imaging; intradermal injection; motor deficit; mouse model; multiple sclerosis patient; multiple sclerosis treatment; nanomaterials; nanotechnology platform; neuroinflammation; novel; pathogen; preservation; prevent; restraint; side effect; subcutaneous; therapeutic evaluation; therapy development; trafficking

Multiple sclerosis (MS) is an autoimmune disease that develops when the immune system loses tolerance for myelin in the sheath wrapping axons of the central nervous system (CNS). Damage to the myelin sheath can result in paralysis, vision impairment, and other neurological complications that significantly diminishes MS patient quality of life. There is no cure and many MS therapies also eliminate beneficial immunity. One experimental strategy to specifically counter autoimmunity is the generation of regulatory cell types, such as regulatory T cells (TREGS). The goal of such approaches is to selectively suppress the inflammatory T and B cells that are overactive and target myelin through cytotoxic pathways or antibody generation, respectively. Generation of antigen-specific TREGS and tolerance that counter autoimmunity could provide long-lasting treatments, while preserving protective immunity. A new idea to promote TREGS is suppression of toll-like receptor (TLR) signaling. TLRs regulate a power set of pathways that regulate immunity and evolved to detect the pathogens associated molecular patterns to initiate inflammation and eliminate dangerous pathogens. While TLRs are well known for their role in pathogen detection, surprising new studies show TLRs are also over-active during autoimmunity. To harness TLR signaling, the Jewell lab developed a nanotechnology platform where a regulatory TLR ligand (GpG) is synthesized with myelin self-antigen (MOG) to ensure immune cells receive both the signals to promote myelin-specific TREGS. Since these nanomaterials – termed immune polyelectrolyte multilayers (iPEMs) – are built entirely from the immune signals, they display the cues at a high density to potently modulate immune function. Administration of the iPEMs containing GpG and MOG prevents disease-associated paralysis in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. While promising, these effects were transient, and required multiple, high doses of iPEM injections. To overcome these challenges, I will develop microneedle arrays (MNAs) to deliver iPEMs built from myelin self- antigen and regulatory TLR ligands directly to the skin. MNAs are small patches (~1 cm dia.) with polymer needles several hundred microns in length, designed to target the immune-rich layers in skin. Skin is our largest immunological organ and contains a high density of immune cells, with specialized phenotypes that are constantly surveying the skin for foreign pathogens. Recent evidence indicates that some of these immune cells have a unique ability to promote TREGS in vivo, which were then able to suppress symptoms of paralysis in a common mouse model of MS. These exciting and recent results suggest that if the tolerance biased immune cells in skin could be harnessed through their TLR signaling pathways, they may be directed towards a tolerogenic phenotype. The central hypothesis of this VA CDA-2 proposal is that tolerogenic iPEMs delivered through MNAs will drive tolerogenic phenotypes in skin-resident antigen-presenting cells that will migrate to draining lymph nodes (LNs) and instruct T cells toward a TREG phenotype that restrains autoimmunity in a mouse model of MS. To test this hypothesis, I have designed three specific aims to: 1) assemble iPEM coatings on MNAs and predict their efficacy in vitro, 2) deliver iPEMs to skin using MNAs to test efficacy and specificity in mouse models of MS, and 3) test the role of TREGS in promoting efficacy of iPEM coated MNAs and investigate tolerance biomarkers in skin- draining LNs. This approach will provide two unique opportunities to address both disease and quality of life issues facing Veterans and their families. First, leveraging the unique immune environment in skin to achieve antigen-specific tolerance for MS could improve therapeutic efficacy and specificity. Second, MNAs can be applied independently by MS patients with motor deficits, which would improve independence and compliance. Collectively, achieving these goals would elevate Veteran MS patient quality of life.

多发性硬化症（MS）是一种自身免疫性疾病，当免疫系统失去容忍度时会发展 中枢神经系统（CNS）的护套包裹轴突中的髓磷脂。损伤髓鞘可以 导致瘫痪，视力障碍和其他神经系统并发症显着减少MS 病人的生活质量。无法治愈，许多MS疗法也消除了有益的免疫力。一 专门反击自身免疫性的实验策略是生成调节细胞类型的生成 调节性T细胞（Tregs）。这种方法的目的是选择性抑制炎症T和B细胞 过度活跃和通过细胞毒性途径或抗体产生靶向髓磷脂。 抗原特异性的Treg和耐受性可以提供长期持久的自身免疫性 治疗，同时保留受保护的免疫力。促进Tregs的一个新想法是抑制类似收费的接收器 （TLR）信号传导。 TLR调节了调节免疫力并进化以检测到的途径的功率集 病原体相关的分子模式引发炎症并消除危险的病原体。尽管 TLR以其在病原体检测中的作用而闻名，令人惊讶的新研究表明，TLR也过度活跃 在自身免疫期间。为了利用TLR信号，Jewell Lab开发了一个纳米技术平台 调节性TLR配体（GPG）与髓磷脂自抗原（MOG）合成以确保免疫细胞接受两者 促进髓磷脂特异性treg的信号。由于这些纳米材料 - 称为免疫聚电解质 多层（IPEM） - 完全由免疫信号构建，它们以高密度显示线索 调节免疫功能。含有GPG和MOG的IPEM的施用可防止与疾病相关的 MS的实验自身免疫性脑脊髓炎（EAE）小鼠模型的麻痹。 在承诺的同时，这些效果是短暂的，需要多剂量的高剂量IPEM注射。克服 这些挑战，我将开发微针阵列（MNA），以提供由髓磷脂自抗原和 调节性TLR配体直接到皮肤。 MNA是小斑块（〜1 cm直径），多个聚合物针 一百微米的长度，旨在靶向皮肤中的免疫层。皮肤是我们最大的免疫学 器官并包含高密度的免疫电池，并具有不断调查的专门表型 外国病原体的皮肤。最近的证据表明，其中一些免疫细胞具有独特的能力 在体内促进tregs，然后能够抑制常见小鼠模型中的麻痹症状 MS。这些令人兴奋和最新的结果表明，如果耐受性偏向皮肤中的免疫细胞可能是 通过其TLR信号通路利用，它们可以针对耐受性表型。 该VA CDA-2提案的中心假设是通过MNA传递的耐受性IPEM会驱动 皮肤居民抗原呈递细胞中的耐受性表型，将迁移到排水淋巴结（LNS） 并指示T细胞达到限制MS小鼠模型中自身免疫性的Treg表型。测试这个 假设，我设计了三个特定的目的是：1）在MNA上组装iPem涂料并预测其有效性 在体外，2）使用MNA将IPEM传递给皮肤，以测试MS鼠标模型中的效率和特异性，3）测试 Treg在促进iPem涂层的MNA效率和研究皮肤中的耐受性生物标志物中的作用 排出LN。这种方法将提供两个独特的机会来解决疾病和生活质量 退伍军人及其家人面临的问题。首先，利用皮肤中独特的免疫环境实现 MS的抗原特异性耐受性可以提高治疗效率和特异性。第二，MNA可以是 由有运动定义的MS患者独立应用，这将提高独立性和依从性。 共同实现这些目标将提升资深MS患者生活质量。