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: 10456094
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456094
• 关键词: Address; Affect; Allergens; Allergy Shot; Animal Model; Antibodies; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune; Autoimmune Diseases; 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; antagonist; autoimmune pathogenesis; base; career; career development; cell type; curative treatments; cytotoxic; density; design; draining lymph node; effective therapy; efficacy testing; experience; extracellular; immune function; 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，当免疫系统失去对多发性硬化症的耐受性时， 包裹中枢神经系统（CNS）轴突的鞘中的髓鞘。髓鞘的损伤 导致瘫痪、视力障碍和其他神经系统并发症，显著减少MS 患者的生活质量。没有治愈方法，许多MS疗法也会消除有益的免疫力。一 特异性对抗自身免疫的实验策略是产生调节细胞类型，例如 调节性T细胞（Tregs）。这些方法的目的是选择性地抑制炎性T和B细胞 其分别通过细胞毒性途径或抗体产生而过度活跃并靶向髓鞘。 抗原特异性TREGS的产生和对抗自身免疫的耐受性可以提供持久的免疫应答。 治疗，同时保持保护性免疫力。抑制Toll样受体是促进TREGS表达的新思路 (TLR)发信号。TLR调节一系列调节免疫力的途径，并进化为检测免疫力。 病原体相关的分子模式，以启动炎症和消除危险的病原体。而 TLR在病原体检测中的作用是众所周知的，令人惊讶的新研究表明TLR也过度活跃 在自身免疫中。为了利用TLR信号，朱厄尔实验室开发了一个纳米技术平台， 调节性TLR配体（GpG）与髓磷脂自身抗原（MOG）一起合成，以确保免疫细胞同时接受 促进髓鞘特异性TREGS的信号。由于这些纳米材料-称为免疫球蛋白 多层膜（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。施用含有GpG和MOG的iPEM可预防疾病相关的免疫缺陷。 MS的实验性自身免疫性脑脊髓炎（EAE）小鼠模型中的瘫痪。 虽然有希望，但这些影响是短暂的，需要多次高剂量的iPEM注射。克服 为了应对这些挑战，我将开发微针阵列（MNAs）来递送由髓鞘自身抗原构建的iPEM， 调节性TLR配体直接与皮肤接触。MNAs是小块（直径约1 cm）使用聚合物针， 长达100微米，专门针对皮肤中免疫力丰富的层。皮肤是我们最大的免疫系统 器官，并含有高密度的免疫细胞，具有不断调查的专门表型， 寻找外来病原体最近的证据表明，这些免疫细胞中的一些具有独特的能力， 在体内促进TREGS，然后能够在普通小鼠模型中抑制瘫痪症状 这些令人兴奋的和最近的结果表明，如果皮肤中的耐受性偏向免疫细胞可以 通过其TLR信号传导途径，它们可被导向致耐受性表型。 该VA CDA-2提案的中心假设是，通过MNAs递送的致耐受性iPEM将驱动 将迁移至引流淋巴结（LN）的皮肤驻留抗原呈递细胞中的致耐受性表型 并指导T细胞朝向抑制MS小鼠模型中自身免疫的TREG表型。 假设，我设计了三个具体的目标：1）在MNA上组装iPEM涂层并预测其功效 在体外，2）使用MNAs将iPEM递送至皮肤以测试MS小鼠模型中功效和特异性，和3）测试 TREGS在促进iPEM涂覆的MNA的功效和研究皮肤中的耐受性生物标志物中的作用- 排出淋巴结。这一方法将提供两个独特的机会来解决疾病和生活质量问题 退伍军人及其家属面临的问题。首先，利用皮肤中独特的免疫环境， 对MS的抗原特异性耐受可提高治疗效果和特异性。第二，多边核方案可以 运动缺陷的MS患者独立应用，这将提高独立性和依从性。 总的来说，实现这些目标将提高退伍军人MS患者的生活质量。