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，当免疫系统失去耐受性时就会发生。 髓磷脂存在于包裹中枢神经系统（CNS）轴突的鞘中。髓鞘损伤可 导致瘫痪、视力障碍和其他神经系统并发症，从而显着减少多发性硬化症 患者的生活质量。目前尚无治愈方法，许多多发性硬化症疗法也会消除有益的免疫力。一 专门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)。此类方法的目标是选择性抑制炎症 T 细胞和 B 细胞 过度活跃并分别通过细胞毒性途径或抗体生成靶向髓磷脂。 产生抗原特异性 TREGS 和抵抗自身免疫的耐受性可以提供持久的效果 治疗，同时保留保护性免疫力。促进TREGS的新思路是抑制Toll样受体 （TLR）信号。 TLR 调节一组强大的途径来调节免疫并进化为检测 病原体相关的分子模式，以引发炎症并消除危险的病原体。尽管 TLR 因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 自身免疫期间。为了利用 TLR 信号传导，Jewell 实验室开发了一个纳米技术平台，其中 调节性 TLR 配体 (GpG) 与髓磷脂自身抗原 (MOG) 合成，以确保免疫细胞同时接收 促进髓磷脂特异性 TREGS 的信号。由于这些纳米材料被称为免疫聚电解质 多层膜（iPEM）——完全由免疫信号构建，它们以高密度有效地显示信号 调节免疫功能。施用含有 GpG 和 MOG 的 iPEM 可预防疾病相关的疾病 实验性自身免疫性脑脊髓炎（EAE）小鼠 MS 模型中的瘫痪。 虽然很有希望，但这些效果是短暂的，并且需要多次、高剂量的 iPEM 注射。克服 这些挑战，我将开发微针阵列（MNA）来提供由髓磷脂自身抗原构建的 iPEM 调节TLR配体直接作用于皮肤。 MNA 是小片（直径约 1 厘米），带有数个聚合物针 长度为数百微米，旨在针对皮肤中富含免疫的层。皮肤是我们最大的免疫系统 器官，含有高密度的免疫细胞，具有不断调查的特殊表型 皮肤是否有外来病原体。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，从而能够抑制常见小鼠模型中的瘫痪症状 女士。这些令人兴奋的最新结果表明，如果皮肤中存在耐受性偏差的免疫细胞可以 通过 TLR 信号通路的利用，它们可能会产生耐受性表型。 VA CDA-2 提案的中心假设是，通过 MNA 传递的耐受性 iPEM 将驱动 皮肤驻留抗原呈递细胞中的耐受性表型将迁移至引流淋巴结 (LN) 并指导 T 细胞形成 TREG 表型，从而抑制多发性硬化症小鼠模型中的自身免疫。为了测试这个 假设，我设计了三个具体目标：1）在 MNA 上组装 iPEM 涂层并预测其功效 体外，2) 使用 MNA 将 iPEM 递送至皮肤，以测试多发性硬化症小鼠模型的功效和特异性，以及 3) 测试 TREGS 在促进 iPEM 涂层 MNA 功效中的作用并研究皮肤耐受性生物标志物 排空 LN。这种方法将为解决疾病和生活质量提供两个独特的机会 退伍军人及其家人面临的问题。首先，利用皮肤独特的免疫环境来实现 对多发性硬化症的抗原特异性耐受可以提高治疗效果和特异性。其次，MNA 可以 由患有运动缺陷的多发性硬化症患者独立应用，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多发性硬化症患者的生活质量。