Defining the induction and maintenance of myelin-specific tolerance in T cells and B cells using local lymph node depots

使用局部淋巴结库定义 T 细胞和 B 细胞中髓磷脂特异性耐受的诱导和维持

• 批准号: 10462052
• 负责人: Christopher M Jewell
• 金额: $ 56.83万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462052
• 关键词: Address; Adopted; Adoptive Transfer; Aftercare; Antibodies; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Biocompatible Materials; Cell Communication; Cell Differentiation process; Cell physiology; Cells; Chronic; Clinical; Cues; Data; Deposition; Diffusion; Disease; Distant; Engineering; Environment; Equilibrium; Experimental Autoimmune Encephalomyelitis; Face; Family; Goals; Health Care Costs; Histology; Human; Humira; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunocompromised Host; Immunologics; Immunology; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Infiltration; Inflammation; Inflammatory; Infusion procedures; Injections; Interleukin-10; Kinetics; Knockout Mice; Knowledge; Life; Link; Lymph Node Tissue; Magnetic Resonance Imaging; Maintenance; Memory; Modeling; Monoclonal Antibodies; Multiple Sclerosis; Mus; Myelin; Nanotechnology; Nature; Nerve Degeneration; Nervous System Physiology; Neuraxis; Paralysed; Pathogenicity; Patients; Peptides; Pharmaceutical Preparations; Play; Polymers; Population; Pre-Clinical Model; Preclinical Testing; Process; Production; Regulatory T-Lymphocyte; Reporter; Rest; Route; Signal Transduction; Sirolimus; Site; Societies; Specificity; Structure; Structure of germinal center of lymph node; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Transgenic Organisms; Vaccines; Vision; Work; biodegradable polymer; combat; controlled release; cytokine; design; draining lymph node; efficacy testing; immune function; immunoengineering; immunoregulation; injection/infusion; lymph node microenvironment; lymph nodes; migration; multiple sclerosis treatment; nanoparticle; neuroinflammation; novel therapeutics; polarized cell; preclinical study; prevent; programs; remyelination; response; side effect; therapeutic target

PROJECT SUMMARY: During autoimmunity, the body incorrectly identifies “self” molecules as foreign. In multiple sclerosis (MS) attack of myelin in the central nervous system (CNS) leads to neurodegeneration. Existing therapies for MS range from immunosuppressants to newer monoclonal antibodies, but even the latter do not distinguish between healthy and self-reactive cells displaying the antibody target. Thus, while beneficial, existing therapies are not curative, cause immunocompromising side effects, and require life-long compliance. These limitations have motivated efforts to control autoimmunity with vaccine-like specificity, leaving the rest of the immune system intact. One such antigen-specific tolerance strategy being studied pre-clinically and in human trials is co-delivery of myelin peptide and tolerizing immune signals to promote populations, such as regulatory T cells (TREG) that combat MS. The polarization of T cells into inflammatory T cells (e.g., TH17) or TREG is localized to lymph nodes (LNs), tissues that coordinate immunity. New studies also reveal TREG can adopt memory functions to maintain tolerance. Further, in appropriate tissue niches, inflammatory TH17 cells can transdifferentiate to TREG. Likewise, B cells are relevant to MS in several ways, including producing pathogenic myelin-specific antibodies, and as therapeutic targets able to adopt regulatory function. LNs play key roles in these processes, directing dynamic stromal organization to promote and regulate cell interaction and modulatory cues that control T and B cell polarization between (auto)inflammatory and tolerance functions. From a therapeutic view, controlling this niche is challenging using conventional delivery technologies (e.g., systemic injections/infusions), and even biomaterial approaches such as targeted nanoparticles face difficulty establishing durable tissue environments after injection. However, the ability to understand and control the integration of signals in the LN microenvironment could enable potent, myelin-specific immunotherapies that avoid immunosuppression. We propose tackling this goal using a platform that combines direct intra-LN (i.LN.) injection with controlled release biomaterial depots. We have shown diffusion-restricted polymer depots that are too large to drain from LNs after injection concentrate and retain depot-loaded cargo in LNs. Using depots loaded with myelin peptide and rapamycin - an immunoregulatory drug, we have shown a single treatment at the peak of disease in a pre-clinical model of MS reverses paralysis for over 90 days. Efficacy is not achieved with i.LN. injection of soluble cargo, or during injection of depots via traditional routes. We will use this interdisciplinary immune engineering approach to understand how local controlled release promotes a tolerogenic stromal LN environment and how these effects induce and maintain long-lasting tolerizing function against myelin in T and B cells. The aims are 1) Define the robustness of efficacy and the underpinning therapeutic effects on neuroinflammation, 2) Show the durability of tolerance is antigen-dependent and driven by TREG maintenance & plasticity, 3) Show i.LN. depots disrupt germinal centers, reduce auto-antibodies, & induce tolerogenic B cells.

项目摘要：在自身免疫期间，身体错误地将“自我”分子识别为外国分子。在 髓磷脂在中枢神经系统（CNS）中的多发性硬化症（MS）导致神经变性。现存的 MS的疗法范围从免疫抑制剂到新的单克隆抗体，但即使是后者也不 显示抗体靶标的健康和自我反应性细胞之间的区别。那虽然有益，但现有 疗法无法治愈，会导致免疫促进副作用，需要终身依从性。这些 限制已经成熟地以类似疫苗的特异性来控制自身免疫，其余的 免疫系统完整。一种这样的抗原特异性耐受性策略是在人工界和人类中研究的 试验是髓磷脂肽的共同交付和耐受的免疫信号以促进人群，例如调节 打击MS的T细胞（Treg）。 T细胞在炎性T细胞中的极化（例如Th17）或Treg局部 至淋巴结（LNS），是协调免疫力的组织。新研究还表明，Treg可以采用记忆 保持容忍度的功能。此外，在适当的组织壁ches中，炎性Th17细胞可以 转变为Treg。同样，B细胞以多种方式与MS有关，包括产生致病性 髓磷脂特异性抗体，并且作为治疗靶标可以采用调节功能。 LNS在 这些过程指导动态基质组织促进和调节细胞相互作用和调节 （自动）炎症和耐受功能之间控制T和B细胞极化的提示。来自 治疗视图，控制这个利基市场的挑战是使用常规交付技术（例如，系统性的 注射/输液），甚至是靶向纳米颗粒等生物材料方法都面临困难 注射后耐用的组织环境。但是，理解和控制集成的能力 LN微环境中的信号可以使潜在的髓磷脂特异性免疫疗法避免 免疫抑制。我们建议使用将直接内部内部（I.Ln）注入的平台解决此目标 具有受控的释放生物材料沉积物。我们已经显示出太大的扩散限制聚合物沉积物 注射浓缩物并将其保留在LNS中的沉积货物后排出LN。使用加载的沉积物 髓粉和雷帕霉素 - 一种免疫调节药物，我们在峰值上显示了一次治疗 在MS的临床前模型中，疾病逆转了瘫痪超过90天。 I.Ln无法实现功效。 注入固体货物，或通过传统路线注入沉积物。我们将使用这个跨学科 免疫工程方法了解局部受控释放如何促进耐受性基质LN 环境以及这些影响如何影响和维持对T和 B细胞。目的是1）定义效率的鲁棒性和基础治疗对 神经炎症，2）表明耐受性的耐用性是抗原依赖性的，并且由Treg维护和驱动 塑性，3）显示I.Ln。沉积物破坏生发中心，减少自身抗体并诱导耐受性B细胞。