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：在自身免疫过程中，身体错误地将“自身”分子识别为外来分子。 中枢神经系统（CNS）中髓磷脂的多发性硬化症（MS）攻击会导致现有的神经变性。 多发性硬化症的治疗方法从免疫抑制剂到更新的单克隆抗体，但即使是后者也没有 区分展示抗体靶标的健康细胞和自身反应细胞因此，虽然有益，但现有的。 疗法没有疗效，会导致免疫功能低下的副作用，并且需要终生依从。 局限性促使人们努力以类似疫苗的特异性来控制自身免疫，而剩下的 免疫系统完好无损，一种这样的抗原特异性耐受策略正在临床前和人体中进行研究。 试验是共同递送髓磷脂肽和耐受免疫信号以促进群体，例如监管 对抗多发性硬化症的 T 细胞 (TREG) 极化为炎症性 T 细胞（例如 TH17）或 TREG 是局部的。 新的研究还表明，调节免疫的组织淋巴结（LN）可以采用记忆。 此外，在适当的组织环境中，炎症性 TH17 细胞可以发挥维持耐受性的功能。 类似地，B 细胞在多种方面与 MS 相关，包括产生致病性。 髓磷脂特异性抗体，并且作为能够采用 LN 调节功能的治疗靶点，发挥着关键作用。 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 控制（自身）炎症和耐受功能之间 T 细胞和 B 细胞极化的线索。 从治疗的角度来看，使用传统的递送技术（例如全身给药）控制这一利基具有挑战性 注射/输注），甚至生物材料方法（例如靶向纳米粒子）也面临建立困难 然而，注射后持久的组织环境具有理解和控制整合的能力。 LN 微环境中的信号可以实现有效的、髓磷脂特异性的免疫疗法，从而避免 我们建议使用一个结合直接腹腔内（i.LN.）注射的平台来实现这一目标。 我们已经展示了太大的扩散限制聚合物储存库。 注入后从液氮中排出，浓缩并保留液氮中的仓库装载的货物。 髓磷脂肽和雷帕霉素 - 一种免疫调节药物，我们已经展示了在高峰期的单一治疗 在多发性硬化症临床前模型中，i.LN 未达到逆转麻痹的效果。 可溶货物的注入，或通过传统路线注入仓库期间，我们将使用这种跨学科的方法。 免疫工程方法了解局部控制释放如何促进耐受性基质 LN 环境以及这些影响如何诱导和维持 T 和 T 中髓磷脂的持久耐受功能 B 细胞的目标是 1) 确定疗效的稳健性和基础治疗效果。 神经炎症，2) 显示耐受的持久性是抗原依赖性的，并由 TREG 维持驱动 & 可塑性，3) 显示 i.LN 破坏生发中心，减少自身抗体，并诱导耐受性 B 细胞。