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: 10557140
• 负责人: Christopher M Jewell
• 金额: $ 55.47万
• 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/10557140
• 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; Central Nervous System; 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; Link; Magnetic Resonance Imaging; Maintenance; Memory; Modeling; Monoclonal Antibodies; Multiple Sclerosis; Mus; Myelin; Nanotechnology; Nature; Nerve Degeneration; Nervous System Physiology; 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; particle; polarized cell; preclinical study; prevent; programs; remyelination; response; side effect; therapeutic target; transdifferentiation

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.

在自身免疫过程中，身体错误地将“自我”分子识别为外来分子。在 中枢神经系统（CNS）中髓鞘的多发性硬化（MS）发作导致神经变性。现有 MS的治疗方法从免疫抑制剂到较新的单克隆抗体，但即使后者也没有 区分健康细胞和显示抗体靶标的自身反应性细胞。因此，虽然有益， 这些疗法不能治愈，会导致免疫功能低下的副作用，并且需要终生的依从性。这些 这些局限性促使人们努力用疫苗样特异性控制自身免疫，剩下的就是免疫学。 免疫系统完好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 试验是共同传递髓鞘肽和耐受性免疫信号，以促进群体，如调节 T细胞极化成炎性T细胞（例如，TH 17）或TREG是局部的 淋巴结（LN），协调免疫的组织。新的研究还表明，TREG可以采用记忆 保持宽容的功能。此外，在适当的组织小生境中，炎性TH 17细胞可以 转分化为TREG。同样地，B细胞以几种方式与MS相关，包括产生致病性的 髓鞘特异性抗体，以及作为能够采用调节功能的治疗靶标。LN在以下方面发挥关键作用： 这些过程，指导动态基质组织，以促进和调节细胞相互作用和调节 控制T和B细胞在（自身）炎症和耐受功能之间极化的信号。从 从治疗的角度来看，使用常规的递送技术（例如，系统性 注射/输注），甚至生物材料方法（如靶向纳米颗粒）也难以建立 注射后持久的组织环境。然而，理解和控制集成的能力 LN微环境中的信号可以实现有效的髓鞘特异性免疫治疗， 免疫抑制我们建议使用一个平台来解决这个目标，该平台将直接的LN内（i. LN.）注射 具有控释生物材料库。我们已经证明了扩散限制聚合物仓库太大 在注入浓缩物后从LNG中排出，并将仓库装载的货物保留在LNG中。使用装有 髓磷脂肽和雷帕霉素-一种免疫调节药物，我们已经证明了在峰值时的单一治疗。 在MS的临床前模型中，疾病逆转瘫痪超过90天。i. LN未达到疗效。 可溶性货物的注入，或在通过传统途径注入仓库期间。我们将利用这个跨学科的 了解局部控释如何促进致耐受性基质LN的免疫工程方法 环境以及这些作用如何诱导和维持T细胞中针对髓鞘的持久耐受功能， B细胞。目的是：1）定义疗效的稳健性和对以下疾病的基础治疗效果： 2）显示耐受性的持久性是抗原依赖性的并且由TREG维持驱动， 塑性; 3）显示i. LN.库破坏生发中心，减少自身抗体，并诱导耐受性B细胞。