Harnessing biomaterials to study the link between local lymph node function and systemic tolerance

利用生物材料研究局部淋巴结功能与全身耐受性之间的联系

• 批准号: 10066352
• 负责人: Christopher M Jewell
• 金额: $ 33.1万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-03 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066352
• 关键词: Address; Adjuvant; Adoptive Transfer; Antibodies; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Biocompatible Materials; Biological Assay; Cell physiology; Cells; Cellular Immunity; Chronic; Clinical Trials; Crystallization; Cues; Data; Delayed Hypersensitivity; Deposition; Development; Disease; Disease Progression; Distal; Distant; Dose; Encapsulated; Experimental Autoimmune Encephalomyelitis; FRAP1 gene; Generations; Goals; High Pressure Liquid Chromatography; Histology; Humira; Immune; Immune Tolerance; Immune response; Immune signaling; Immune system; Immunize; Immunocompromised Host; Immunologics; Immunosuppression; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injections; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Kinetics; Knowledge; Link; Location; Lupus; Lymph Node Tissue; Modeling; Monoclonal Antibodies; Multiple Sclerosis; Mus; Muscle; Myelin; Nature; Nervous System Physiology; Neuraxis; Neurodegenerative Disorders; Paralysed; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Phenotype; Play; Polymers; Process; Recovery; Regulatory T-Lymphocyte; Relapse; Reporting; Rest; Rheumatoid Arthritis; Role; Route; Signal Transduction; Sirolimus; Site; Specificity; Spleen; Stains; Structure; System; T cell differentiation; T-Lymphocyte; TNF gene; Testing; Therapeutic; Time; Tissues; Vaccination; Vaccines; Work; adaptive immune response; adaptive immunity; anergy; biodegradable polymer; combat; controlled release; conventional therapy; cytokine; design; disorder control; draining lymph node; improved; in vivo; insight; interest; lymph nodes; migration; mouse model; novel strategies; novel therapeutics; novel vaccines; polarized cell; pre-clinical; prevent; programs; small molecule; theories; tool; trafficking

PROJECT SUMMARY During autoimmune disease, the body incorrectly identifies “self” molecules as foreign and mounts a chronic immune attack. Conventional therapies employ broad immunosuppression, which has provided significant benefits to patients, but can leave these individuals immunocompromised. This limitation, along with the lack of cures for most autoimmune diseases, has sparked intense interest in strategies that could control autoimmunity with vaccine-like specificity, leaving the rest of the immune system intact. Several pre-clinical reports and clinical trials have investigated this theory to combat multiple sclerosis (MS), a neurodegenerative disease in which myelin in the central nervous system (CNS) is attacked by the immune system. An important finding from these studies is that co-administration of myelin peptide and tolerizing immune signals can promote the development of regulatory T cells (TREGS) that ameliorate disease. The polarization of naïve T cells into inflammatory T cells (e.g., TH17) or TREGS is localized to lymph nodes (LNs), the tissues that coordinate adaptive immunity. However, the link between the combinations, concentrations and persistence of immune cues in LNs, and the extent and specificity of systemic tolerance elicited, is not well understood. New knowledge of how signal integration in LNs drives tolerance could help address limitations associated with current therapies, such as incomplete control of disease and non-specific suppression. This proposal will study these fundamental questions in disease using a new platform that combines direct intra-LN (i.LN.) injection with controlled release biomaterial depots. Preliminary data in mice demonstrate that a single dose of depots co-encapsulating two of the most studied signals – myelin peptide and rapamycin, a drug known to promote TREGS – permanently reverses disease-induced paralysis in a model of MS (EAE). These effects occur even when depots are administered at the peak of disease, confirming the power of this system to serve as a tool to locally control the function of one LN, while dissecting the impact on systemic tolerance and at distant sites such as the CNS, spleen, and distal LNs. We hypothesize that this platform will allow previously inaccessible questions to be addressed, including the roles that local signals, combinations, and kinetics within LNs play in programming the nature of tolerance. The specific aims are 1) determine how local signals in LNs polarize T cell function and program systemic tolerance, 2) decipher the impact of signal location, delivery route, and kinetics on T cell polarization, 3) compare the local structure and function of depot-treated LNs to distal LNs, spleen, and CNS, and 4) test if the link between local function and systemic tolerance is generalizable to other self-antigens. This work will generate insight that informs design of new therapies that aim to promote tolerogenic function in an antigen-specific manner during autoimmune diseases such as MS, Type 1 diabetes, and rheumatoid arthritis.

项目摘要 在自身免疫性疾病期间，身体错误地将“自我”分子识别为外国人，并固定慢性 免疫攻击。常规疗法员工广泛的免疫抑制，这提供了重要的 对患者的好处，但可以使这些人免疫受损。这个限制，以及缺乏 大多数自身免疫性疾病的治疗 具有类似疫苗的特异性，使其余的免疫系统完好无损。几个临床前报告和临床 试验研究了这一理论以对抗多发性硬化症（MS），这是一种神经退行性疾病，其中 中枢神经系统（CNS）中的髓磷脂受到免疫系统的攻击。这些重要发现 研究是，髓磷脂肽的共同给药和耐受的免疫信号可以促进发展 改善疾病的调节T细胞（Tregs）。幼稚的T细胞极化为炎性T细胞 （例如，Th17）或Tregs定位于淋巴结（LNS），该组织是协调适应性免疫学的组织。然而， LNS中免疫线索的组合，浓度和持久性之间的联系以及程度和 引起的全身耐受性的特异性尚不清楚。关于LNS中信号积分的新知识 驱动容忍度可以帮助解决与当前疗法相关的限制，例如对 疾病和非特异性抑制。该建议将使用 新平台将直接内部（I.Ln.）注入与受控释放的生物材料沉积物相结合。初步的 小鼠中的数据表明，单剂量的沉积物共同包裹了两个最固定的信号 - 髓磷脂 肽和雷帕霉素是一种已知促进Tregs的药物 - 永久逆转疾病诱导的麻痹 MS（EAE）的模型。即使在疾病峰值处进行沉积物，这些影响也会发生 该系统作为局部控制一个LN功能的工具的力量，同时剖析撞击 在全身耐受性和远处的位点，例如中枢神经系统，脾和远端LN。我们假设这是 平台将允许以前无法访问的问题解决，包括本地的角色 LNS中的信号，组合和动力学在编程宽容的性质时发挥作用。具体 目的是1）确定LNS中的局部信号如何极化T细胞功能和程序全身耐受性，2） 解释信号位置，输送路线和动力学对T细胞极化的影响，3）比较局部 仓库处理的LN与远端LN，脾和CNS的结构和功能，以及4）测试如果局部之间的联系 功能和系统耐受性可推广到其他自我抗原。这项工作将产生见解 为旨在以抗原特异性方式促进耐受性功能的新疗法的设计。 自身免疫性疾病，例如MS，1型糖尿病和类风湿关节炎。