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.

项目总结 在自身免疫性疾病期间，身体错误地将“自我”分子识别为外源分子，从而导致慢性 免疫攻击。传统疗法使用广泛的免疫抑制，这提供了显著的 给患者带来好处，但可能会使这些人的免疫功能受损。这一限制，以及缺乏 治疗大多数自身免疫性疾病的药物，引发了人们对控制自身免疫的策略的浓厚兴趣 具有疫苗般的特异性，保持免疫系统的其余部分完好无损。几份临床前报告和临床报告 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， 中枢神经系统(CNS)中的髓鞘受到免疫系统的攻击。来自这些的一个重要发现 研究表明，联合应用髓鞘多肽和耐受免疫信号可以促进疾病的发展。 可以缓解疾病的调节性T细胞(Treg)。幼稚T细胞向炎性T细胞的极化 (例如，TH17)或Tregs定位于淋巴结(LNS)，即协调适应性免疫的组织。然而， LNS中免疫信号的组合、浓度和持久性之间的联系，以及程度和 引起全身耐受性的特异性，还不是很清楚。关于LNS中的信号整合的新知识 驾驶耐受性可以帮助解决与当前治疗相关的限制，例如不完全控制 疾病和非特异性抑制。这项提案将研究疾病中的这些基本问题， 结合直接内部LN(I.LN)的新平台注射用控释生物材料仓库。初步 在小鼠身上的数据表明，单剂量的仓库共同包裹了两个研究最多的信号-髓鞘 多肽和雷帕霉素，一种已知的促进Tregs的药物-永久逆转疾病引起的瘫痪 MS模型(EAE)。即使在疾病高峰期给药，这些影响也会发生，证实 这个系统作为一个工具来局部控制一个LN的功能，同时剖析其影响的能力 全身耐受性和远端部位，如中枢、脾和远端淋巴结。我们假设这是 平台将允许解决以前无法访问的问题，包括本地 LNS中的信号、组合和动力学在规划耐受性的本质上起着作用。具体的 目标是1)确定局部信号如何极化T细胞功能和编程系统耐受性，2) 破译信号位置、传递途径和动力学对T细胞极化的影响，3)比较局部 4)检测局部淋巴结与远端淋巴结、脾和中枢神经系统的联系。 功能和系统耐受性可推广到其他自身抗原。这项工作将产生洞察力 告知设计的新疗法，旨在以抗原特异性的方式促进耐受功能 自身免疫性疾病，如多发性硬化症、1型糖尿病和类风湿关节炎。