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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要在自身免疫性疾病期间，身体错误地将“自身”分子识别为外来分子，并形成慢性传统疗法采用广泛的免疫抑制，这提供了显着的效果。对患者有好处，但可能会使这些人免疫功能低下，并且缺乏免疫功能。治愈大多数自身免疫性疾病，引发了人们对控制自身免疫策略的浓厚兴趣具有类似疫苗的特异性，使免疫系统的其余部分保持完整。一些临床前报告和临床。试验研究了这一理论来对抗多发性硬化症 (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，这是一项重要的发现。研究表明，髓磷脂肽和耐受性免疫信号的共同给药可以促进发育调节性 T 细胞 (TREGS) 可以改善疾病，将幼稚 T 细胞极化为炎症 T 细胞。（例如，TH17）或 TREGS 位于淋巴结（LN），即协调适应性免疫的组织。 LN 中免疫信号的组合、浓度和持久性之间的联系，以及程度和系统耐受性的特异性尚未得到很好的理解。驱动耐受性可以帮助解决与当前疗法相关的局限性，例如不完全控制该提案将使用以下方法研究疾病中的这些基本问题。新平台将直接液氮内 (i.LN.) 注射与控释生物材料储库相结合。小鼠数据表明，单剂量的储库共同封装了两种研究最多的信号——髓磷脂肽和雷帕霉素（一种已知可促进 TREGS 的药物）可永久逆转疾病引起的麻痹 MS (EAE) 模型即使在疾病高峰期施用长效制剂也会发生这些效应，这证实了这一点。该系统作为一种工具的强大功能可以在本地控制一个逻辑网络的功能，同时剖析其影响我们发现了这一点。平台将允许解决以前无法访问的问题，包括本地人员的角色 LN 内的信号、组合和动力学在编程耐受性的本质中发挥着作用。目标是 1) 确定 LN 中的局部信号如何极化 T 细胞功能并编程系统耐受性，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) 比较局部长效处理的淋巴结与远端淋巴结、脾脏和中枢神经系统的结构和功能，以及 4) 测试局部淋巴结之间是否存在联系功能和系统耐受性可推广到其他自身抗原。这项工作将产生这样的见解。为新疗法的设计提供信息，旨在以抗原特异性方式促进耐受性功能自身免疫性疾病，如多发性硬化症、1 型糖尿病和类风湿性关节炎。