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

项目摘要 在自身免疫性疾病期间，身体错误地将“自我”分子识别为外来分子，并产生慢性炎症。 免疫攻击常规疗法采用广泛的免疫抑制，这提供了显著的 对患者有益，但可能使这些人免疫功能低下。这种限制，沿着缺乏 治疗大多数自身免疫性疾病的方法，引发了人们对控制自身免疫性疾病的强烈兴趣。 具有类似疫苗的特异性，使免疫系统的其余部分保持完整。几份临床前报告和临床 试验研究了这一理论，以对抗多发性硬化症（MS），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。一个重要的发现是， 研究表明，共同给予髓鞘肽和耐受性免疫信号可以促进发展， 调节性T细胞（Tregs）可以改善疾病。幼稚T细胞向炎性T细胞的极化 (e.g., TH 17）或TREGS定位于淋巴结（LN），即协调适应性免疫的组织。但是，在这方面， LN中免疫信号的组合、浓度和持久性之间的联系，以及免疫信号的程度和 引起的全身耐受的特异性还不清楚。LNs中信号集成的新知识 驱动器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 疾病和非特异性抑制。这项建议将研究这些基本问题的疾病使用一个 新平台结合了直接LN内（i. LN.）注射用控释生物材料贮库。初步 小鼠中的数据表明，单剂量的贮库共包封了两种研究最多的信号-髓磷脂 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（EAE）模型。即使在疾病高峰期给予长效制剂，这些作用也会发生，证实 这个系统的力量，作为一种工具，以本地控制一个LN的功能，同时解剖的影响， 对全身耐受性和远端部位（如CNS、脾脏和远端LN）的影响。我们假设这 平台将允许解决以前无法解决的问题，包括当地 LN内的信号、组合和动力学在编程耐受性的性质中起作用。具体 目的是1）确定LNs中的局部信号如何刺激T细胞功能和程序系统耐受性，2） 破译信号位置、递送途径和动力学对T细胞极化的影响，3）比较局部 贮库处理的LN与远端LN、脾脏和CNS的结构和功能，以及4）测试局部LN与远端LN、脾脏和CNS之间的联系， 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， 为设计新的治疗提供了信息，这些治疗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MS、1型糖尿病和类风湿性关节炎。

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.