Developing controlled release immune complexes to treat multiple sclerosis

开发控释免疫复合物来治疗多发性硬化症

• 批准号: 10679346
• 负责人: Marian Adriana Ackun-Farmmer
• 金额: $ 7.18万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-05 至 2025-03-04
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679346
• 关键词: Adaptive Immune System; Address; Amines; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; Biocompatible Materials; Cells; Central Nervous System; Characteristics; Charge; Cues; Data; Dendritic Cells; Disease; Disease Progression; Drug Delivery Systems; Drug Modelings; Electrostatics; Environment; Exhibits; FRAP1 gene; Gene Expression; Goals; High Pressure Liquid Chromatography; Immune; Immune Targeting; Immune Tolerance; Immune response; Immune signaling; Immune system; Immunocompromised Host; Immunohistochemistry; Immunology; Immunosuppression; Immunosuppressive Agents; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Innate Immune System; Insulin-Dependent Diabetes Mellitus; Investigational Therapies; Investments; Kinetics; Lead; Libraries; Link; Lipids; Lymphocyte; Macrophage; Measures; Modeling; Molecular; Morphology; Multiple Sclerosis; Myelin; Myelin Sheath; Natural Immunity; Natural Killer Cells; Neurologic; Neurons; Oligonucleotides; Pathogen detection; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Play; Polymers; Predisposition; Property; Quality of life; Reaction; Receptor Signaling; Regulatory T-Lymphocyte; Reporter; Research; Rheumatoid Arthritis; Role; Severities; Signal Pathway; Signal Transduction; Sirolimus; Structure; Surface; T-Lymphocyte; Techniques; Testing; Time; Toll-like receptors; Training; United States National Institutes of Health; Work; adaptive immunity; antagonist; blood-brain barrier crossing; capsule; career; career development; combat; compliance behavior; controlled release; crosslink; cytotoxic CD8 T cells; density; design; draining lymph node; immune modulating agents; immunoregulation; improved; insight; interest; mouse model; multiple sclerosis patient; multiple sclerosis treatment; new technology; novel therapeutics; polarized cell; post-doctoral training; pre-clinical; receptor function; response; secondary lymphoid organ; self assembly; skills; trafficking; treatment strategy; uptake

In autoimmune diseases, the immune system mistakenly identifies “self”-molecules/antigens as foreign, resulting in an orchestrated attack of the body. In multiple sclerosis (MS), the immune system attack of the protective neuronal sheath – myelin - results in debilitating neurological impairment and poor quality of life. Current MS therapies are non-curative, require life-long compliance, and exhibit non-specific effects that increase patient susceptibility to infection. To circumvent MS treatment challenges, emerging therapies seek to direct myelin self-antigens (MOG) and immunomodulatory cues to redirect the immune response. Toll-like receptors, which detect pathogen-associated patterns on antigen presenting cells (APCs) are involved in MS. Recently, TLR9 antagonist, GpG has been shown to downregulate APC activation while promoting TREGS. Similarly, Rapamycin (Rapa), an immunosuppressant drug has garnered interest because it inhibits major pathways and promotes regulatory T cells (TREGS). Since coordination between the innate and adaptive immune system in MS drives disease, the proposed study will target these pathways simultaneously to promote antigen-specific immune tolerance in MS. We have previously developed self-assembled carriers built entirely from immune cues – termed immune polyelectrolyte multilayers (iPEMs) that enable combinatory delivery of multiple cues, controlled loading, and high cargo densities. iPEMs assembled using MOG and GpG reduce TLR9 signaling while promoting TREGS but show moderate efficacy in preclinical MS models. Since TREGS play a crucial role in moderating immune responses, the proposed work aims to load Rapa in the core of MOG/GpG iPEMs to enable co-delivery of MOG to induce antigen-specific immune responses, GpG to downregulate APC activity, and incorporate cross-links to control Rapa delivery to induce TREGS. In Aim 1, the hypothesis that cross-link density in MOG/GpG (Rapa) iPEMs is correlated to release intervals will be tested. This will be accomplished by generating a library of iPEMs from combinations of MOG, control antigen (ANT-CTRL), GpG, inactive control ODN (ODNCTRL), as well as Rapa with distinct cross-linking conditions to control release. In Aim 2, cross-linked iPEM release kinetics will be linked to APC activation and T cell polarization. In Aim 3, the efficacy of crosslinked iPEMs in preclinical MS models will be assessed to test the hypothesis that dual-targeting of innate and adaptive immunity is necessary to drive antigen-specific TREGS in MS. These studies will show that modulating both innate and adaptive immunity is necessary to generate robust antigen-specific responses in MS and will provide insight that informs the design of new therapies to treat MS and other autoimmune diseases. At the same time, new skills and techniques will be acquired throughout the course of the studies to propel the goal of the trainee to lead an academic research lab focused on developing immunomodulatory drug delivery systems after postdoctoral training.

在自身免疫性疾病中，免疫系统错误地将“自我” - 分子/抗原识别为外国，由此产生 在精心策划的身体攻击中。在多发性硬化症（MS）中，受保护神经元鞘的免疫系统攻击 - 髓磷脂 - 导致神经系统障碍和生活质量差。当前的MS疗法是非耐药的， 需要终身依从性，并表现出非特异性影响，以增加患者对感染的敏感性。绕开 MS治疗挑战，新兴疗法试图指导髓磷脂自我抗原（MOG）和免疫调节提示 重定向免疫响应。 Toll样接收器，该接收器检测抗原呈现细胞上与病原体相关的模式 （APC）参与MS。最近，TLR9拮抗剂GPG已显示出下调APC激活，而 促进tregs。同样，雷帕霉素（Rapa），一种免疫抑制剂药物也引起了兴趣，因为它抑制了主要 途径并促进调节性T细胞（Tregs）。由于先天和适应性免疫系统之间的协调 MS Drive疾病，拟议的研究将仅针对这些途径，只是为了促进抗原特异性免疫 MS的公差。 我们以前已经开发了完全由免疫线索构建的自组装的载体 - 称为免疫 聚电解质多层（IPEMS），可实现多个提示，受控载荷和高货物的组合交付 密度。使用MOG和GPG组装的IPEM在促进Treg时降低TLR9信号传导，但显示中等 临床前MS模型的功效。由于Tregs在调节免疫反应中起着至关重要的作用，因此拟议的工作目标 将RAPA加载到MOG/GPG iPEM的核心中，以使MOG的共同传递诱导抗原特异性免疫反应， GPG下调APC活性，并结合交联以控制RAPA递送以诱导Treg。在AIM 1中 假设将测试MOG/GPG（RAPA）IPEM中的交联密度与释放间隔相关。这将是 通过从MOG，对照抗原（ANT-CTRL），GPG，不活动的组合中生成iPEM库来完成 控制ODN（ODNCTRL）以及具有独特的交联条件的RAPA控制释放。在AIM 2，交联 IPEM释放动力学将与APC激活和T细胞极化有关。在AIM 3中，交联的IPEM的效率 将评估临床前MS模型，以检验以下假设，即先天性和适应性免疫性史的双重目标 在MS中驱动抗原特异性Treg所必需的。这些研究将表明，调节先天和适应性免疫学 对于在MS中产生强大的抗原响应是必要的，并将提供洞察力，以告知新的设计 治疗MS和其他自身免疫性疾病的疗法。同时，将获得新的技能和技术 通过整个研究，推动学员的目标领导一个专注于发展的学术研究实验室 博士后培训后的免疫调节药物输送系统。