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“自身”分子/抗原识别为外来分子，从而导致 在多发性硬化症 (MS) 中，免疫系统攻击保护性神经元鞘。 – 髓鞘质 - 导致神经系统衰弱和生活质量下降，目前的多发性硬化症治疗方法是非治愈性的。 需要终生依从，并表现出非特异性作用，增加患者对感染的易感性。 MS 治疗面临挑战，新兴疗法寻求将髓磷脂自身抗原 (MOG) 和免疫调节信号引导至 重定向免疫反应，检测抗原呈递细胞上的病原体相关模式。 最近，TLR9 拮抗剂 GpG 已被证明可以下调 APC 的激活。 同样，雷帕霉素（Rapa）这种免疫抑制剂也引起了人们的兴趣，因为它能抑制主要的免疫反应。 途径并促进调节性 T 细胞 (TREGS)，因为先天性免疫系统和适应性免疫系统之间的协调。 MS 驱动疾病，拟议的研究将同时针对这些途径以促进抗原特异性免疫 MS 的耐受性。 我们之前开发了完全由免疫信号构建的自组装载体——称为免疫 聚电解质多层膜（iPEM）能够组合输送多种信号、受控装载和高载量 使用 MOG 和 GpG 组装的 iPEM 会减少 TLR9 信号传导，同时促进 TREGS，但表现出中等强度。 由于 TREGS 在调节免疫反应中发挥着至关重要的作用，因此拟议的工作目标是在临床前 MS 模型中发挥作用。 将 Rapa 加载到 MOG/GpG iPEM 的核心，以实现 MOG 的共同传递，从而诱导抗原特异性免疫反应， GpG 下调 APC 活性，并结合交联来控制 Rapa 递送以诱导 TREGS。 MOG/GpG (Rapa) iPEM 中的交联密度与释放间隔相关的假设将得到测试。 通过从 MOG、对照抗原 (ANT-CTRL)、GpG、无活性组合生成 iPEM 文库来完成 控制 ODN (ODNCTRL) 以及具有不同交联条件的 Rapa，以控制释放。 在目标 2 中，交联。 iPEM 释放动力学将与 APC 激活和 T 细胞极化相关。在目标 3 中，交联 iPEM 的功效。 将评估临床前 MS 模型中的模型，以检验先天免疫和适应性免疫的双重靶向是的假设 这些研究将表明，调节先天免疫和适应性免疫是必需的。 对于在多发性硬化症中产生强大的抗原特异性反应是必要的，并将提供为新的设计提供信息的见解 同时，还将获得新的技能和技术来治疗多发性硬化症和其他自身免疫性疾病。 在整个研究过程中，推动学员领导一个专注于开发的学术研究实验室的目标 博士后培训后的免疫调节药物输送系统。