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/抗原识别为外来的，从而导致免疫缺陷。 对尸体进行了精心策划的攻击在多发性硬化症（MS）中，免疫系统攻击保护性神经鞘， - 髓磷脂-导致衰弱性神经损伤和生活质量差。目前的MS疗法是非治愈性的， 需要终生的依从性，并表现出增加患者感染易感性的非特异性作用。规避 MS治疗面临挑战，新兴疗法寻求将髓鞘自身抗原（MOG）和免疫调节因子引导至 改变免疫反应的方向Toll样受体，检测抗原呈递细胞上的病原体相关模式 最近，TLR 9拮抗剂GpG已经显示出下调APC活化， 促进TREGS。类似地，雷帕霉素（Rapa），一种免疫抑制剂药物，因为它抑制主要的 调节性T细胞（Tregs）。由于先天免疫系统和适应性免疫系统之间的协调， MS驱动疾病，拟议的研究将同时靶向这些途径，以促进抗原特异性免疫 MS的耐受性。 我们以前已经开发出完全由免疫信号构建的自组装载体-称为免疫 可实现多个提示、受控装载和高负载的组合传送的智能多层膜（iPEM） 密度使用MOG和GpG组装的iPEM减少TLR 9信号传导，同时促进TREGS，但显示出适度的 在临床前MS模型中的疗效。由于TREGS在调节免疫反应中起着至关重要的作用，因此拟议的工作旨在 为了将Rapa装载在MOG/GpG iPEM的核心中以使得能够共同递送MOG以诱导抗原特异性免疫应答， GpG下调APC活性，并掺入交联以控制Rapa递送以诱导TREGS。在目标1中， 将检验MOG/GpG（Rapa）iPEM中的交联密度与释放间隔相关的假设。这将是 通过从MOG、对照抗原（ANT-CTRL）、GpG、失活抗原（ANT-CTRL）和GpG的组合产生iPEM文库来完成。 对照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活化和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，以检验先天性和适应性免疫的双重靶向是 这些研究将表明，调节先天性和适应性免疫， 是在MS中产生稳健的抗原特异性应答所必需的，并将提供深入的见解，为新的免疫治疗设计提供信息。 治疗MS和其他自身免疫性疾病的疗法。与此同时，新的技能和技术将获得 在整个研究过程中，以推动受训者的目标，领导一个学术研究实验室，重点是发展 免疫调节药物输送系统后，博士后培训。