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/抗原识别为外来物，导致