Local immunometabolism modulating biomaterials for immunosuppressive applications

用于免疫抑制应用的局部免疫代谢调节生物材料

• 批准号: 10598113
• 负责人: Abhinav Acharya
• 金额: $ 32.14万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-14 至 2023-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598113
• 关键词: Adaptive Immune System; Aftercare; Animal Model; Animals; Ankle; Antigen Presentation; Antigen-Presenting Cells; Antigens; Arthritis; Autoantigens; Autoimmune Diseases; Biocompatible Materials; Biological Assay; Biological Products; CCL22 gene; CD86 gene; Cattle; Cell Separation; Cell physiology; Cells; Cervical; Chemotaxis; Chondrocytes; Citric Acid Cycle; Clinical; Clinical Trials; Collagen; Collagen Arthritis; DBA/1J Mouse; Data; Dendritic Cell Vaccine; Dendritic Cells; Dendritic cell activation; Disease; Disease remission; Dose; Drug Delivery Systems; Encapsulated; Enzymes; Fibroblasts; Flow Cytometry; Formulation; Foundations; Frequencies; Future; Genus Hippocampus; Glucosephosphate Isomerase; Glycolysis; Glycolysis Inhibition; Goals; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Immune; Immune response; Immunohistochemistry; Immunosuppression; Immunosuppressive Agents; In Vitro; Inflammation; Innate Immune System; Joints; K/BxN model; Kidney; Kinetics; Knee; Kynurenine; Lead; Lethal Dose 50; Liver; Lung; Lymphoid Tissue; Macrophage; Manuscripts; Maximum Tolerated Dose; Measures; Mediating; Membrane Proteins; Memory; Metabolic; Metabolism; Mission; Modeling; Monitor; Mus; Mutation; Organ; Oxygen Consumption; PPBP gene; Pathway interactions; Peripheral; Phagocytosis; Pharmaceutical Preparations; Phenotype; Physiological; Play; Polymers; Prevention; Process; Production; Protocols documentation; Provider; Public Health; Regulatory T-Lymphocyte; Research; Research Project Grants; Rheumatoid Arthritis; Role; Safety; Saline; Serum; Symptoms; T cell anergy; T cell response; T memory cell; T-Lymphocyte; Testing; Thick; Tissues; Toxic effect; Tryptophan; United States National Institutes of Health; Weight Gain; alpha ketoglutarate; ankle joint; antigen test; appropriate dose; autoreactive T cell; biodegradable polymer; cancer clinical trial; comparison control; cytokine; delivery vehicle; experimental study; extracellular; fatty acid oxidation; immunoregulation; improved; in vivo; inflammatory marker; inhibitor; interest; lymph nodes; lymphoid organ; metabolomics; meter; novel; particle; prevent; response; scale up; subcutaneous; technology development; transcriptome sequencing

Abstract Biomaterials-based strategies to modulate the immune responses has generated tremendous interest in the past decade. Notably, biomaterials can not only be used for delivering drugs (synthetic or biologics) but by themselves can modulate the function of different cells. Recently, we have demonstrated that the metabolite alpha-ketoglutarate (aKG) can be polymerized, and these polymers by themselves are able to suppress activation of dendritic cells (DCs – forms the bridge between innate and adaptive immune system). Interestingly, our preliminary data also demonstrates that delivery of PFK15, an inhibitor of PFKFB3 enzyme (a key step in glycolysis) downregulates CD86 (co-stimulatory molecule) but maintains MHC-II (stimulatory antigen presenting molecules) on DCs. Notably, glycolysis can control the function of activated DCs. Therefore, glycolysis-inhibition mediated prevention of DC activation and simultaneous antigen expression, can lead to antigen-specific immunosuppression responses. However, systemic inhibition of glycolysis has inherent toxicity (clinical trials) associated with it, and have regulatory hurdles for clinical use. Therefore, the main goal of this R01 program is to develop drug delivery vehicles that can deliver glycolysis inhibitors and antigens locally to DCs, which will then systemically suppress inflammation. The central hypothesis of this proposal is that co-delivery of antigen and glycolytic inhibitor will induce DC tolerance and generate peripheral antigen-specific suppressive T-cells, which will then promote reversal of tissue inflammation. This strategy will be tested in a rheumatoid arthritis animal model. This hypothesis will be tested by performing experiments in the following aims: AIM 1: Test if paKG formulations can generate long-term remission of RA by maintaining metabolic homeostasis in joint tissues. AIM 2: Determine the effect of paKG formulations on cells associated with arthritic tissue. AIM 3: Test the ability of paKG formulations to prevent progression of RA in K/BxN mice AIM 4: Develop scaled paKG formulations for safety/toxicity profiles. This research will be an important foundation in the development of technologies based on metabolic modulation of immune cells for autoimmune disorder treatment. The results from this project will generate a sustained release platform, which after application can prevent the progression of RA, or even reverse the damage.

抽象的 基于生物材料调节免疫回报的策略引起了人们对 过去十年。值得注意的是，生物材料不仅可以用于输送药物（合成或生物制剂），还可以通过 自己可以调节不同单元的功能。最近，我们证明了代谢物 可以聚合α-酮戊二酸（AKG），并且这些聚合物本身能够抑制 树突状细胞的激活（DCS - 形成了先天和适应性免疫抑制系统之间的桥梁）。 有趣的是，我们的初步数据还表明，PFK15（PFKFB3酶的抑制剂）的递送（A 糖酵解的关键步骤）下调CD86（共刺激分子），但保持MHC-II（刺激性 DC上的抗原呈现分子）。值得注意的是，糖酵解可以控制活化的DC的功能。 因此，糖酵解抑制介导的DC激活和简单抗原表达的预防，可以 导致抗原特异性免疫抑制反应。然而，全身抑制糖酵解具有 与之相关的固有毒性（临床试验），并具有临床用途的调节障碍。因此， 该R01计划的主要目标是开发可以提供糖酵解抑制剂和 抗原与DC的本地抗原，然后将其系统地抑制注射。中心假设 提案是抗原和糖酵解抑制剂的共递送将诱导直流耐受性并产生周围 抗原特异性抑制T细胞，然后将促进组织注射的反向。这个策略将 在类风湿关节炎动物模型中进行测试。该假设将通过在 以下目的：目标1：测试PAKG公式是否可以通过维护RA产生长期的缓解 关节组织中的代谢稳态。目标2：确定PAKG公式对相关细胞的影响 与关节炎组织。 AIM 3：测试PAKG公式防止K/BXN小鼠RA进展的能力 AIM 4：为安全/毒性概况开发规模的PAKG公式。这项研究将是一项重要的 基于免疫细胞的代谢调节技术开发技术的基础 疾病治疗。该项目的结果将产生一个持续的发布平台，此后 应用可以防止RA的进展，甚至可以逆转损坏。