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 基于生物材料的免疫反应调节策略引起了人们的极大兴趣 值得注意的是，生物材料不仅可以用于输送药物（合成或生物制品），还可以用于输送药物。 最近，我们证明了代谢物本身可以调节不同细胞的功能。 α-酮戊二酸（aKG）可以聚合，这些聚合物本身能够抑制 树突状细胞（DC——形成先天性免疫系统和适应性免疫系统之间的桥梁）的激活。 暗示，我们的初步数据还表明，PFK15（一种 PFKFB3 酶抑制剂）的递送（a 糖酵解的关键步骤）下调 CD86（共刺激分子）但维持 MHC-II（刺激分子） 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 激活和同时抗原表达的预防，可以 导致抗原特异性免疫抑制反应然而，糖酵解的全身抑制。 与其相关的固有毒性（临床试验），并且在临床使用方面存在监管障碍。 该 R01 项目的主要目标是开发能够递送糖酵解抑制剂和 抗原局部作用于树突状细胞，然后系统性地抑制炎症。 提议是抗原和糖酵解抑制剂的共同递送将诱导 DC 耐受并产生外周血 抗原特异性抑制性 T 细胞，然后将促进组织炎症的逆转。 该假设将通过在类风湿性关节炎动物模型中进行实验来检验。 目标如下： 目标 1：测试 paKG 制剂是否可以通过维持治疗来实现 RA 的长期缓解 目标 2：确定 paKG 制剂对相关细胞的影响。 目标 3：测试 paKG 制剂预防 K/BxN 小鼠 RA 进展的能力。 目标 4：开发规模化的 paKG 制剂以了解安全性/毒性特征。这项研究将是一项重要的研究。 开发基于免疫细胞代谢调节的自身免疫技术的基础 该项目的结果将产生一个持续释放的平台，之后该平台将用于治疗疾病。 应用可以阻止 RA 的进展，甚至逆转损害。