Particulate-based in vivo modulation for immunotherapy of Rheumatoid Arthritis

基于颗粒的体内调节用于类风湿性关节炎的免疫治疗

• 批准号: 10623684
• 负责人: Jamal S Lewis
• 金额: $ 34.41万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-24 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10623684
• 关键词: Address; Adult; Affect; Allergic Disease; Analgesics; Antigens; Arthritis; Attenuated; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Biocompatible Materials; Biodistribution; Biological Factors; Biomedical Engineering; Blood Vessels; Bovine Serum Albumin; Cell Therapy; Cells; Cellular Immunology; Cholecalciferol; Chronic; Clinic; Collagen; Collagen Arthritis; Communicable Diseases; Dendritic Cells; Dendritic cell activation; Disease; Disease model; Disease remission; Encapsulated; Engineering; Epidemic; Eye; Fibrinogen; Fibroblasts; Gene Expression; Generations; Glycolic-Lactic Acid Polyester; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Human; Hyperplasia; Immune; Immune Tolerance; Immunomodulators; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Impairment; Infiltration; Inflammatory; Inflammatory Response; Injectable; Institutes; Interleukin-1; Interleukin-6; Investigation; Joints; Lymphocyte Function; Mediator of activation protein; Mission; Modeling; Modification; Mus; Outcome; Particle Size; Particulate; Pathogenesis; Patient risk; Peptides; Phagocytes; Pharmaceutical Preparations; Phenotype; Plant Roots; Polymers; Prevention; Production; Property; Public Health; Quality of life; Research; Research Support; Rheumatoid Arthritis; Rheumatology; Role; Safety; Steroids; Subcutaneous Injections; Surface; Synovial Membrane; System; Systems Development; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Therapeutic; Toxic effect; Translations; Vaccination; Vaccines; antiangiogenesis therapy; antigen-specific T cells; arthritis therapy; autoimmune arthritis; autoinflammatory; base; biophysical properties; clinical translation; conditioning; cost; cytokine; extracellular; gene function; immunogenic; immunoregulation; in vivo; innovation; joint destruction; macrophage; manufacturability; medical schools; monocyte; mouse model; novel; novel strategies; receptor; recruit; research and development; response; socioeconomics; stem; subcutaneous; success; systemic autoimmune disease; targeted delivery; therapeutic target; transcriptomics; translational impact; vaccination outcome; vaccine delivery; vaccine platform

PARTICULATE-BASED IN VIVO MODULATION FOR IMMUNOTHERAPY OF RHEUMATOID ARTHRITIS PROJECT SUMMARY/ ABSTRACT Rheumatoid arthritis (RA) is a chronic, systemic, auto-inflammatory disease that affects approximately 1% of adults worldwide, and commonly results in joint destruction and significant impairment in the quality of life. The underlying cause of RA is dendritic cell (DC) activation of antigen-specific T cell subsets in the joints, which drive inflammatory responses to the synovial membrane that are typically characterized by hyperplasia, increased vascularity, inflammatory cell infiltration and over production of pro-inflammatory cytokines (particularly IL-1, IL-6 and TNF-α) by monocytes, macrophages and synovial fibroblasts. Due to their critical role in RA progression, these cytokines have become the major therapeutic targets for RA therapy. Other therapeutic approaches include administration of steroids, as well as, anti-angiogenesis drugs. However, these strategies do not address the root cause of RA – stimulation of T lymphocytes by DCs. A number of factors are known to promote advantageous dendritic cell responses in experimental systems for autoimmune diseases. However, systemic delivery of these agents often results in significant harmful off-target effects. The Lewis Lab at UC, Davis is developing a novel, biomaterial-based, microparticle `anti-vaccine' for in vivo co-delivery of pro-tolerance factors and autoantigens, targeted to DCs. Exogenous conditioning of DCs with certain immuno-modulatory agents has been shown to induce a pro-tolerance DC phenotype, as well as, ameliorate RA. However, vaccination with a microparticle anti-vaccine promises to correct aberrant autoimmune responses, whilst circumventing problems associated with DC-based cellular therapy such as DC phenotypic stability and survivability, and autoantigen plurality. The long-term goal is to develop a modular, anti-vaccine system for autoimmune disease therapy. The overall objective of this R01 proposal is to engineer a multi-component, MP anti-vaccine to attenuate RA progression in an aggressive, murine RA model, and investigate the extent of immune modulation following anti-vaccination. The central hypothesis is that this MP anti-vaccine will induce autoantigen-specific tolerance by targeted delivery of model-relevant autoantigen and tolerance-inducing factors to immune cells, especially DCs, thereby generating aAg-specific tDCs that will retrain downstream adaptive responses and promote the remission of RA. This hypothesis will be tested by pursuing four specific aims: 1) Assess the effect of material properties and anti-vaccine agent presentation on the tolerogenicity of DC immunotherapy; 2) Evaluate the capacity of this platform system to limit RA in the FIA-CIA mouse model; 3) Investigate mechanisms of immune tolerance using well-defined antigen-specific mouse models; and 4) Investigate preliminary manufacturing and safety metrics with an eye towards clinical translation. The approach is innovative, in the applicant's opinion, because it departs from the status quo by generating specific tolerance- inducing cellular mediators in vivo with a simple subcutaneous injection of polymeric microparticles. Ultimately, the research and development of this system has the potential to significantly stem the growing epidemic of autoimmunity in the US.

基于颗粒的体内调节类风湿性关节炎的免疫治疗 项目概要/摘要 类风湿性关节炎 (RA) 是一种慢性、全身性自身炎症性疾病，影响约 1% 的患者 全世界成年人的疾病，通常会导致关节破坏和生活质量的严重损害。 RA 的根本原因是关节中抗原特异性 T 细胞亚群的树突状细胞 (DC) 激活，这 驱动滑膜的炎症反应，其典型特征是增生， 血管分布增加、炎症细胞浸润和促炎细胞因子过度产生（特别是 IL-1、IL-6 和 TNF-α）由单核细胞、巨噬细胞和滑膜成纤维细胞产生。由于它们在 RA 中的关键作用 随着进展，这些细胞因子已成为 RA 治疗的主要治疗靶点。其他治疗 方法包括施用类固醇以及抗血管生成药物。然而，这些策略 没有解决 RA 的根本原因——DC 刺激 T 淋巴细胞。已知有许多因素 在自身免疫性疾病的实验系统中促进有利的树突状细胞反应。然而， 这些药物的全身递送通常会导致显着有害的脱靶效应。加州大学刘易斯实验室， 戴维斯正在开发一种新型的、基于生物材料的微粒“抗疫苗”，用于体内共同传递亲耐受性 针对 DC 的因子和自身抗原。具有某些免疫调节作用的 DC 的外源调节 药物已被证明可诱导促耐受 DC 表型，并改善 RA。然而， 接种微粒抗疫苗有望纠正异常的自身免疫反应，同时 规避与基于 DC 的细胞疗法相关的问题，例如 DC 表型稳定性和 生存能力和自身抗原复数。长期目标是开发一种模块化的抗疫苗系统 自身免疫性疾病治疗。该 R01 提案的总体目标是设计一个多组件、MP 抗疫苗可在侵袭性小鼠 RA 模型中减缓 RA 进展，并研究其程度 抗疫苗接种后的免疫调节。中心假设是这种 MP 抗疫苗会诱导 通过靶向递送模型相关自身抗原和耐受诱导因子来实现自身抗原特异性耐受 免疫细胞，尤其是 DC，从而产生 aAg 特异性 tDC，从而重新训练下游适应性 反应并促进 RA 的缓解。该假设将通过追求四个具体目标来检验：1) 评估材料特性和抗疫苗剂呈现对 DC 耐受性的影响 免疫疗法； 2）评估该平台系统在FIA-CIA小鼠模型中限制RA的能力； 3） 使用明确的抗原特异性小鼠模型研究免疫耐受机制；和 4) 研究初步制造和安全指标，着眼于临床转化。方法 在申请人看来，这是创新的，因为它通过产生特定的容差而偏离了现状- 通过简单的皮下注射聚合物微粒来诱导体内细胞介质。最终， 该系统的研究和开发有可能显着遏制日益严重的流行病 美国的自身免疫。