Engineered biomaterials modulating inflammatory T cells in rheumatic arthritis

工程生物材料调节风湿性关节炎中的炎症 T 细胞

• 批准号: 10494088
• 负责人: David Ambrose McBride
• 金额: $ 3.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10494088
• 关键词: Address; Affect; Alleles; Animals; Anti-Inflammatory Agents; Antigens; Arthritis; Attenuated; Autoimmune; Autoimmune Diseases; Autoimmunity; Biocompatible Materials; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Clinical; Complex; Computer Models; Contralateral; Cues; Cyclodextrins; Development; Disease; Disease Progression; Disease remission; Distal; Dose; Encapsulated; Engineering; Epitopes; Equilibrium; Exposure to; FOXP3 gene; Formulation; Frequencies; Genetic Polymorphism; Glycolates; Goals; Homeostasis; Immune; Immune Tolerance; Immune response; Immune signaling; Immunocompetence; Immunologics; Immunomodulators; Immunophenotyping; Immunosuppression; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Arthritis; Injectable; Interleukin-17; Interleukin-6; Joints; Kinetics; Label; Malignant Neoplasms; Measurement; Measures; Mediating; Metabolic; Methods; Modeling; Molecular; Mus; Mutation; Orphan; Outcome; Ovalbumin; Paper; Pathogenesis; Pathogenicity; Patients; Peptide Hydrolases; Polymers; Protein Tyrosine Phosphatase; Proteins; Publishing; RNA; Regulatory T-Lymphocyte; Research; Rheumatoid Arthritis; Risk; Running; Severities; Severity of illness; Signal Transduction; Sirolimus; Site; Specificity; Susceptibility Gene; Synovial Membrane; System; Systemic disease; T cell differentiation; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Tretinoin; Vaccination; Work; arthropathies; autoimmune arthritis; autoreactivity; base; biodegradable polymer; biomaterial compatibility; clinically translatable; controlled release; cytokine; disability; dosage; effector T cell; efficacy evaluation; experience; experimental study; fluorophore; forkhead protein; genetic variant; immune function; immunoengineering; immunoregulation; improved; improved outcome; in vivo; in vivo fluorescence; inflammatory milieu; inhibitor; joint inflammation; loss of function; novel; patient subsets; prevent; receptor; targeted treatment; tool; transcription factor; treatment comparison; treatment strategy

PROJECT SUMMARY Immune tolerance is mediated via a number of molecular and cellular mechanisms, including regulatory T cells (Treg). Breakdown of this immune tolerance leads to debilitating autoimmune disease, of which rheumatoid arthritis (RA) is exemplary. Polymorphisms in alleles associated with immune signaling can predispose individuals to the development of RA. Genetic variants at the protein tyrosine phosphatase non-receptor 2 (PTPN2) locus are one such set of mutations that are well characterized to contribute to disease pathogenesis and RA severity in a well-established subset of patients. This altered signaling results in changes to the immunological landscape, and particularly influences the balance between anti-inflammatory Treg and the pro- inflammatory T helper 17 (Th17) cells that are involved in RA development. Diminished PTPN2 function results in Treg instability, in which Treg convert to pathogenic “Th17-like” effector T cells in the inflammatory arthritic microenvironment, leading to self-perpetuating cycle of severe inflammation. However, currently there are no therapies that target Treg instability to rescue Treg function and promote immune homeostasis to help resolve inflammation. Cyclodextrin/all-trans retinoic acid complexes (CAC) are a promising tool to address the need for a clinically translatable therapy to restore and maintain Treg function in PTPN2 haploinsufficient (PTPN2+/-) individuals, as CAC are capable of preventing Treg destabilization in inflammatory conditions. However, the systemic administration of CAC to promote Treg is not a feasible strategy, as this may run the risk of systemic immune suppression that could increase the risk of serious infection and cancer. To address this, it is hypothesized that the local, sustained delivery of CAC at the joint will enhance Treg stability and improve clinical outcomes in the PTPN2 compromised endotype. To achieve prolonged, site specific immune modulation, an injectable biomaterial system for the release of CAC is necessary. The goal of this project is to (i) develop and characterize an injectable biomaterial system for the sustained delivery of CAC and (ii) elucidate the efficacy, mechanisms, and specificity of CAC-mediated Treg stabilization. This will be achieved in the following Specific Aims: Aim 1. A microparticle formulation (CAC-MP) comprising CAC encapsulated by poly (lactic-co- glycolic) acid (PLGA) will be characterized and optimized for in vivo release kinetics. Subsequently, a dosage study will be conducted to examine efficacy of CAC-MP at different doses in the Ptpn2+/- SKG model of RA. Aim 2. The mechanism of action by which CAC-MP mediate improvement in Ptpn2+/- SKG arthritis will be elucidated, and the impact of CAC-MP on systemic immune response will be examined. The immediate results of this project will determine the feasibility of localized immune modulation to rescue Treg instability to improve outcomes in a well-defined subset of RA patients using clinically approved materials. Additionally, the injectable biomaterial platformed developed herein will have broader applicability as a tool to mediate local immune modulation and may be used to probe questions of immune tolerance and tolerance breakdown.

项目摘要 免疫耐受性是通过多种分子和细胞机制介导的，包括调节性T细胞 （Treg）。这种免疫耐受性的崩溃导致虚弱的自身免疫性疾病，其中类风湿病 关节炎（RA）是典范。与免疫信号相关的等位基因中的多态性可能易感性 个人发展RA。蛋白质酪氨酸磷酸酶非受体2的遗传变异 （PTPN2）基因座是一组突变，这些突变被很好地表征有助于疾病发病机理 以及公认的患者子集中的RA严重程度。这改变了信号导致对 免疫局势，尤其影响抗炎TREG与促进症之间的平衡 参与RA发育的炎性T辅助辅助器17（Th17）细胞。 PTPN2功能结果降低 在Treg的不稳定性中，Treg转化为炎症性Artritic的致病性“ Th17样”效应T细胞 微环境，导致严重感染的自我延续周期。但是，目前没有 针对Treg不稳定的疗法可以挽救Treg功能并促进免疫稳态以帮助解决 炎。环糊精/全反式视黄酸配合物（CAC）是满足需求的有前途的工具 可恢复和维持PTPN2单倍弹性的临床翻译疗法（PTPN2 +/-） 个体，因为CAC能够防止在炎症条件下Treg不稳定。但是， 全身管理CAC来促进Treg不是一个可行的策略，因为这可能会冒着系统性的风险 免疫抑制可能会增加严重感染和癌症的风险。为了解决这个问题，是 假设在关节处局部持续的CAC持续交付将增强Treg稳定性并改善 PTPN2损害内种的临床结果。为了实现长时间的特定部位免疫 调制是必要的，用于释放CAC的可注射生物材料系统。这个项目的目标是 （i）开发并表征可持续交付CAC和（ii）阐明的可注射生物材料系统 CAC介导的Treg稳定的效率，机制和特异性。这将在以下 具体目的：AIM 1。一个微粒公式（CAC-MP），其中包含由聚（乳酸胶 - 糖酸）酸（PLGA）将被特征和优化用于体内释放动力学。随后，一种剂量 将进行研究以检查PTPN2 +/- SKG模型中不同剂量的CAC-MP的效率。目的 2。CAC-MP介导PTPN2 +/- SKG关节炎改善的作用机理，将阐明， CAC-MP对全身免疫响应的影响将进行检查。该项目的直接结果 将确定局部免疫调节以挽救Treg不稳定性以改善预后的可行性 使用临床认可的材料定义明确的RA患者子集。此外，可注射的生物材料 此处开发的平台将具有更广泛的适用性，作为调解局部免疫调节和的工具 可用于探测免疫耐受性和耐受性崩溃的问题。