Central and peripheral immune cross-talk in Alzheimer's disease and their modulation by a novel immunotherapy

阿尔茨海默氏病的中枢和外周免疫串扰及其通过新型免疫疗法的调节

• 批准号: 10589269
• 负责人: Alireza Faridar
• 金额: $ 65.15万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589269
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid; Amyloid beta-42; Animal Model; Anti-Inflammatory Agents; Astrocytes; Biological Markers; Blood; Brain; Brain imaging; Cells; Central Nervous System; Cerebrospinal Fluid; Chronic; Clinical; Clinical Research; Clinical Trials; Cognition; Data; Development; Disease; Disease Progression; Dose; Double-Blind Method; Encephalitis; Enrollment; Epidemiology; Funding; Grant; IL2 gene; Immune; Immune system; Immunologic Markers; Immunotherapy; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-2; Intervention; Light; Link; Macrophage; Measurement; Measures; Mediating; Microglia; Neuroglia; Outcome; Patient Participation; Peripheral; Persons; Phase; Plasma; Play; Population; Positron-Emission Tomography; Process; Proteins; Proteomics; Randomized; Regulatory T-Lymphocyte; Role; Safety; Sample Size; Serum; Spinal Puncture; Synapses; Therapeutic Intervention; Therapeutic Trials; Treatment Efficacy; Up-Regulation; Work; chemokine; cytokine; efficacy trial; experience; follow-up; glial activation; immunomodulatory therapies; immunoreaction; immunoregulation; improved; in vivo; inflammatory marker; interest; monocyte; mouse model; neurofilament; neuroinflammation; neuroprotection; novel; novel strategies; placebo controlled study; placebo group; post intervention; public health relevance; recruit; restoration; risk variant; safety assessment; tau Proteins; tau-1; therapeutic target; transcriptome

Project Summary/Abstract Alzheimer’s disease (AD) gene-risk data, epidemiological findings and animal models converge to indicate the critical role of inflammation for the onset and progression of AD. Inflammation could provide a new focus for therapeutic intervention. However, inflammation biomarkers are poorly characterized in AD. In this project, we will measure blood and cerebrospinal fluid (CSF) inflammation biomarkers and compare them to measurements of brain glial activation obtained by positron emission tomography (PET). In addition, we will determine the effect of low-dose interleukin-2 (IL-2) immunotherapy, given over 22 weeks, on these inflammation biomarkers. For this purpose, we will measure these biomarkers in AD individuals enrolled in a phase 2a safety and efficacy trial of low-dose IL-2 therapy. Regulatory T cells (Tregs) play a neuroprotective role by suppressing inflammation in the blood and the brain. We have shown that Treg immunomodulatory mechanisms are compromised in AD patients, resulting in activation of pro-inflammatory monocytes and upregulation of inflammatory mediators. In a Phase 1 clinical study, we showed that IL-2 administration induced Treg expansion and restoration; the therapy was safe, and it was associated with improved cognition. Supported by a “Part-the-Cloud” grant from the Alzheimer’s Association, we will conduct a follow up phase 2a study which includes the measurement of cognition, as well as CSF T-tau, P-tau, Aβ42, and neurofilament light chain (NFL) before and after 22 weeks of IL-2 treatment in the subjects with mild to moderate AD. Taking advantage of this novel trial, and by evaluating the 40 AD patients participating in it, the current study will investigate systemic and central nervous system (CNS) biomarkers of inflammation and their modulation by IL-2 administration. We will analyze the impact of IL-2 immunotherapy on peripheral immune biomarkers (Aim 1) as well as CNS inflammation, measured through CSF inflammation biomarkers (Aim 2) and brain inflammation positron emission tomography (Aim 3). To determine which blood biomarkers correlate best with central nervous system biomarkers (Aim 4), the associations among blood, CSF, and brain imaging measures of neuroinflammation before and after IL-2 therapy will be determined. Our novel approach will explore the potential link between systemic and CNS inflammation in AD clinical setting and advance the use of inflammatory biomarkers in AD anti- inflammatory clinical trials.

项目总结/摘要 阿尔茨海默病（AD）基因风险数据、流行病学发现和动物模型 表明炎症在AD发病和进展中的关键作用。炎症 可以为治疗干预提供一个新的焦点。然而，炎症生物标志物是 在AD中表现不佳。在这个项目中，我们将测量血液和脑脊液（CSF） 炎症生物标志物，并将其与获得的脑胶质细胞活化的测量结果进行比较。 正电子发射断层扫描（PET）。此外，我们还将确定低剂量 白细胞介素-2（IL-2）免疫疗法，给予超过22周，对这些炎症生物标志物。 为此，我们将在2a期研究中招募的AD个体中测量这些生物标志物。 低剂量IL-2治疗的安全性和有效性试验。调节性T细胞（Tcells）在免疫系统中发挥重要作用。 通过抑制血液和大脑中的炎症来发挥神经保护作用。我们已经表明 AD患者的Treg免疫调节机制受损，导致 促炎单核细胞的活化和炎性介质的上调。中 在1期临床研究中，我们显示IL-2施用诱导Treg扩增， 恢复;该疗法是安全的，并且与认知改善有关。支持 阿尔茨海默氏症协会的“部分云”赠款，我们将进行后续阶段2a 一项研究，包括测量认知以及CSF T-tau、P-tau、Aβ42和 在IL-2治疗22周之前和之后， 轻度至中度AD。利用这项新的试验，通过评估40名AD患者， 参与其中，本研究将探讨全身和中枢神经系统 (CNS)炎症生物标志物及其通过IL-2给药的调节。我们将 分析IL-2免疫治疗对外周免疫生物标志物（Aim 1）的影响，以及 CNS炎症，通过CSF炎症生物标志物（Aim 2）和脑 炎症正电子发射断层扫描（Aim 3）。为了确定哪些血液生物标志物 与中枢神经系统生物标志物（目标4）相关性最好，血液， CSF和脑成像测量的神经炎症之前和之后的IL-2治疗将是 测定我们的新方法将探索系统和中枢神经系统之间的潜在联系， 炎症在AD临床环境中的作用，并推进炎症生物标志物在AD抗 炎症临床试验