Multi-pronged therapy for immune system regeneration and recovery in a FIP model of MIS-C

MIS-C FIP 模型中免疫系统再生和恢复的多管齐下疗法

• 批准号: 10289230
• 负责人: Amir Kol
• 金额: $ 23.55万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10289230
• 关键词: 2019-nCoV; 21 year old; Affect; Animal Model; Anti-Inflammatory Agents; Antibodies; Antigen Presentation; Antigen Presentation Pathway; Antiviral Agents; Atrophic; Biological Response Modifier Therapy; Blood; Cell Therapy; Cellular biology; Child; Childhood; Client; Clinical Trials; Combined Modality Therapy; Coronavirus; Coronavirus Infections; Cytotoxic T-Lymphocytes; Data; Development; Disease; Double-blind trial; Enrollment; Family Felidae; Feline infectious peritonitis; Felis catus; Fever; Flow Cytometry; GS-441524; HIV; Helper Viruses; Helper-Inducer T-Lymphocyte; Hospitalization; IL6 gene; IL7 gene; IL8 gene; Immune; Immune response; Immune system; Immunity; Immunoassay; Immunofluorescence Immunologic; Immunotherapy; Impairment; Infection; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interferons; Interleukin-6; Laboratories; Life; Lymph Node Tissue; Lymphocyte Depletion; Lymphocyte Subset; Lymphoid; Lymphoid Tissue; Lymphopenia; Mission; Modeling; Molecular; Multisystem Inflammatory Syndrome in Children; National Institute of Child Health and Human Development; Natural regeneration; Organ; Outcome Study; Pathogenesis; Pathway interactions; Patients; Peripheral; Plasma; Positioning Attribute; Prodrugs; Property; Public Health; RNA Polymerase Inhibitor; Recovery; Research; Role; Safety; Sampling; Stromal Cells; Structure; Structure of germinal center of lymph node; Subcutaneous Injections; Syndrome; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; TimeLine; Tissue Banks; Tissue Sample; Viral; Viral Load result; Virus; Virus Diseases; Virus Replication; antiviral immunity; apoptosis in lymphocytes; clinically relevant; coronavirus disease; cytotoxic CD8 T cells; disability; effusion; exhaustion; experience; experimental group; injured; injury and repair; innovation; lymph nodes; multidisciplinary; nonhuman primate; novel; novel therapeutic intervention; novel therapeutics; nucleoside analog; organ injury; pediatric patients; peripheral blood; remdesivir; response; restoration; stem; systemic inflammatory response; therapeutic candidate; therapeutic development; tissue injury; tissue regeneration; transcriptome sequencing; treatment response; treatment strategy; viral RNA

This R21 proposes to fill a major scientific gap by investigating a new therapeutic approach for multisystem inflammatory syndrome in children (MIS-C) using an innovative and clinically relevant feline model. We propose to test a novel multi-pronged therapeutic paradigm targeting viral replication, lymphoid tissue injury and hyper-inflammatory host response in cats with naturally occurring feline infectious peritonitis (FIP) to accelerate viral clearance and immune restoration. Our long-term objective is to develop new therapeutic approaches for the treatment of MIS-C. The overall objectives of this proposal are to test a novel multi-pronged chemo-biologic therapeutic strategy and determine its underlying mechanism of action in a clinically relevant animal model. The central hypothesis is that a combined GS-441524-multipotent stem/stromal cells (MSC) therapy synergistically restores injured lymphoid tissues, decreases systemic inflammation and enhances specific anti-coronavirus (CoV) immunity in cats with FIP. The rationale for this project is supported by our preliminary data indicating that GS-441524 is a potent anti-CoV agent, and that MSC have a novel role in viral infections by enhancing anti-viral immunity, dampening systemic inflammation and regenerating lymphoid tissue structure and function. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the effect of GS-441524-MSC combination treatment on viral loads, lymphoid tissue injury and repair, and elucidate the molecular networks that govern its mechanism of action; and 2) Determine the effect of GS- 441524-MSC combination treatment on T cell activation/exhaustion, inflammation and lymphocyte depletion in peripheral blood compartment of cats with FIP. To test our hypothesis we will enroll client owned cats with FIP into a double blinded trial with two experimental groups: GS-441524 only, or a combined GS-441524 -MSC treatment. Blood, effusion and lymph node tissue samples will be serially collected throughout the study timeline. Parallel samples will be collected from healthy controls. We will further leverage our bio-banked tissues from cats with FIP that succumbed to the disease. Under the first aim we will determine the role of the combined treatment approach in inducing IL-7, IFN type-1 and antigen presentation pathways within lymphoid tissues to mitigate lymphoid depletion and mount an effective and balanced immune response to CoV infection. For the second aim, we will determine the role of the combined treatment approach in inhibiting lymphocyte apoptosis and T cell exhaustion in peripheral blood, and reducing systemic inflammation. The proposed research is innovative because it will determine how monotherapy is affecting immune recovery, and if MSC can enhance and accelerate viral clearance and lymphoid tissue regeneration in a clinically relevant animal model of MIS-C. The proposed research is significant because it is expected to provide a strong scientific justification and mechanistic understanding for the continued development of combined chemo- biologic therapeutic strategies for MIS-C.

R21计划通过研究一种新的多系统治疗方法来填补一个重大的科学空白 使用创新和临床相关的猫模型研究儿童炎症性综合征(MIS-C)。我们 建议测试一种针对病毒复制、淋巴组织损伤的多管齐下的治疗方案 自然发生猫科感染性腹膜炎(FIP)的猫的高炎症宿主反应 加速病毒清除和免疫恢复。我们的长期目标是开发新的治疗方法 管理信息系统-C的治疗方法这项提议的总体目标是测试一种新的多管齐下的 临床相关的化学-生物治疗策略及其潜在作用机制的确定 动物模型。中心假设是结合GS-441524的多潜能干细胞/基质细胞(MSCs) 治疗协同修复受损的淋巴组织，减少全身炎症，增强 FIP猫的特异性抗冠状病毒免疫。这个项目的基本原理是由我们的 初步数据表明，GS-441524是一种有效的抗冠状病毒药物，而间质干细胞在病毒治疗中具有新的作用 通过增强抗病毒免疫、抑制全身炎症和再生淋巴来感染 组织结构和功能。核心假设将通过追求两个具体目标来检验：1)确定 GS-441524-MSCs联合治疗对病毒载量、淋巴组织损伤和修复的影响 阐明支配其作用机制的分子网络；以及2)确定GS- 441524-MSCs联合治疗对小鼠T细胞活化/衰竭、炎症和淋巴细胞耗竭的影响 FIP猫的外周血室。为了验证我们的假设，我们将客户拥有的猫注册到FIP 纳入两个试验组的双盲试验：单独使用GS-441524，或联合使用GS-441524-MSCs 治疗。血液、积液和淋巴组织样本将在整个研究过程中连续采集 时间线。平行样本将从健康对照中收集。我们将进一步利用我们的生物银行 死于这种疾病的FIP猫的组织。在第一个目标下，我们将确定 联合治疗诱导淋巴组织内IL-7、干扰素-1和抗原提呈途径 组织以减轻淋巴消耗和建立有效和平衡的免疫反应对冠状病毒 感染。对于第二个目标，我们将确定联合治疗方法在抑制 外周血中淋巴细胞凋亡和T细胞耗竭，减轻全身炎症。这个 拟议的研究具有创新性，因为它将确定单一疗法如何影响免疫恢复，以及 如果MSC可以增强和加速临床相关的病毒清除和淋巴组织再生 MISC的动物模型。这项拟议的研究具有重要意义，因为它有望为 对联合化疗持续发展的科学论证和机理认识 MISC的生物治疗策略