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: 10706865
• 负责人: Amir Kol
• 金额: $ 19.65万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10706865
• 关键词: 2019-nCoV; 21 year old; Affect; Animal Model; Anti-Inflammatory Agents; Antibodies; Antigen Presentation; Antigen Presentation Pathway; 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.

该 R21 提议通过研究多系统的新治疗方法来填补重大科学空白 使用创新且临床相关的猫科动物模型进行儿童炎症综合征（MIS-C）。我们 提议测试一种针对病毒复制、淋巴组织损伤的新型多管齐下的治疗模式 患有自然发生的猫传染性腹膜炎（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 MIS-C 的治疗方法。该提案的总体目标是测试一种新颖的多管齐下 化学生物治疗策略并确定其在临床相关的潜在作用机制 动物模型。中心假设是组合的 GS-441524-多能干细胞/基质细胞 (MSC) 治疗协同恢复受损的淋巴组织，减少全身炎症并增强 患有 FIP 的猫具有特异性抗冠状病毒 (CoV) 免疫力。该项目的基本原理得到了我们的支持 初步数据表明 GS-441524 是一种有效的抗 CoV 药物，并且 MSC 在病毒感染中具有新的作用 通过增强抗病毒免疫力、抑制全身炎症和再生淋巴来对抗感染 组织结构和功能。将通过追求两个具体目标来检验中心假设：1）确定 GS-441524-MSC联合治疗对病毒载量、淋巴组织损伤和修复的影响，以及 阐明控制其作用机制的分子网络； 2) 确定 GS-的效果 441524-MSC联合治疗对T细胞活化/耗竭、炎症和淋巴细胞耗竭 患有 FIP 的猫的外周血室。为了验证我们的假设，我们将通过 FIP 登记客户拥有的猫 进入具有两个实验组的双盲试验：仅 GS-441524，或组合 GS-441524 -MSC 治疗。在整个研究过程中将连续收集血液、积液和淋巴结组织样本 时间线。将从健康对照中收集平行样本。我们将进一步利用我们的生物库 来自患有 FIP 并死于该疾病的猫的组织。在第一个目标下，我们将确定 诱导淋巴内 IL-7、1 型 IFN 和抗原呈递途径的联合治疗方法 组织以减轻淋巴耗竭并对冠状病毒产生有效且平衡的免疫反应 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，减少全身炎症。这 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，并且 间充质干细胞是否可以在临床相关的疾病中增强和加速病毒清除和淋巴组织再生 MIS-C动物模型。拟议的研究意义重大，因为它有望提供强有力的 联合化学疗法持续发展的科学依据和机制理解 MIS-C 的生物治疗策略。