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.

本R21建议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