Understanding Interleukin-18 Mediated Susceptibility to Systemic Hyperinflammation

了解 Interleukin-18 介导的全身性过度炎症的易感性

基本信息

批准号：
10481855
负责人：
Scott William Canna
金额：
$ 33.13万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10481855
关键词：
Adjuvant Affect American Antibiotics Automobile Driving B-Lymphocytes Bacterial DNA Cessation of life Characteristics Child Childhood Chronic Clinical Clinical Trials Complication DNA sequencing Data Data Set Development Disease Early Diagnosis Evaluation Feces Functional disorder Genetic Genetic Transcription Goals Human Hyperactivity IL18 gene Immune Immunity Immunologic Deficiency Syndromes Immunologics Immunotherapy Impairment Individual Infection Inflammasome Inflammation Inflammatory Interferons Interleukin-1 beta Interleukin-18 Interleukins Intestines Investments Life Lymphocyte Lymphoid Cell Macrophage activation syndrome Measures Mediating Microbe Modeling Molecular Morbidity - disease rate Mus Myelogenous Myeloid Cells Organ Organoids Pathway interactions Patients Persons Phenotype Physiology Predisposition Prevention Prevention strategy Procedures Production Proteins Research Rheumatism Risk Sepsis Serum Source Stem cell transplant Systemic Inflammatory Response Syndrome T-Cell Activation T-Lymphocyte Testing Therapeutic Transgenic Mice adaptive immunity base cytokine cytotoxic cytotoxicity dysbiosis effective therapy experience experimental study gain of function mutation gut colonization gut microbiome high risk immunopathology improved infancy innovation insight intestinal epithelium microbial microbial colonization mortality novel novel therapeutics pediatric rheumatic diseases personalized diagnostics prevent protein complex specific biomarkers systemic juvenile idiopathic arthritis

项目摘要

PROJECT SUMMARY/ABSTRACT Despite major investments, the promise of immunotherapy for Systemic Inflammatory Response Syndrome (SIRS) remains unfulfilled. A hyperinflammatory SIRS subset suffers much higher mortality, and thus is in greatest need of new therapies to limit immunopathology. The clinical factors used to define hyperinflammatory SIRS were inspired by a life-threatening complication of pediatric rheumatic disease called Macrophage Activation Syndrome (MAS). Recently, MAS was genetically associated with hyperactivity of the NLRC4 inflammasome and excess Interleukin (IL)-18, strongly suggesting that excess IL-18 is a fundamental host susceptibility factor for hyperinflammatory SIRS. The objectives of this proposal are to identify the relevant mechanisms driving IL-18 overproduction and to define the pathways by which IL-18 promotes hyperinflammation. Our central hypothesis is that intestinal IL-18 overproduction promotes both lymphocyte hyperactivation and dysfunction to drive hyperinflammation and the MAS phenotype. Our guiding rationale is that understanding the mechanisms driving hyperinflammatory SIRS will enable rational identification of at-risk patients, identify potential prevention strategies, and facilitate the use of targeted immunotherapies necessary to prevent organ dysfunction and death. To accomplish our objectives, we first aim to identify the causes of elevated IL-18 in MAS. This will involve (i) determining the molecular machinery necessary for inflammasome-driven intestinal overproduction of IL-18; (ii) isolating the specific microbial factors affecting intestinal IL-18 production and testing their effects on experimental MAS; (iii) determining the cellular sources (intestinal vs. myeloid) of inducible IL-18 in models of systemic hyperinflammation; and (iv) correlating systemic IL-18 levels with fecal colonization in children with Systemic Juvenile Idiopathic Arthritis, who are at high risk for MAS. Our second aim is to define the mechanisms by which IL-18 promotes hyperinflammation. This will involve (i) determining the immunologic mechanisms by which IL-18 promotes models of hyperinflammation; (ii) determining how cytotoxic impairment and excess IL-18 synergistically promote immunopathology; and (iii) determining how NLRC4 hyperactivity and excess IL-18 promote susceptibility to infection. These experiments will contribute significantly to defining new genetic and mechanistic drivers of hyperinflammation, and they will guide precision diagnostics, prevention strategies, and targeted treatments to prevent morbidity and mortality in hyperinflammatory SIRS. The proposed research is innovative because it originates with mechanisms derived from monogenic human hyperinflammatory diseases to understand and manipulate SIRS physiology more broadly. Ultimately, we expect completion of the proposed studies to provide specific insights useful for guiding early detection of the hyperinflammatory SIRS phenotype and novel means to disrupt life-threatening immunopathology.

项目摘要/摘要尽管进行了大量投资，但免疫疗法的全身性炎症反应的希望综合征（SIRS）仍然无法实现。高炎性的SIRS子集遭受更高的死亡率，并且因此，最需要新疗法来限制免疫病理学。用于定义的临床因素高炎性SIRS的灵感来自儿科风湿病的生命并发症，称为巨噬细胞激活综合征（MAS）。最近，MAS在遗传上与 NLRC4炎症体和多余的白介素（IL）-18，强烈建议过量的IL-18是基本的高炎性SIR的宿主敏感性因子。该提案的目标是确定相关的驱动IL-18的机制过量生产并定义IL-18促进的途径高炎症。我们的中心假设是肠道IL-18过量产生促进两种淋巴细胞过度激活和功能障碍，可驱动高炎症和MAS表型。我们的指导理由是理解驱动高炎性SIRS的机制将使处于危险中的合理识别患者，确定潜在的预防策略，并促进必要的靶向免疫疗法防止器官功能障碍和死亡。为了实现我们的目标，我们首先旨在确定MAS中IL-18升高的原因。这会涉及（i）确定炎症驱动肠道过量生产所需的分子机械 IL-18; （ii）隔离影响肠道IL-18产生并测试其作用的特定微生物因子在实验MAS上；（iii）在模型中确定诱导IL-18的细胞源（肠与髓样）全身性高炎症；（iv）将全身IL-18水平与患有粪便定植相关联全身少年特发性关节炎，有MAS的高风险。我们的第二个目标是定义 IL-18促进过度炎症的机制。这将涉及（i）确定免疫学 IL-18促进过度炎症模型的机制；（ii）确定细胞毒性损伤以及超过IL-18协同促进免疫病理学；（iii）确定NLRC4多动症和如何多余的IL-18促进感染的敏感性。这些实验将对定义新的遗传和机械驱动因素产生重大贡献过度炎症，它们将指导精确诊断，预防策略和有针对性的治疗方法预防高炎性sir的发病率和死亡率。拟议的研究具有创新性，因为它起源于从单基因人类高炎性疾病中得出的机制来理解和更广泛地操纵爵士生理学。最终，我们预计提议的研究完成特定的见解可用于指导早期检测高炎性SIRS表型和新型手段破坏威胁生命的免疫病理学。