Role of CD4-CD8- DN T cells in Chagas Cardiomyopathy

CD4-CD8-DN T 细胞在恰加斯心肌病中的作用

• 批准号: 9767019
• 负责人: Walderez O. Dutra
• 金额: $ 13.5万
• 依托单位: FOUNDATION FOR RESEARCH DEVELOPMENT
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-21 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767019
• 关键词: Adhesions; Affect; Anti-inflammatory; Antigen Presentation; Antigens; Biological Markers; Biological Process; Blood; Brazil; CD1 Antigens; CD8B1 gene; Cardiac; Cardiac development; Cardiomyopathies; Cells; Cessation of life; Chagas Cardiomyopathy; Chagas Disease; Chronic; Clinical; Clinical Immunology; Code; Complex; Consensus; Country; Development; Disease; Disease Outcome; Disease Progression; Economic Burden; Family; Frequencies; Genomics; Glycobiology; Glycolipids; Glycoproteins; Goals; Health; Heart Diseases; Human; Immune response; Immunotherapeutic agent; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Institution; Intervention; Laboratories; Latin America; Molecular; Names; Nature; Parasites; Parasitic Diseases; Pathology; Patients; Play; Polysaccharides; Population; Predisposition; Public Health; Reaction; Retirement; Role; Scientist; Signs and Symptoms; Source; Students; Surface; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Technology Transfer; Testing; Therapeutic Intervention; Time; Tissues; Training; Trypanosoma cruzi; Vaccines; autoreactivity; base; cohort; cytokine; design; immunogenic; immunological intervention; immunoregulation; improved; infection risk; multidisciplinary; premature; prevent; therapeutic target; training opportunity; transcriptome

PROJECT SUMMARY/ABSTRACT Chagas disease (ChD) is a parasitic disease caused by the infection with the protozoan Trypanosoma cruzi. It is estimated that 6million people are infected by T. cruzi worldwide, with 70million at risk of infection. The majority of T. cruzi-chronically infected individuals remain in an asymptomatic clinical form, named indeterminate, while about 30% of the patients develop a severe cardiomyopathy that leads to over 10,000 deaths/year. There is no vaccine to prevent ChD, nor interventions that can prevent the progression of cardiomyopathy. ChD cardiomyopathy is the consequence of an inflammatory reaction, which leads to tissue destruction and pathology. Despite the complexity of the host-parasite interaction that leads to cardiomiopathy, it is a consensus that host's immune response is critical in determining disease outcome. We have previously shown that the indeterminate and cardiac clinical forms of ChD are associated with a predominant expression of down modulatory and inflammatory cytokines, respectively. We have also shown that CD4-CD8- (double- negative – DN) T cells are major sources of these cytokines in patients with chronic ChD (CChD). In addition, we have demonstrated that in vitro blocking of T. cruzi-induced DN T cell activation, through the inhibition of antigen presentation via CD1d, shifts the cytokine expression of DN T cells from an inflammatory to a predominantly anti-inflammatory profile. Thus, we identified, for the first time, a cell population that may be a potential target for an immunotherapeutic approach to inhibit inflammation-induced pathology and prevent cardiomyopathy development. The main objective of this project is to elucidate cellular and molecular mechanisms behind the activation of DN T cells during CChD, with the long-term goal of designing strategies to prevent development of cardiac pathology. Our specific aims are: (1) To identify the T. cruzi-derived antigen(s) responsible for the activation of DN T cells and identify the DN T cell subpopulation most reactive (TCR α/β, TCR γ/δ, and NK T cells) to this(ese) antigen(s) from indeterminate and cardiac Chagas patients with different degrees of cardiomyopathy; (2) To identify the antigen-presenting molecule responsible for presentation to DN T cells and to test if blocking of the antigen-presenting complex will modulate the activation and functional profile of DN T cell subsets from Chagas patients of different clinical forms and stages; (3) To analyze the coding transcriptome of purified DN T cell subsets from distinct Chagas patient groups before and after blocking the activation by the specific parasite component. By bringing together a group of Brazil and US- based scientists with complementary expertise, we hope to dissect the role of DN T cells in disease progression, working towards the development of immunological interventions, finding biomarkers of disease progression, while performing technology transfer and scientific training amongst all involved institutions.

项目总结/摘要 查加斯病（ChD）是由原生动物克氏锥虫感染引起的寄生虫病。它 据估计，有600万人感染了T.全球有7000万人面临感染风险。的 大多数T。克鲁济慢性感染者仍处于无症状临床状态， 不确定，而大约30%的患者发展为严重的心肌病，导致超过10，000 死亡/年没有疫苗可以预防ChD，也没有干预措施可以预防ChD的进展。 心肌病ChD心肌病是炎症反应的结果，导致组织 破坏和病理学。尽管导致心肌病的宿主-寄生虫相互作用的复杂性， 宿主的免疫应答在决定疾病结果方面是关键的，这是共识。我们先前已经 结果表明，ChD的不确定和心脏临床形式与主要表达相关， 下调和炎性细胞因子。我们还发现，CD 4-CD 8-（双- 阴性DN）T细胞是慢性ChD（CChD）患者中这些细胞因子的主要来源。此外，本发明还提供了一种方法， 我们已经证明体外阻断T. cruzi诱导的DN T细胞活化，通过抑制 通过CD 1d的抗原呈递，使DN T细胞的细胞因子表达从炎性转变为炎性。 主要是抗炎作用。因此，我们第一次发现了一个细胞群， 作为免疫疗法的潜在靶点，可抑制炎症诱导的病理学并预防 心肌病发展。这个项目的主要目的是阐明细胞和分子 CChD期间DN T细胞激活背后的机制，长期目标是设计策略 防止心脏病的发展我们的具体目标是：（1）识别T。Cruzi导出的 负责DN T细胞活化的抗原，并鉴定最具反应性的DN T细胞亚群 (TCRα/β、TCR γ/δ和NK T细胞）对该（ese）抗原的反应 不同程度心肌病的患者;（2）确定负责 为了检测抗原呈递复合物的阻断是否会调节DN T细胞的活化， 不同临床形式和阶段恰加斯病患者的DN T细胞亚群及其功能特征;（3）为了 分析来自不同恰加斯病患者组的纯化DN T细胞亚群的编码转录组， 在阻断特定寄生虫成分的激活之后。通过召集巴西和美国的一组- 基于科学家的互补专业知识，我们希望剖析DN T细胞在疾病中的作用， 进展，致力于发展免疫干预措施，寻找疾病的生物标志物 在所有相关机构之间进行技术转让和科学培训的同时，