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: 10223105
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223105
• 关键词: Adhesions; Affect; Anti-Inflammatory Agents; Antigen Presentation; Antigens; Biological Markers; Biological Process; Blood; Brazil; CD1 Antigens; CD8B1 gene; Cardiac; Cardiac development; Cardiomyopathies; Cells; Cessation of life; 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; chagasic cardiomyopathy; 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.

项目概要/摘要 恰加斯病 (ChD) 是一种由原生动物克氏锥虫感染引起的寄生虫病。它 据估计，全球有 600 万人感染克氏锥虫，其中 7000 万人面临感染风险。这 大多数克氏锥虫慢性感染者仍处于无症状的临床状态，称为 不确定，而大约 30% 的患者会出现严重的心肌病，导致超过 10,000 死亡人数/年。没有疫苗可以预防 ChD，也没有干预措施可以阻止 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-寄生虫相互作用非常复杂， 人们一致认为，宿主的免疫反应对于决定疾病的结果至关重要。我们之前有过 表明 ChD 的不确定型和心脏临床形式与主要表达相关 分别下调调节细胞因子和炎症细胞因子。我们还证明了 CD4-CD8-（双 阴性 – DN) T 细胞是慢性 ChD (CChD) 患者这些细胞因子的主要来源。此外， 我们已经证明，通过抑制 T. cruzi 诱导的 DN T 细胞活化，可在体外阻断 通过 CD1d 呈递抗原，将 DN T 细胞的细胞因子表达从炎症性转变为 主要是抗炎作用。因此，我们首次鉴定出一个可能是 免疫治疗方法的潜在目标，以抑制炎症诱发的病理学并预防 心肌病的发展。该项目的主要目标是阐明细胞和分子 CChD 期间 DN T 细胞激活背后的机制，以及设计策略的长期目标 以防止心脏病理学的发展。我们的具体目标是： (1) 鉴定 T. cruzi 衍生的 负责激活 DN T 细胞的抗原并识别最具反应性的 DN T 细胞亚群 （TCR α/β、TCR γ/δ 和 NK T 细胞）针对来自不确定型和心脏病恰加斯患者的这种抗原 患有不同程度的心肌病； (2) 鉴定负责的抗原呈递分子 呈递给 DN T 细胞并测试阻断抗原呈递复合物是否会调节激活 不同临床形式和阶段的 Chagas 患者 DN T 细胞亚群的功能概况； (3) 至 分析来自不同 Chagas 患者组的纯化 DN T 细胞亚群之前和之前的编码转录组 阻断特定寄生虫成分的激活后。通过将巴西和美国的团队聚集在一起—— 基于具有互补专业知识的科学家，我们希望剖析 DN T 细胞在疾病中的作用 进展，致力于开发免疫干预措施，寻找疾病的生物标志物 进步，同时在所有相关机构之间进行技术转让和科学培训。

项目成果

Cytokine Networks as Targets for Preventing and Controlling Chagas Heart Disease.

• DOI: 10.3390/pathogens12020171
• 发表时间: 2023-01-21
• 期刊: Pathogens (Basel, Switzerland)

Double-negative T cells: Setting the stage for disease control or progression.

• DOI: 10.1111/imm.13441
• 发表时间: 2022-04
• 期刊: Immunology
• 影响因子: 6.4

T-cell receptor variable region usage in Chagas disease: A systematic review of experimental and human studies.

• DOI: 10.1371/journal.pntd.0010546
• 发表时间: 2022-09
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8

SBC Guideline on the Diagnosis and Treatment of Patients with Cardiomyopathy of Chagas Disease - 2023.

• DOI: 10.36660/abc.20230269
• 发表时间: 2023-06-26
• 期刊: Arquivos brasileiros de cardiologia
• 影响因子: 2.6
• 作者: Marin-Neto JA;Rassi A Jr;Oliveira GMM;Correia LCL;Ramos Júnior AN;Luquetti AO;Hasslocher-Moreno AM;Sousa AS;Paola AAV;Sousa ACS;Ribeiro ALP;Correia Filho D;Souza DDSM;Cunha-Neto E;Ramires FJA;Bacal F;Nunes MDCP;Martinelli Filho M;Scanavacca MI;Saraiva RM;Oliveira Júnior WA;Lorga-Filho AM;Guimarães AJBA;Braga ALL;Oliveira AS;Sarabanda AVL;Pinto AYDN;Carmo AALD;Schmidt A;Costa ARD;Ianni BM;Markman Filho B;Rochitte CE;Macêdo CT;Mady C;Chevillard C;Virgens CMBD;Castro CN;Britto CFPC;Pisani C;Rassi DDC;Sobral Filho DC;Almeida DR;Bocchi EA;Mesquita ET;Mendes FSNS;Gondim FTP;Silva GMSD;Peixoto GL;Lima GG;Veloso HH;Moreira HT;Lopes HB;Pinto IMF;Ferreira JMBB;Nunes JPS;Barreto-Filho JAS;Saraiva JFK;Lannes-Vieira J;Oliveira JLM;Armaganijan LV;Martins LC;Sangenis LHC;Barbosa MPT;Almeida-Santos MA;Simões MV;Yasuda MAS;Moreira MDCV;Higuchi ML;Monteiro MRCC;Mediano MFF;Lima MM;Oliveira MT;Romano MMD;Araujo NNSL;Medeiros PTJ;Alves RV;Teixeira RA;Pedrosa RC;Aras Junior R;Torres RM;Povoa RMDS;Rassi SG;Alves SMM;Tavares SBDN;Palmeira SL;Silva Júnior TLD;Rodrigues TDR;Madrini Junior V;Brant VMDC;Dutra WO;Dias JCP
• 通讯作者: Dias JCP

Blocking activation of CD4-CD8- T cells modulates their cytotoxic potential and decreases the expression of inflammatory and chemotactic receptors.

• DOI: 10.1016/j.clim.2023.109331
• 发表时间: 2023-04
• 期刊: Clinical immunology
• 影响因子: 8.6
• 作者: E. G. Neves;C. Koh;Pedro Paulo Diniz Lucinda;T. G. Souza-Silva;Nayara I. Medeiros;A. Pantaleão;Antonio Mutarelli;Juliana de Assis Silva Gomes;Silvana de Araújo Silva;K. Gollob;Maria do Carmo Pereira Nunes;W. Dutra