The role of CD28- cells in human Chagas' disease

描述（由申请人提供）：本研究项目的长期目标是更好地了解定义的T细胞亚群在建立人类恰加斯病（一种由克氏锥虫感染引起的流行和地方性寄生虫病）的保护性和/或致病性免疫反应中的作用。通过一系列全面的机制研究，我们将剖析CD28差异表达的CD4+和CD8+ T细胞在人类恰加斯病免疫反应动力学中的作用。具体目标是：1.；检测不同临床形式恰加斯病个体CD28+和CD28- T细胞粘附分子的表达2. 测定来自不同临床形式恰加斯病个体的CD28+和CD28- T细胞毒性功能的强度和特异性；3. 确定来自不同临床形式恰加斯病个体的CD28+和CD28- T细胞的调节功能。为了进行这些研究，我们将使用一组精选的chagasic患者的外周血单个核细胞，仔细分类为属于不确定或严重的心脏临床形式。细胞募集潜力、细胞毒性和调节功能将通过FACS和生物测定分析表面或细胞内分子的表达，在体外和体外用寄生虫和自体抗原刺激后进行评估。这些研究将通过阐明CD28+和CD28-亚群如何与疾病的不同临床演变相关，大大提高对恰加斯病免疫病理学的认识。我们希望，从我们的研究结果中得出的新概念将允许识别疾病演变和/或发病率的标志，为临床干预提供新的可能性，使1700万感染者受益。我们的发现将超越恰加斯病的限制，增加我们对CD28差异表达的人类T细胞生物学的认识，为其他人类疾病的研究开辟新的可能性。最后，主要依靠巴西科研人员和学生的科学核心，这些研究的实施还将通过与国际和国内专家的密切合作，提高巴西的研究能力。

DESCRIPTION (provided by applicant): The long-term aim of this research project is to gain a better understanding of the involvement of defined T- cell subpopulations in the establishment of protective and/or pathogenic immune responses in human Chagas' disease, a prevalent and endemic parasitic disease caused by the infection with Trypanosoma cruzi. Through a series of comprehensive mechanistic studies we will dissect the role of CD4+ and CD8+ T cells with differential expression of CD28 in the dynamics of the immune response in human Chagas' disease. Specific aims are: 1.Determine the adhesion molecule expression by CD28+ and CD28- T cells from individuals with different clinical forms of Chagas' disease; 2. Determine the intensity and specificity of the cytotoxic function of CD28+ and CD28- T cells from individuals with different clinical forms of Chagas' disease; 3. Determine the regulatory function of CD28+ and CD28- T cells from individuals with different clinical forms of Chagas' disease. To perform these studies we will use peripheral blood mononuclear cells from a selected group of chagasic patients, carefully classified as belonging to the indeterminate or severe cardiac clinical forms. Cellular recruitment potential, cytotoxicity and regulatory functions will be evaluated ex vivo and after in vitro stimulation with parasite, as well as autologous antigens, through the analysis of expression of surface or intracellular molecules by FACS and by biological assays. These studies will greatly improve the knowledge on Chagas' disease immunopathology by clarifying how CD28+ and CD28- sub- populations relate to the differential clinical evolution of disease. We hope that the new concepts derived from our findings will allow for the identification of markers of disease evolution and/or morbidity, offering new possibilities of clinical intervention to benefit the 17 million infected people. Transcending the limits of Chagas' disease, our findings will add to our knowledge on the biology of human T cells with differential expression of CD28, opening new possibilities of studies in other human diseases. Finally, depending largely on a Brazilian scientific core of researchers and students, the implementation of these studies will also lead to increased research capacities in Brazil through intense collaborations with international and national specialists.