Mechanisms and consequences of T cell inflammasome activation in Graft-Versus Host Disease

移植物抗宿主病中 T 细胞炎性体激活的机制和后果

基本信息

批准号：
10511777
负责人：
Edward M Campbell
金额：
$ 19.25万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10511777
关键词：
Acute Graft Versus Host Disease Adaptive Immune System Affect Allogenic Attenuated Autoimmune Diseases Automobile Driving B-Lymphocytes CASP1 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Caspase Cell Death Cells Cellular biology Development Disease Donor person Goals Grant Human Immune Immune response Immunologic Deficiency Syndromes In Vitro Individual Inflammasome Inflammation Inflammatory Intervention Literature Measures Mediating Mediator of activation protein Methods Modeling Mus Pathogenesis Pathologic Pathology Pathway interactions Patients Peripheral Blood Mononuclear Cell Persons Population Protein Isoforms Proteins Reporter Role Severity of illness Sterility Stimulus T-Cell Activation T-Lymphocyte Testing Transcript cancer genetics cell type cytokine cytotoxic graft vs host disease graft vs leukemia effect hematopoietic cell transplantation hematopoietic transplantation in vivo neoplastic cell novel pathogen prevent response

项目摘要

Graft Versus Host Disease (GVHD) remains a significant issue in people receiving hematopoietic cell transplants to treat various cancers, genetic immunodeficiencies and other diseases. In GVHD, alloreactive T cells mediate this pathology, as T cell depleted hematopoietic transplants to not induce GVHD. We have observed that following transplantation, donor CD8 T cells undergo inflammasome activation, as measured by the activation of caspase‐1. However, these cells do not die via pyroptosis, which may alleviate their cytotoxic consequences in the host. We also observe that these cells in which the inflammasome is activated hyperexpress a protein, Ifi202, which is known to attenuate inflammasome activation, and human T cells similarly express IFI16, which functions similarly in human cells. We hypothesize that Ifi202 limits the degree of caspase‐1 activation in these cells, and thus prevents these cells from undergoing pyroptosis. The goal of this project is to determine the mechanism of inflammasome activation in these T cells, and to determine the role of Ifi202 in preventing pyroptosis in CD8 T cells during GVHD. We hypothesize that reduced Ifi202 expression in these cells will attenuate GVHD pathology by increasing pyroptosis in alloreactive CD8 T cells.

在接受造血的人中，移植物与宿主病（GVHD）仍然是一个重大问题细胞移植以治疗各种癌症，遗传免疫缺陷和其他疾病。在 GVHD，同种异体T细胞介导该病理，因为T细胞耗尽造血移植不要诱导GVHD。我们已经观察到移植后，供体CD8 T细胞通过caspase -1的激活测量，经历炎症体激活。但是，这些细胞不会通过凋亡而死亡，这可能会减轻其在宿主中的细胞毒性后果。我们还观察到，这些细胞在其中激活了炎性小体的蛋白质， IFI202，已知会减弱炎性体激活，人类T细胞类似表达IFI16，在人类细胞中起作用类似。我们假设IFI202限制了这些细胞中caspase -1激活的程度，因此阻止了这些细胞进行凋亡。该项目的目的是确定炎性体激活的机制在这些T细胞中，并确定IFI202在预防CD8 T细胞中凋亡中的作用在GVHD期间。我们假设这些细胞中IFI202的表达降低会减弱GVHD 通过增加同种反应性CD8 T细胞中的凋亡来增加病理。