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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：
10684330
负责人：
Edward M Campbell
金额：
$ 23.1万
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/10684330
关键词：
Acute Graft Versus Host Disease Adaptive Immune System Affect Allogenic Attenuated Autoimmune Diseases Automobile Driving CASP1 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Caspase Cell Death Cell Separation Cells Cellular biology Development Disease Genetic Goals Grant Human Immune Immune response Immunologic Deficiency Syndromes In Vitro Individual Inflammasome Inflammatory Intervention Literature Malignant Neoplasms Measures Mediating Mediator Methods Modeling Mus Pathogenesis Pathologic Pathology Pathway interactions Patients Peripheral Blood Mononuclear Cell Persons Population Predisposition Protein Isoforms Proteins Reporter Role Severity of illness Sorting Sterility Stimulus T-Cell Activation T-Cell Depletion T-Lymphocyte T-cell inflamed Testing Transcript Transplantation cell type cytokine cytotoxic cytotoxic CD8 T cells 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.

移植物抗宿主病(GVHD)仍然是接受造血者的一个重要问题细胞移植用于治疗各种癌症、遗传免疫缺陷和其他疾病。在……里面 GVHD，同种异体反应性T细胞介导了这种病理，因为T细胞耗尽了造血移植不要诱发移植物抗宿主病。我们观察到，移植后，供者CD8 T细胞通过caspase-1的激活来衡量炎性小体的激活。然而，这些细胞不会因上睑下垂而死亡，这可能会减轻它们对宿主的细胞毒性后果。我们还可以观察到这些炎症小体被激活的细胞高表达一种蛋白质，已知可减弱炎症体激活的IFI202与人类T细胞类似表达IFI16，它在人类细胞中的功能类似。我们假设IFI202限制了 Caspase-1在这些细胞中的激活程度，从而阻止这些细胞经历上睑下垂。这个项目的目标是确定炎症小体激活的机制。并确定IFI202在预防CD8T细胞下垂中的作用在GVHD期间。我们推测，这些细胞中IFI202的表达减少将减弱GVHD 同种异体反应性CD8 T细胞上睑下垂增加的病理学。