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

• 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
• 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

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）在接受造血的人群中仍然是一个重要的问题