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）对于接受造血的人来说仍然是一个重要问题 细胞移植治疗各种癌症、遗传性免疫缺陷和其他疾病。 GVHD、同种异体反应性 T 细胞介导这种病理学，因为 T 细胞耗尽的造血移植 我们观察到移植后，供体 CD8 T 细胞不会诱发 GVHD。 通过 caspase-1 的激活来测量，这些物质经历了炎症小体激活。 细胞不会通过焦亡而死亡，这可以减轻它们对宿主的细胞毒性后果。 还观察到这些炎症小体被激活的细胞过度表达蛋白质， Ifi202 已知可减弱炎症小体激活，与人类 T 细胞类似 表达 IFI16，其在人类细胞中的功能类似。我们发现 IFI202 限制了 这些细胞中 caspase-1 的激活程度，从而防止这些细胞经历 该项目的目标是确定炎症小体激活的机制。 并确定 Ifi202 在预防 CD8 T 细胞焦亡中的作用 我们认为减少这些细胞中的 Ifi202 表达会减轻 GVHD。 通过增加同种异体反应性 CD8 T 细胞的焦亡来实现病理学。