Cytotoxic Cell Dysfunction in HGA

HGA 中的细胞毒性细胞功能障碍

基本信息

批准号：
8306751
负责人：
JOHN STEPHEN Dumler
金额：
$ 24.3万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8306751
关键词：
Admission activity Adrenal Cortex Hormones Anaplasma phagocytophilum Animals Antigen-Presenting Cells Antigens Bacteremia Bacteria Bovine Anaplasmosis CD8-Positive T-Lymphocytes CD8B1 gene Cell physiology Cells Clinical Cytolysis Data Defect Dendritic Cells Disease Disease model Dissociation Equus caballus Event Functional disorder Granzyme Hemophagocytic Syndrome Histopathology Human Immune Immune system In Vitro Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Interleukin-10 Interleukin-12 Laboratories Lead Lesion Life Light Link Macrophage Activation Metalloproteases Modeling Mus Natural Immunity Natural Killer Cells Organism Pathogenesis Process Production Reactive Nitrogen Species Research SCID Mice Septic Shock Serum Severities Signal Pathway Systemic disease T-Lymphocyte Therapeutic Intervention Tick-Borne Infections Ticks Tissues Toxic Shock Syndrome adaptive immunity base cell killing combat cytokine cytotoxic cytotoxicity in vivo killings macrophage mouse model pathogen perforin reactive oxygen intermediate response vector

项目摘要

DESCRIPTION (provided by applicant): This proposal is directed at dissecting the immunopathogenetic mechanisms of A. phagocytophilum infection in its dichotomous ability to cause mild and severe disease. We previously identified supportive data and provide preliminary studies that show the importance of NK and NKT cells in the induction of inflammatory disease. Moreover, studies in mice and humans both provide evidence of macrophage activation and hemophagocytic syndrome-like processes as the potential basis of inflammatory tissue injury and severe disease. Since macrophage activation and hemophagocytic syndromes are biologically linked to defective cytotoxic cell responses that lack the ability to dampen and resolve inflammation, we propose here to study whether A. phagocytophilum infection induces defects in direct cell killing by cytotoxic cells such as NK, NKT, and CD8 T lymphocytes, yet does not alter the profile of induced proinflammatory and macrophage activating cytokines. We expect to study this by in vitro analyses using purified cells and bacteria as a highly defined and controlled experimental approach and to verify the results in vivo using the mouse model we developed. We anticipate that these studies could shed light on the specific immunological abnormalities that occur with A. phagocytophilum infection and allow a more focused and intensive search for targets that could provide new opportunities for therapeutic interventions that diminish the severe consequences of infection.

描述（由申请人提供）：该提案旨在解剖吞噬细胞杆菌感染的免疫发育机制，以引起轻度和严重疾病的二分法能力。我们先前鉴定出支持性数据并提供初步研究，以表明NK和NKT细胞在诱导炎症性疾病中的重要性。此外，对小鼠和人类的研究都提供了巨噬细胞激活和类造血综合征过程的证据，这是炎症组织损伤和严重疾病的潜在基础。由于巨噬细胞活化和胞藻综合征在生物学上与缺乏抑制和解决炎症的能力的细胞毒性细胞反应联系在一起，因此我们在这里提议研究吞噬细胞嗜血杆菌感染是否会导致诸如NK，NKT和CD8 tlym nk的细胞毒性细胞中的直接细胞中的直接细胞中的缺陷诱导，并诱发了CD8 T lymphy nk，nkt和cd8 t lym t。促炎和巨噬细胞激活细胞因子。我们希望通过使用纯化的细胞和细菌作为高度定义和受控的实验方法进行体外分析来研究这一点，并使用我们开发的小鼠模型在体内验证结果。我们预计，这些研究可以阐明吞噬细胞嗜血杆菌感染带来的特定免疫学异常，并更加集中，更深入地搜索靶标，这些靶标可以为减少严重感染后果的治疗干预提供新的机会。