The Role of Gut Bacteria in Kupffer Cell Development and Function

肠道细菌在枯否细胞发育和功能中的作用

基本信息

批准号：
8460573
负责人：
NATASHA CORBITT
金额：
$ 3.04万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2011-02-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8460573
关键词：
Adult Allogenic Anti-Inflammatory Agents Anti-inflammatory Antigen-Presenting Cells Bacteria Bacterial Antigens Birth CD4 Positive T Lymphocytes Cell Adhesion Molecules Cell Communication Cell Maturation Cells Characteristics Cirrhosis Cyclosporine Data Dendritic Cells Development Drug toxicity Endothelial Cells Enzyme-Linked Immunosorbent Assay Family suidae Fetal Development Flow Cytometry Foundations Frequencies Future Goals Graft Rejection Graft Tolerance Helper-Inducer T-Lymphocyte Hepatic Host Defense Human Immune Immune system Immunofluorescence Immunologic Infection Inflammatory Interleukin-6 Intestines Kupffer Cells Latex Bead Leukocytes Life Liver Liver Failure Malignant Neoplasms Measures Mediating Methodology Mixed Lymphocyte Culture Test Modeling Mus Natural Immunity Organ Outcome Pathway interactions Phagocytes Phagocytosis Play Population Production Property Quality of life Recruitment Activity Regulatory T-Lymphocyte Reporting Reverse Transcriptase Polymerase Chain Reaction Rodent Role Route Stem cells T-Lymphocyte Testing Therapeutic Therapeutic immunosuppression Transplant Recipients Transplantation United States Weaning Western Blotting adaptive immunity arm cell type chemokine commensal microbes cytokine fetal improved killer T cell liver transplantation macrophage monocyte mycophenolate mofetil prevent public health relevance receptor stellate cell transcription factor uptake

项目摘要

DESCRIPTION (provided by applicant): Over 6,000 people require liver transplants every year in the Unites States alone. To date, several human liver transplant recipients have developed liver graft tolerance without immunosuppressive therapy, which suggests that the liver has tolerogenic properties. Kupffer Cells (KC), liver macrophages, have reported involvement in liver tolerance. Depletion of KC results in loss of tolerance and graft rejection in transplant models. Although KC play an important role in liver tolerance, the exact mechanisms behind liver tolerance remain unknown. Interestingly, gut bacteria are essential to the development of many aspects of the immune system. Additionally, bacteria of the intestinal flora influence the development of immune cells involved in liver tolerance. Because of the role of KC in liver tolerance, identifying the significance of gut bacteria in the development of these cells is an important goal. We hypothesize that the gut flora stimulates the development of the KC population and can modulate the tolerogenic potential of KC. Our preliminary data demonstrate a reduction in liver leukocytes in the absence of gut bacteria. Moreover, we observed a reduction in KC frequency in the absence of gut bacteria as well. This study will evaluate when gut bacteria influence KC development, the route of KC expansion promoted by gut bacteria, and the mechanism by which gut bacteria promote KC expansion. Moreover, we aim to determine the effect of gut bacteria on KC maturation, function, and tolerogenic potential. The results of this study will provide the foundation for future studies evaluating the therapeutic potential of gut flora manipulation to achieve liver tolerance via development of tolerogenic KC.

描述（由申请人提供）：仅在美国，每年就有超过 6,000 人需要进行肝脏移植。迄今为止，一些人类肝移植受者在没有进行免疫抑制治疗的情况下已经产生了肝移植耐受性，这表明肝脏具有耐受性。据报道，库普弗细胞（KC）（肝脏巨噬细胞）参与肝脏耐受性。 KC 耗尽会导致移植模型中耐受性丧失和移植物排斥。尽管 KC 在肝脏耐受性中发挥重要作用，但肝脏耐受性背后的确切机制仍不清楚。有趣的是，肠道细菌对于免疫系统许多方面的发育至关重要。此外，肠道菌群的细菌影响参与肝脏耐受性的免疫细胞的发育。由于 KC 在肝脏耐受性中的作用，确定肠道细菌在这些细胞发育中的重要性是一个重要目标。我们假设肠道菌群刺激 KC 群体的发育并可以调节 KC 的耐受性潜力。我们的初步数据表明，在没有肠道细菌的情况下，肝脏白细胞会减少。此外，我们还观察到在没有肠道细菌的情况下 KC 频率也会降低。本研究将评估肠道细菌何时影响 KC 发育、肠道细菌促进 KC 扩张的途径以及肠道细菌促进 KC 扩张的机制。此外，我们的目标是确定肠道细菌对 KC 成熟、功能和耐受潜力的影响。这项研究的结果将为未来的研究奠定基础，评估肠道菌群调控通过发展耐受性 KC 来实现肝脏耐受的治疗潜力。