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

• 批准号: 8004301
• 负责人: NATASHA CORBITT
• 金额: $ 4.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8004301
• 关键词: Bacteria; Cell Maturation; Cells; Cyclosporine; Data; Development; Drug toxicity; Foundations; Frequencies; Future; Goals; Graft Rejection; Graft Tolerance; Human; Immune; Immune system; Infection; Intestines; Kupffer Cells; Leukocytes; Liver; Malignant Neoplasms; Modeling; Outcome; Play; Population; Property; Quality of life; Reporting; Role; Route; Therapeutic; Therapeutic immunosuppression; Transplant Recipients; Transplantation; United States; improved; liver transplantation; mycophenolate mofetil; prevent; public health relevance

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. PUBLIC HEALTH RELEVANCE: Liver transplantation outcome has drastically improved with immunosuppressive therapies like Cyclosporin A and Mycophenolate mofetil. However, many of the complications associated with liver transplantation (drug toxicity, infection, and malignancy) are caused by immunosuppressive therapy. By furthering our understanding of the mechanisms responsible for liver tolerance, identification of new strategies to achieve liver tolerance will be possible. Alternative strategies preventing liver graft rejection without suppressing the immune system have the potential to change the quality of life of thousands of people.

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。 公共卫生相关性：通过环孢素 A 和吗替麦考酚酯等免疫抑制疗法，肝移植的结果已得到显着改善。然而，许多与肝移植相关的并发症（药物毒性、感染和恶性肿瘤）是由免疫抑制治疗引起的。通过进一步了解肝脏耐受性的机制，将有可能确定实现肝脏耐受性的新策略。在不抑制免疫系统的情况下预防肝移植排斥的替代策略有可能改变成千上万人的生活质量。