The Role of Gut Bacteria in Kupffer Cell Development and Function

描述（由申请人提供）：仅在美国，每年就有超过6000人需要肝脏移植。迄今为止，一些人类肝移植受者在没有免疫抑制治疗的情况下已经产生了肝移植耐受，这表明肝脏具有耐受性。库普弗细胞（KC），肝巨噬细胞，已报道参与肝脏耐受。在移植模型中，KC的缺失导致耐受性丧失和移植物排斥反应。虽然KC在肝脏耐受中起重要作用，但肝脏耐受背后的确切机制尚不清楚。有趣的是，肠道细菌对免疫系统的许多方面的发育都至关重要。此外，肠道菌群的细菌影响参与肝脏耐受的免疫细胞的发育。由于KC在肝脏耐受中的作用，确定肠道细菌在这些细胞发育中的意义是一个重要的目标。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。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。本研究将探讨肠道细菌对KC发育的影响，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，我们的目的是确定肠道细菌对KC成熟、功能和耐受性的影响。本研究的结果将为未来的研究提供基础，以评估肠道菌群操纵的治疗潜力，通过耐受性KC的发展来实现肝脏耐受。

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.