调控Kupffer细胞中Notch1-Jagged1通路诱导大鼠肝移植免疫耐受形成

Kupffer cells（KCs），the most important and special macrophages resident in the liver，and the inducible tolerogenic properties of the liver are widely recognized. Therefore，a great attention has been focused on the possible roles and mechanism of KCs from liver allograft in tolerance induction and actue rejection. However, researches failed to reveal the whole picture. our group demonstrated that KCs possess a bidirectional feature during the proceeding of actue rejection after liver transplantation, and the mechanism is most likely associated with modulated T help (Th) cell differentiation and its immune function. Our current studies indicated that the regulation of KCs polarity and Th cell differentiation via multi-level cordination are the keys to induce immune tolerance post-transplantation, thus the normally single-way modulators may not achieved its supposed efficacy in immune tolerance. Recently, sereval studies reported that the member of Notch receptor family, an ancient signal tranduction pathway, Notch1, binding to its ligand Jagged1, has gain new properties in the regulation of immune system,mainly including APCs polarity and Th differentiation perference toward Th2/Treg. But so far there were rare related research in solid organ transplantation, especially in liver. We hereby put forward a hypothesis that up-regulation of Notch1-Jagged1 pathway in KCs may induce liver transplant tolerance via KCs immune deviation and cytokine-related Th cell imbalanced. To clarify the role of this pathway in liver tolerance induction, we will separate KCs and establish liver transplantation model in rats, gene knock out/in technique, gene sequencing will be uesed to enhance or inhibit exact pathway both in vitro and in vivo. Once the hypothesis of up-regulation of Notch1-Jagged1 in KCs mediating the self-tolerance induction in liver transplantation is corroborated, this pathway could be considered as a novel target for treatment of acute rejection in parctice.

Kupffer 细胞（KCs）在肝移植免疫中起着即促进排斥反应又诱导免疫耐受的双重作用，其确切机制尚不明确。课题组前期发现：对KCs极性及对Th细胞分化的双重调节是诱导移植肝免疫耐受形成的关键。新近发现Notch1-Jagged1通路参与了机体诸多免疫调控环节，增强该通路可调节抗原呈递细胞极性及改变Th细胞分化倾向，其免疫调节机制可能比单因素调节因子更强，但针对Notch1-Jagged1通路的研究尚未涉及移植领域。我们认为该通路在移植肝免疫中也可能起着重要作用。因此，本项目选择肝KCs为靶细胞，以Notch1-Jagged1通路为切入点，采用基因调控、转录测序等手段，从多环节调控该通路，初步探讨Notch1-Jagged1通路通过对KCs极性及Th亚群分化的影响，进而诱导移植肝免疫耐受形成的具体分子机制，为进一步阐明移植肝脏免疫耐受形成机制做一些探索性的工作。

Kupffer 细胞（KCs）在肝移植免疫中起着即促进排斥反应又诱导免疫耐受的双重作用，其确切机制尚不明确。课题组前期发现：对KCs极性及对Th细胞分化的双重调节是诱导移植肝免疫耐受形成的关键。新近发现Notch1-Jagged1通路参与了机体诸多免疫调控环节，增强该通路可调节抗原呈递细胞极性及改变Th细胞分化倾向，因此，本项目选择肝KCs为靶细胞，以Notch1-Jagged1通路为切入点，采用基因调控、转录测序等手段，从多环节调控该通路，初步探讨Notch1-Jagged1通路通过对KCs极性及Th亚群分化的影响。主要发现如下：     .1.发现上调Notch-Jagged1 通路可诱导KCs向M2型极化，减少炎性细胞因子IL-2等分泌，使抗炎因子IL-10等分泌增加。.2.发现上调 Notch-Jagged1 通路能诱导大鼠肝移植后免疫耐受微环境形成，其效果好于或等同于常用免疫抑制剂所致效果。.3.其机制可能为调节PTEN/AKT/TLR4/NF-Kb通路减少炎性反应。