抑制Kupffer细胞中SCIMP蛋白活性诱导大鼠肝移植免疫耐受

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 acute 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 multilamellar coordination 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 SCIMP（SLP65/SLP76, Csk-interacting membrane protein）, a member of the palmitoylated transmembrane adaptor protein (pTRAP) family, can regulate the antigen presentation function of MHC-II molecule and the expression of IL-12p40 synthesis and secretion, the immune regulation mechanism of which may be stronger than single regulatory factor. But so far there were rare related research in organ transplantation, especially in liver. We hereby put forward a hypothesis that down-regulation of SCIMP pathway in KCs may induce liver transplant tolerance via reducing the antigen presentation function of MHC-II molecule 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 regulation, gene transfection will be uesed to enhance or inhibit exact pathway both in vitro and in vivo. Once the hypothesis of down-regulation of SCIMP 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）在肝移植免疫中起既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极性和对T辅助细胞（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。新近发现棕榈酰化跨膜衔接蛋白SCIMP通路参与了机体诸多免疫调控环节，抑制该蛋白活性可降低抗原呈递细胞MHC-II类分子抗原呈递作用，减少控制Th细胞分化程序的细胞因子IL-6和IL-12p40的合成和分泌，其免疫调节机制可能比单因素更强，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SCIMP蛋白为切入点，采用基因调控、转染等方法，从多环节调控该通路，初步探讨SCIMP蛋白活性通过对KCs抗原提呈作用及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。

Kupffer细胞（KCs）在肝移植免疫中起既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极性和对T辅助细胞（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。新近发现棕榈酰化跨膜衔接蛋白SCIMP通路参与了机体诸多免疫调控环节，抑制该蛋白活性可降低抗原呈递细胞MHC-II类分子抗原呈递作用，减少控制Th细胞分化程序的细胞因子IL-6和IL-12p40的合成和分泌，其免疫调节机制可能比单因素更强，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SCIMP蛋白为切入点，采用基因调控、转染等方法，从多环节调控该通路，初步探讨SCIMP蛋白活性通过对KCs抗原提呈作用及Th亚群分化的影响，我们发现肝移植术后KCs SCIMP表达增加，并且SCIMP与MHCII功能呈正相关；干扰KCs SCIMP通过抑制TLR4/NFκB/MAPK以及激活JAK3/STAT6/PPARγ促进KCs向免疫耐受的M2型极化，减少炎症因子释放，促进KCs清除凋亡T细胞的能力，改善肝组织病理改变，并且延长了大鼠肝移植术后的生存时间，有利于免疫耐受微环境的形成