半乳糖凝集素-1通过诱导耐受型树突状细胞分化改善大鼠肝移植排斥反应预后的机制研究

Immunologic rejection leads to bad prognosis of liver transplantation (LTx) recipients. Regulatory T cell (Treg) plays a critical role in induction of immunologic tolerance and prevention from graft rejection. Reportedly, galectin (Gal) -1 could alter the differentiation of CD4+ naïve T cells, antagonize Th17 functions and inhibit immune reaction; meanwhile, Gal-1 might induce differentiation of tolerangenic dendritic cells (DCs) from immature DCs, resulting in peripheral tolerance. Expressions and functions of IL27, NF-κB and STAT3/STAT5 also changed as DCs regulated immune functions, while the underlying mechanisms remain unclear. Our preliminary results suggested that administration of recombinant Gal-1 (rGal-1) could attenuate graft injury after LTx and improve the survival; besides, concentrations of IL27 and IL10 increased as IL17 decreased. So, we propose that rGal-1 could prevent rejection and improve prognosis through NF-κB-tolerangenic DC-IL27-Treg/Th17 signal pathway. Rat LTx using allogenic graft will be performed to explore the role of Gal-1 and the mechanisms underlined; ex vivo proliferation of tolerangenic DCs activated by Gal-1 will be transferred into recipients which might provide new insights for clinical therapy.

排斥反应导致肝移植受者预后不良。调节性T细胞（Treg）对于诱导免疫耐受，预防排斥具有重要作用。研究表明，半乳糖凝集素（Galectin，Gal）-1改变CD4+ 幼稚型T细胞分化，促进免疫抑制，拮抗Th17；同时，Gal-1诱导未成熟DCs向耐受型DCs分化，引起外周耐受。Gal-1的这种免疫调节作用伴随IL-27、NF-κB及STAT3/STAT5信号通路表达及功能的改变，但是其具体机制仍不明确。前期研究发现rGal-1减轻大鼠肝移植术后肝功能损伤，提高生存率，且受者体内IL27、IL10增加，IL17减少。因此，课题假设rGal-1通过NF-κB-耐受性DC-IL27-Treg/Th17通路减轻排斥，改善预后。课题建立大鼠肝移植排斥模型，研究Gal-1对其作用及机制，并初步探讨Gal-1诱导的耐受型DCs对于移植排斥的治疗效应，为临床治疗肝移植排斥提供思路。

器官移植患者需要相应的策略预防器官排斥反应，而调节性T细胞（Treg）/辅助性T细胞17（TH17）的相对平衡对机体免疫平衡和免疫耐受有重要作用。两者比例的失调将导致移植术后移植物功能衰竭。虽然半乳糖凝集素-1（Gal-1）负调节T细胞的增殖，但Gal-1如何影响DC细胞存在下的Treg和Th17平衡仍然是有争议的。我们的研究表明，GAL-1能够通过对 NF-κB/RelB 基因表达的负调控扰乱imDC细胞的成熟，并且Gal-1通过IL-27信号通路负调节CD4+细胞的增殖。同时，GAL-1通过调节 NF-κB/RelB-IL-27通路促进Treg细胞分化。我们通过这些结果发现了一种新的调节Treg细胞的治疗手段。