The Role of Liver Sinusoidal Endothelial Cells in Induction of Carbohydrate Reactive B Cells Tolerance Through the Programmed Death 1/Programmed Death Ligand 1 Pathway
The Role of Liver Sinusoidal Endothelial Cells in Induction of Carbohydrate Reactive B Cells Tolerance Through the Programmed Death 1/Programmed Death Ligand 1 Pathway
复制标题
肝窦内皮细胞在通过程序性死亡 1/程序性死亡配体 1 途径诱导碳水化合物反应性 B 细胞耐受中的作用
DOI：
10.1097/tp.0000000000000831
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发表时间：
2015
期刊：
影响因子：
6.2
通讯作者：
Ohdan H.
中科院分区：
文献类型：
--
作者：
Igarashi Y;Onoe T;Ohdan H.
背景：在ABO血型不合的小儿肝移植（LT）中，经常发生B细胞对血型抗原的自发耐受。肝窦内皮细胞（LSECs），专门表达血型抗原的肝脏，具有诱导同种抗原特异性耐受的能力。在这项研究中，我们阐明了LSEC在ABO不相容LT后血型抗原反应性B细胞耐受诱导中的作用，使用缺乏类似血型碳水化合物抗原的半乳糖-α（1，3）半乳糖（Gal）表位的小鼠。我们建立了正交各向异性GalT+/+→ GalT−/− LSEC嵌合体小鼠。抗半乳糖抗体（抗体）生产后，评估免疫的GalT+/+→ GalT−/− LSEC嵌合体小鼠与Gal+ rabbit RBC. ResultsRecretive转移的LSEC分离自WT GalT+/+小鼠通过门静脉导致持续植入Gal+ LSEC在同源GalT−/−小鼠肝脏。只有当GalT−/−小鼠在LSEC接种前切除脾脏时，GalT+/+→ GalT−/− LSEC嵌合体才失去产生抗Gal Ab的能力。对程序性死亡配体1的脾切除GalT+/+→ GalT−/− LSEC嵌合体的阻断单克隆抗体（mAb）的管理导致抗Gal Ab production.ConclusionsThese研究结果表明，LSEC采取的一部分，在耐受性的不成熟，但不成熟的B细胞特异性半乳糖。此外，程序性死亡1/程序性死亡配体1途径可能在LT中B细胞对ABO血型抗原应答的自发耐受化机制中起关键作用。
BackgroundA spontaneous tolerance of B cells responding to blood group antigens frequently develops in ABO-incompatible pediatric liver transplantation (LT). Liver sinusoidal endothelial cells (LSECs), which exclusively express blood group antigens in the liver, possess a capacity to induce alloantigen-specific tolerance. In this study, we elucidated the role of LSECs in the tolerance induction of blood group antigen-reactive B cells after ABO-incompatible LT using mice that lack galactose-α (1, 3) galactose (Gal) epitopes resembling blood group carbohydrate antigens.MethodsUsing adoptive transfer of LSECs from wild type (WT) C57BL/6J mice to congenic α1, 3-galactosyltransferase gene knockout (GalT−/−) mice, we established orthotropic GalT+/+→ GalT−/− LSEC chimera mice. Anti-Gal Ab (antibody) production was evaluated after immunization of GalT+/+→ GalT−/− LSEC chimera mice with Gal+ rabbit RBC.ResultsAdoptive transfer of LSECs isolated from WT GalT+/+ mice via the portal vein resulted in persistent engraftment of Gal+ LSECs in congenic GalT−/− mouse livers. Only when GalT−/− mice were splenectomized before LSEC inoculation, the GalT+/+→ GalT−/− LSEC chimera lost the ability to produce anti-Gal Abs. The administration of blocking monoclonal Abs (mAbs) against programmed death ligand 1 to the splenectomized GalT+/+→ GalT−/− LSEC chimera resulted in the recovery of anti-Gal Ab production.ConclusionsThese findings suggest that LSECs take a part in tolerization of immature but not mature B cells specifically for Gal. Furthermore, the programmed death 1/programmed death ligand 1 pathway likely plays a crucial role in the mechanisms underlying spontaneous tolerization of B cells responding to ABO-blood group antigens in LT.