HLA Class II Antibody Activation of Endothelial Cells Promotes Th17 and Disrupts Regulatory T Lymphocyte Expansion
HLA Class II Antibody Activation of Endothelial Cells Promotes Th17 and Disrupts Regulatory T Lymphocyte Expansion
复制标题
DOI：
10.1111/ajt.13644
复制
发表时间：
2016-05-01
影响因子：
8.8
通讯作者：
Mooney, N.
中科院分区：
文献类型：
--
作者：
Lion, J.;Taflin, C.;Mooney, N.
肾移植是终末期肾病患者最成功的治疗选择，而慢性抗体介导的排斥反应是导致移植物失功的主要原因。慢性排斥反应的预测因素包括高水平的HLA同种抗体（特别是HLA II类）和移植物内皮细胞（EC）的活化。这种联系的机械基础尚未解决。我们用HLA-DR抗体刺激微血管内皮细胞的实验模型来研究HLA II类抗体、内皮细胞活化和同种异体移植物损伤之间相关性的机制。用HLA-DR抗体F（Ab）（2）片段激活内皮细胞，可导致Akt、ERK和MEK磷酸化，并以Akt依赖的方式增加与同种异体外周血单个核细胞（PBMC）共培养的内皮细胞产生IL-6。我们先前表明，表达HLA-DR的EC诱导Th 17和FoxP 3（亮）调节性T细胞（Treg）亚群的极化。用抗HLA-DR抗体预活化EC通过减少功能性Treg的扩增和进一步增加IL-6依赖性Th 17扩增将EC同种异体性重定向到促炎反应。含有相关HLA-DR同种抗体的同种免疫患者血清选择性结合并增加与PBMC共培养的EC分泌IL-6。在抗体介导的排斥反应模型中，在同种异体外周血单核细胞存在下，抗HLA-DR抗体与微血管内皮细胞的结合诱导Akt依赖性内皮细胞IL-6分泌，并扭曲随后的CD 4 + T细胞极化，有利于促炎反应。
Kidney transplantation is the most successful treatment option for patients with end-stage renal disease, and chronic antibody-mediated rejection is the principal cause of allograft loss. Predictive factors for chronic rejection include high levels of HLA alloantibodies (particularly HLA class II) and activation of graft endothelial cells (ECs). The mechanistic basis for this association is unresolved. We used an experimental model of HLA-DR antibody stimulation of microvascular ECs to examine the mechanisms underlying the association between HLA class II antibodies, EC activation and allograft damage. Activation of ECs with the F(Ab)(2) fragment of HLA-DR antibody led to phosphorylation of Akt, ERK and MEK and increased IL-6 production by ECs cocultured with allogeneic peripheral blood mononuclear cells (PBMCs) in an Akt-dependent manner. We previously showed that HLA-DR-expressing ECs induce polarization of Th17 and FoxP3(bright) regulatory T cell (Treg) subsets. Preactivation of ECs with anti-HLA-DR antibody redirected EC allogenicity toward a proinflammatory response by decreasing amplification of functional Treg and by further increasing IL-6-dependent Th17 expansion. Alloimmunized patient serum containing relevant HLA-DR alloantibodies selectively bound and increased EC secretion of IL-6 in cocultures with PBMCs. These data contribute to understanding of potential mechanisms of antibody-mediated endothelial damage independent of complement activation and FcR-expressing effector cells.In a model of antibody-mediated rejection, binding an anti-HLA-DR antibody to microvascular endothelial cells induces Akt-dependent endothelial cell IL-6 secretion in the presence of allogeneic peripheral blood mononuclear cells, and distorts subsequent CD4+ T cell polarization in favor of a proinflammatory response.