HLA-DQ alloantibodies directly activate the endothelium and compromise differentiation of FoxP3high regulatory T lymphocytes
HLA-DQ alloantibodies directly activate the endothelium and compromise differentiation of FoxP3high regulatory T lymphocytes
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DOI：
10.1016/j.kint.2019.04.023
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发表时间：
2019-09-01
影响因子：
19.6
通讯作者：
Mooney, Nuala
中科院分区：
文献类型：
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作者：
Cross, Amy R.;Lion, Julien;Mooney, Nuala
肾移植中供体特异性抗体的产生与移植物存活率降低有关。最近的临床研究强调了人类白细胞抗原（HLA）-DQ抗体在新生供体特异性抗体（DSA）中的流行，但这些DSA对排斥反应的具体贡献尚未得到研究。抗体介导的排斥反应主要靶向微血管，因此本研究探讨了患者HLA-DQ同种抗体如何调节内皮激活和免疫调节。HLA-DQ抗体磷酸化微血管内皮细胞中的Akt和S6激酶。在与同种异体反应性淋巴细胞培养之前，这种激活增加了IL-6和RANTES的分泌。抗体介导的IL-6上调确实是Akt依赖性的。HLA-DQ抗体与内皮细胞的结合选择性地减少T细胞同种异体增殖和FoxP 3（高）Treg分化。在临床研究中，检测到HLA-DQ DSA与其他DSA相比，移植物存活率更差。用HLA-DR和HLA-DQ抗体刺激的内皮细胞显示促炎细胞因子分泌的协同增加和Treg扩增的减少。HLA-DQ抗体单独和与其他HLA抗体组合强烈促进促炎反应。因此，我们的数据提供了新的见解HLA-DQ DSA的致病性。
Development of donor-specific antibodies is associated with reduced allograft survival in renal transplantation. Recent clinical studies highlight the prevalence of human leukocyte antigen (HLA)-DQ antibodies amongst de novo donor-specific antibodies (DSAs), yet the specific contribution of these DSAs to rejection has not been examined. Antibody-mediated rejection primarily targets the microvasculature, so this study explored how patient HLA-DQ alloantibodies can modulate endothelial activation and so immunoregulation. HLA-DQ antibodies phosphorylated Akt and S6 kinase in microvascular endothelial cells. This activation prior to culture with alloreactive lymphocytes increased IL-6 and RANTES secretion. The antibody-mediated upregulation of IL-6 was indeed Akt-dependent. The binding of HLA-DQ antibodies to endothelial cells selectively reduced T cell alloproliferation and FoxP3(high) Treg differentiation. In clinical studies, detection of HLA-DQ DSAs with other DSAs is associated with worse graft survival than either alone. Endothelial cells stimulated with HLA-DR and HLA-DQ antibodies showed a synergistic increase in proinflammatory cytokine secretion and a decrease in Treg expansion. HLA-DQ antibodies strongly promote proinflammatory responses in isolation and in combination with other HLA antibodies. Thus, our data give new insights into the pathogenicity of HLA-DQ DSAs.