Early Acute Microvascular Kidney Transplant Rejection in the Absence of Anti-HLA Antibodies Is Associated with Preformed IgG Antibodies against Diverse Glomerular Endothelial Cell Antigens
Early Acute Microvascular Kidney Transplant Rejection in the Absence of Anti-HLA Antibodies Is Associated with Preformed IgG Antibodies against Diverse Glomerular Endothelial Cell Antigens
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DOI：
10.1681/asn.2018080868
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发表时间：
2019-04-01
影响因子：
13.6
通讯作者：
Anglicheau, Dany
中科院分区：
文献类型：
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作者：
Delville, Marianne;Lamarthee, Baptiste;Anglicheau, Dany
背景尽管抗HLA抗体（Abs）引起大多数抗体介导的同种异体肾移植排斥反应，但非抗HLA抗体也被认为是原因之一。更好地了解这样的抗体在rejection is needed.Methods我们进行了一项全国性的研究，以确定肾移植受者没有抗HLA供体特异性抗体谁经历了急性移植物功能障碍移植后3个月内，并显示微血管损伤的证据，称为急性微血管排斥反应（AMVR）。我们开发了一种交叉配型试验，以评估血清对人微血管内皮细胞的反应性，并使用转录组学和蛋白质组学方法相结合，以确定非HLA Abs.Results我们确定了一个高度选择的队列38例早期急性AMVR患者。活检标本显示强烈的微血管炎症和血管炎（60.5%），间质性血管炎（31.6%）或血栓性微血管病（15.8%）的存在。移植时采集的血清样本显示，与稳定肾移植受者对照组相比，AMVR患者中先前提出的抗内皮细胞Abs-血管紧张素1型受体（AT 1 R）、内皮素-1 A型和天然多反应性Abs-并未显著增加。然而，当使用10 IU/ml的阈值时，26%的检测AMVR样本对AT 1 R Ab呈阳性。交叉配型试验确定了一种常见的IgG反应，特异性针对AMVR患者微血管肾小球细胞组成型表达的抗原。转录组学和蛋白质组学分析确定了新的非HLA抗体的目标，与individual.Conclusions之间的冗余很少，我们的研究结果表明，预先形成的IgG抗体针对肾小球内皮细胞上表达的非HLA抗原与早期AMVR，并在体外细胞为基础的测定，需要提高移植前的风险评估。
Background Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed.Methods We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs.Results We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals.Conclusions Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that in vitro cell-based assays are needed to improve risk assessments before transplant.