Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, New York.
Department of Kidney Transplantation, Hopital Necker, Université Paris Descartes and Assistance Publique Hopitaux de Paris, Paris, France.
J Am Soc Nephrol. 2018 Jun;29(6):1761-1770. doi: 10.1681/ASN.2017111157. Epub 2018 Mar 30.
The development of antibodies specific to HLA expressed on donor tissue (donor-specific antibodies [DSAs]) is a prominent risk factor for kidney graft loss. Non-HLA antibodies with pathogenic potential have also been described, including natural antibodies (Nabs). These IgG Nabs bind to immunogenic self-determinants, including oxidation-related antigens. To examine the relationship of Nabs with graft outcomes, we assessed Nabs in blinded serum specimens collected from a retrospective cohort of 635 patients who received a transplant between 2005 and 2010 at Necker Hospital in Paris, France. Serum samples were obtained immediately before transplant and at the time of biopsy-proven rejection within the first year or 1 year after transplant. Nabs were detected by ELISA through reactivity to the generic oxidized epitope malondialdehyde. Univariate Cox regression analysis identified the development of post-transplant Nabs (defined as 50% increase in reactivity to malondialdehyde) as a significant risk factor for graft loss (hazard ratio, 2.68; 95% confidence interval, 1.49 to 4.82; =0.001). Post-transplant Nabs also correlated with increased mean Banff scores for histologic signs of graft injury in post-transplant biopsy specimens. Multivariable Cox analyses confirmed Nabs development as a risk factor independent from anti-HLA DSAs (hazard ratio, 2.07; 95% confidence interval, 1.03 to 4.17; =0.04). Moreover, patients with Nabs and DSAs had a further increased risk of kidney graft loss. These findings reveal an association between Nabs, kidney graft injury, and eventual graft failure, suggesting the involvement of Nabs in immune mechanisms of rejection.
抗体针对供体组织上表达的 HLA 的特异性发展（供体特异性抗体 [DSA]）是导致肾移植失败的主要危险因素。还描述了具有潜在致病性的非 HLA 抗体，包括天然抗体 (Nab)。这些 IgG Nab 与免疫原性自身决定簇结合，包括与氧化相关的抗原。为了研究 Nab 与移植物结果的关系，我们评估了在法国巴黎 Necker 医院接受移植的 635 名患者的回顾性队列的盲血清标本中的 Nab。在移植前和移植后第一年或移植后 1 年内活检证实排斥反应时获得血清样本。通过对通用氧化表位丙二醛的反应性，通过 ELISA 检测 Nab。单变量 Cox 回归分析确定移植后 Nab 的发展（定义为丙二醛反应性增加 50%）是移植物丢失的显著危险因素（风险比，2.68；95%置信区间，1.49 至 4.82；=0.001）。移植后 Nab 还与移植后活检标本中组织学损伤的平均 Banff 评分升高相关。多变量 Cox 分析证实，Nab 的发展是独立于抗 HLA DSA 的危险因素（风险比，2.07；95%置信区间，1.03 至 4.17；=0.04）。此外，具有 Nab 和 DSA 的患者发生肾移植失败的风险进一步增加。这些发现揭示了 Nab、肾移植损伤和最终移植失败之间的关联，表明 Nab 参与了排斥反应的免疫机制。
