Predicting Humoral Alloimmunity from Differences in Donor and Recipient HLA Surface Electrostatic Potential
Predicting Humoral Alloimmunity from Differences in Donor and Recipient HLA Surface Electrostatic Potential
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DOI：
10.4049/jimmunol.1800683
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发表时间：
2018-12-15
影响因子：
4.4
通讯作者：
Kosmoliaptsis, Vasilis
中科院分区：
文献类型：
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作者：
Mallon, Dermot H.;Kling, Christiane;Kosmoliaptsis, Vasilis
在移植中，针对供体人类白细胞抗原的体液同种异体免疫是器官移植失败的主要原因，但我们评估潜在供体-受体人类白细胞抗原组合的免疫学风险的能力是有限的。我们推测，供体人类白细胞抗原诱导特异性同种异体抗体反应的能力取决于它们与受体人类白细胞抗原在结构和物理化学上的不同。为了验证这一假设，我们首先开发了一种新的计算评分系统，该系统能够在三级结构水平上定量评估供体和受体之间的表面静电势差异[三维静电失配评分(EMS-3D)]。然后，我们检查了接受标准化的男性伴侣供体淋巴细胞注射的健康女性的体液同种免疫反应。这项分析表明供体人类白细胞抗原的EMS-3D与供体特异性同种异体抗体的产生有很强的相关性；这种关系在人类白细胞抗原-DQ同种异体抗原中最强。在临床移植环境中，供体肾脏表达的HLA-DRB1和-DQ不匹配的免疫原性潜力，如其EMS-3D评估，是移植失败后发生供体特异性同种异体抗体的独立预测因子。总而言之，这些发现证明了我们的方法在改进免疫风险评估和减少器官移植中体液同种免疫负担方面的翻译潜力。
In transplantation, development of humoral alloimmunity against donor HLA is a major cause of organ transplant failure, but our ability to assess the immunological risk associated with a potential donor-recipient HLA combination is limited. We hypothesized that the capacity of donor HLA to induce a specific alloantibody response depends on their structural and physicochemical dissimilarity compared with recipient HLA. To test this hypothesis, we first developed a novel computational scoring system that enables quantitative assessment of surface electrostatic potential differences between donor and recipient HLA molecules at the tertiary structure level [three-dimensional electrostatic mismatch score (EMS-3D)]. We then examined humoral alloimmune responses in healthy females subjected to a standardized injection of donor lymphocytes from their male partner. This analysis showed a strong association between the EMS-3D of donor HLA and donor-specific alloantibody development; this relationship was strongest for HLA-DQ alloantigens. In the clinical transplantation setting, the immunogenic potential of HLA-DRB1 and -DQ mismatches expressed on donor kidneys, as assessed by their EMS-3D, was an independent predictor of development of donor-specific alloantibody after graft failure. Collectively, these findings demonstrate the translational potential of our approach to improve immunological risk assessment and to decrease the burden of humoral alloimmunity in organ transplantation.