The development of donor-specific antibodies (DSAs) is a major complication in transplantation, which is associated with inferior graft survival, impaired quality of life, and increased healthcare costs. DSA develop upon recognition of nonself HLA by the recipient's immune system. HLA molecules contain epitopes, which are the surface regions of HLA molecules recognized by antibodies. HLAMatchmaker is an algorithm for assessing donor:recipient HLA compatibility at the level of structurally defined HLA targets called eplets. The consideration of eplets, rather than the whole HLA molecule, could offer some advantages when classifying the immune risk associated with particular donor:recipient pairs. Assessing compatibility at the level of HLA eplets could decrease misclassification of post-transplant immune risk by improving specificity, when antibodies are confirmed to be directed against donor eplets missing from the recipient's repertoire of eplets. Consideration of eplets may also increase the sensitivity of immune risk assessment, when identifying mismatched eplets that could give rise to new, not previously detected, donor-specific antibodies post-transplant. Eplet matching can serve as a rational strategy for immune risk mitigation. Herein, we review the evolution of HLA (in) compatibility assessment for organ allocation. We outline challenges in the implementation of eplet-based donor:recipient matching, including unavailability of allele-level donor genotypes for 11 HLA loci at the time of organ allocation and difficulty in assessing the hierarchy of immune risk associated with particular HLA eplet mismatches. Opportunities to address some of the current shortcomings of donor genotyping and HLAMatchmaker are also discussed. While there is a demonstrated benefit in the application of HLAMatchmaker for donor: recipient HLA (in)compatibility assessment, evolving long-read genotyping methods, compilation of large data sets with allele-level genotypes, and standardization of methods to verify eplets as determinants of immune-mediated injuries are required before HLA eplet matching is implemented in organ allocation to improve upon transplant outcomes.

中文翻译：

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媒人，媒人让我成为对手：优化移植HLA eplets兼容性的机遇与挑战

供体特异性抗体 (DSA) 的产生是移植过程中的一个主要并发症，它与较差的移植物存活率、生活质量受损和医疗保健成本增加有关。DSA 在接受者免疫系统识别非自身 HLA 后发展。HLA 分子含有表位，即被抗体识别的 HLA 分子的表面区域。HLAMatchmaker 是一种算法，用于在称为 eplets 的结构定义的 HLA 目标水平上评估供体：受体 HLA 兼容性。在对与特定供体：受体对相关的免疫风险进行分类时，考虑 eplets 而不是整个 HLA 分子可以提供一些优势。在 HLA eplets 水平上评估相容性可以通过提高特异性来减少移植后免疫风险的错误分类，当确认抗体针对受体 eplets 库中缺失的供体 eplets 时。考虑 eplets 还可以提高免疫风险评估的敏感性，当识别不匹配的 eplets 时，可能会在移植后产生新的、以前未检测到的供体特异性抗体。Eplet 匹配可以作为缓解免疫风险的合理策略。在此，我们回顾了用于器官分配的 HLA (in) 相容性评估的演变。我们概述了实施基于 eplet 的供体：受体匹配的挑战，包括在器官分配时无法获得 11 个 HLA 位点的等位基因水平供体基因型，以及难以评估与特定 HLA eplet 错配相关的免疫风险等级。还讨论了解决当前供体基因分型和 HLAMatchmaker 的一些缺点的机会。虽然 HLAMatchmaker 对供体的应用已证明有好处：受体 HLA (in) 相容性评估、进化的长读基因分型方法、具有等位基因水平基因型的大型数据集的汇编，以及验证 eplets 作为决定因素的方法的标准化在器官分配中实施 HLA eplet 匹配以改善移植结果之前，需要免疫介导的损伤。