PDF(Pubmed)
Abstract：
Prolonging the lifespan of transplanted organs is critical to combat the shortage of this life-saving resource. Chronic rejection, with irreversible demise of the allograft, is often caused by the development of donor-specific HLA antibodies. Currently, enumerating molecular (amino acid) mismatches between recipient and donor is promoted to identify patients at higher risk of developing HLA antibodies, for use in organ allocation, and immunosuppression-minimization strategies. We have counseled against the incorporation of such approaches into clinical use and hypothesized that not all molecular mismatches equally contribute to generation of donor-specific immune responses. Herein, we document statistical shortcomings in previous study design: for example, use of individuals who lack the ability to generate donor-specific-antibodies (HLA identical) as part of the negative cohort. We provide experimental evidence, using CRISPR-Cas9-edited cells, to rebut the claim that the HLAMatchmaker eplets represent \"functional epitopes.\" We further used unique sub-cohorts of patients, those receiving an allograft with two HLA-DQ mismatches yet developing antibodies only to one mismatch (2MM1DSA), to interrogate differential immunogenicity. Our results demonstrate that mismatches of DQα05-heterodimers exhibit the highest immunogenicity. Additionally, we demonstrate that the DQα chain critically contributes to the overall qualities of DQ molecules. Lastly, our data proposes that an augmented risk to develop donor-specific HLA-DQ antibodies is dependent on qualitative (evolutionary and functional) divergence between recipient and donor, rather than the mere number of molecular mismatches. Overall, we propose an immunological mechanistic rationale to explain differential HLA-DQ immunogenicity, with potential ramifications for other pathological processes such as autoimmunity and infections.
摘要：
延长移植器官的寿命对于解决这种挽救生命的资源短缺至关重要。慢性排斥反应,随着同种异体移植物的不可逆转的死亡，通常是由供体特异性HLA抗体的发展引起的。目前,促进列举受体和供体之间的分子（氨基酸）错配，以识别发生HLA抗体风险较高的患者，用于器官分配，和免疫抑制最小化策略。我们建议不要将此类方法纳入临床使用，并假设并非所有分子错配都同样有助于产生供体特异性免疫反应。在这里，我们记录了以前研究设计中的统计缺陷：例如，使用缺乏产生供体特异性抗体（HLA相同）能力的个体作为阴性队列的一部分。我们提供实验证据,使用CRISPR-Cas9编辑的细胞，反驳HLAMatchmakereplet代表“功能性表位”的说法。“我们进一步使用了独特的患者亚组，那些接受同种异体移植物与两个HLA-DQ错配，但发展抗体只有一个错配（2MM1DSA），询问差异免疫原性。我们的结果表明DQα05-异二聚体的错配表现出最高的免疫原性。此外,我们证明了DQα链对DQ分子的整体质量至关重要。最后,我们的数据表明，开发供体特异性HLA-DQ抗体的风险增加取决于受体和供体之间的定性（进化和功能）差异，而不仅仅是分子错配的数量。总的来说,我们提出了一种免疫学机制原理来解释差异HLA-DQ免疫原性，对其他病理过程如自身免疫和感染的潜在影响。
