美国丹娜-法伯癌症研究所Catherine J. Wu课题组发现，系统识别次要组织相容性抗原可预测异体造血干细胞移植的结果。2024年8月21日，《自然—生物技术》杂志在线发表了这项成果。

研究人员表示，T细胞对次要组织相容性抗原（mHAg）的排斥反应是异体造血干细胞移植（allo-HCT）治疗效果的核心。mHAg是由于供体与受体（D–R）之间的遗传多态性差异产生的多态性肽，它们在移植物抗白血病（GvL）和移植物抗宿主病（GvHD）反应中发挥重要作用。然而，将患者特异性mHAg库与临床结果一致关联仍然具有挑战性。

研究人员设计了一种分析框架，以系统性地识别mHAg，包括在HLA类I配体组上的检测以及对其免疫原性的功能验证。该方法依赖于通过全外显子组测序对D–R配对的种系DNA进行多态性检测，并结合器官特异性转录组和蛋白组水平的表达。将该流程应用于220对HLA匹配的allo-HCT D–R配对的研究表明，总体和器官特异性mHAg负荷可以独立预测急性GvHD和慢性肺部GvHD的发生，并在58对D–R配对的验证队列中确认了有前景的GvL靶点，这些靶点对预防或治疗移植后疾病复发具有潜力。

附：英文原文

Title: Systematic identification of minor histocompatibility antigens predicts outcomes of allogeneic hematopoietic cell transplantation

Author: Cieri, Nicoletta, Hookeri, Nidhi, Stromhaug, Kari, Li, Liang, Keating, Julia, Daz-Fernndez, Paula, Gmez-Garca de Soria, Valle, Stevens, Jonathan, Kfuri-Rubens, Raphael, Shao, Yiren, Kooshesh, Kameron A., Powell, Kaila, Ji, Helen, Hernandez, Gabrielle M., Abelin, Jennifer, Klaeger, Susan, Forman, Cleo, Clauser, Karl R., Sarkizova, Siranush, Braun, David A., Penter, Livius, Kim, Haesook T., Lane, William J., Oliveira, Giacomo, Kean, Leslie S., Li, Shuqiang, Livak, Kenneth J., Carr, Steven A., Keskin, Derin B., Muoz-Calleja, Cecilia, Ho, Vincent T., Ritz, Jerome, Soiffer, Robert J., Neuberg, Donna, Stewart, Chip, Getz, Gad, Wu, Catherine J.

Issue&Volume: 2024-08-21

Abstract: T cell alloreactivity against minor histocompatibility antigens (mHAgs)—polymorphic peptides resulting from donor–recipient (D–R) disparity at sites of genetic polymorphisms—is at the core of the therapeutic effect of allogeneic hematopoietic cell transplantation (allo-HCT). Despite the crucial role of mHAgs in graft-versus-leukemia (GvL) and graft-versus-host disease (GvHD) reactions, it remains challenging to consistently link patient-specific mHAg repertoires to clinical outcomes. Here we devise an analytic framework to systematically identify mHAgs, including their detection on HLA class I ligandomes and functional verification of their immunogenicity. The method relies on the integration of polymorphism detection by whole-exome sequencing of germline DNA from D–R pairs with organ-specific transcriptional- and proteome-level expression. Application of this pipeline to 220 HLA-matched allo-HCT D–R pairs demonstrated that total and organ-specific mHAg load could independently predict the occurrence of acute GvHD and chronic pulmonary GvHD, respectively, and defined promising GvL targets, confirmed in a validation cohort of 58 D–R pairs, for the prevention or treatment of post-transplant disease recurrence.

DOI: 10.1038/s41587-024-02348-3

Source: https://www.nature.com/articles/s41587-024-02348-3