Autosomal Minor Histocompatibility Antigens: How Genetic Variants Create Diversity in Immune Targets.
Autosomal Minor Histocompatibility Antigens: How Genetic Variants Create Diversity in Immune Targets.
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DOI：
10.3389/fimmu.2016.00100
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发表时间：
2016
影响因子：
7.3
通讯作者：
Falkenburg JH
中科院分区：
文献类型：
--
作者：
Griffioen M;van Bergen CA;Falkenburg JH
异基因造血干细胞移植（alloSCT）是治疗恶性血液病的有效方法。不幸的是，所需的抗肿瘤或移植物抗白血病（GvL）作用通常伴随着对健康组织的不期望的副作用，称为移植物抗宿主病（GvHD）。在HLA匹配的alloSCT后，GvL和GvHD均由供体来源的T细胞介导，所述T细胞识别由患者细胞上的HLA表面分子呈递的多态性肽。这些多态性肽或次要组织相容性抗原（MiHA）是由患者和供体之间的遗传差异产生的。由于多态性肽可能是操纵GvL和GvHD之间的平衡的有用靶标，因此需要发现MiHA的优势库。在这篇综述中，多样性的常染色体MiHA的特点，迄今为止，以及各种分子机制，遗传变异创建免疫目标和神秘的转录本和蛋白质作为抗原来源的作用进行了描述。MiHA作为GvL和GvHD中的重要因素的组织分布被认为是造血MiHA如何用于免疫治疗以在alloSCT后增加GvL的可能性。虽然更多的MiHA仍然需要全面了解的生物学GvL和GvHD和操作的免疫治疗，这篇评论显示洞察的组成和动力学的体内免疫反应的特异性，多样性和频率的特定的T细胞和表面表达的HLA-肽复合物和其他（辅助）分子的靶细胞。这些因素及其环境之间复杂的相互作用最终决定了alloSCT后免疫反应引起的临床表现谱。
Allogeneic stem cell transplantation (alloSCT) can be a curative treatment for hematological malignancies. Unfortunately, the desired anti-tumor or graft-versus-leukemia (GvL) effect is often accompanied with undesired side effects against healthy tissues known as graft-versus-host disease (GvHD). After HLA-matched alloSCT, GvL and GvHD are both mediated by donor-derived T-cells recognizing polymorphic peptides presented by HLA surface molecules on patient cells. These polymorphic peptides or minor histocompatibility antigens (MiHA) are produced by genetic differences between patient and donor. Since polymorphic peptides may be useful targets to manipulate the balance between GvL and GvHD, the dominant repertoire of MiHA needs to be discovered. In this review, the diversity of autosomal MiHA characterized thus far as well as the various molecular mechanisms by which genetic variants create immune targets and the role of cryptic transcripts and proteins as antigen sources are described. The tissue distribution of MiHA as important factor in GvL and GvHD is considered as well as possibilities how hematopoietic MiHA can be used for immunotherapy to augment GvL after alloSCT. Although more MiHA are still needed for comprehensive understanding of the biology of GvL and GvHD and manipulation by immunotherapy, this review shows insight into the composition and kinetics of in vivo immune responses with respect to specificity, diversity, and frequency of specific T-cells and surface expression of HLA–peptide complexes and other (accessory) molecules on the target cell. A complex interplay between these factors and their environment ultimately determines the spectrum of clinical manifestations caused by immune responses after alloSCT.