Oostvogels Rimke, Lokhorst Henk M, Minnema Monique C, van Elk Maureen, van den Oudenalder Kelly, Spierings Eric, Mutis Tuna, Spaapen Robbert M
Department of Clinical Chemistry and Hematology, University Medical Center Utrecht; Department of Hematology, University Medical Center Utrecht, Utrecht;
Department of Hematology, University Medical Center Utrecht, Utrecht; Department of Hematology, VU University Medical Center, Amsterdam;
Haematologica. 2014 Dec;99(12):1854-9. doi: 10.3324/haematol.2014.109801. Epub 2014 Aug 22.
Minor histocompatibility antigens are highly immunogeneic polymorphic peptides playing crucial roles in the clinical outcome of HLA-identical allogeneic stem cell transplantation. Although the introduction of genome-wide association-based strategies significantly has accelerated the identification of minor histocompatibility antigens over the past years, more efficient, rapid and robust identification techniques are required for a better understanding of the immunobiology of minor histocompatibility antigens and for their optimal clinical application in the treatment of hematologic malignancies. To develop a strategy that can overcome the drawbacks of all earlier strategies, we now integrated our previously developed genetic correlation analysis methodology with the comprehensive genomic databases from the 1000 Genomes Project. We show that the data set of the 1000 Genomes Project is suitable to identify all of the previously known minor histocompatibility antigens. Moreover, we demonstrate the power of this novel approach by the identification of the new HLA-DP4 restricted minor histocompatibility antigen UTDP4-1, which despite extensive efforts could not be identified using any of the previously developed biochemical, molecular biological or genetic strategies. The 1000 Genomes Project-based identification of minor histocompatibility antigens thus represents a very convenient and robust method for the identification of new targets for cancer therapy after allogeneic stem cell transplantation.
次要组织相容性抗原是高度免疫原性的多态性肽段，在人类白细胞抗原（HLA）相合同种异体干细胞移植的临床结局中发挥关键作用。尽管在过去几年中，基于全基因组关联的策略显著加速了次要组织相容性抗原的鉴定，但为了更好地理解次要组织相容性抗原的免疫生物学特性，并将其在血液系统恶性肿瘤治疗中进行优化临床应用，仍需要更高效、快速且可靠的鉴定技术。为了开发一种能够克服所有早期策略缺点的方法，我们现在将我们之前开发的遗传相关性分析方法与来自千人基因组计划的综合基因组数据库相结合。我们表明，千人基因组计划的数据集适合鉴定所有先前已知的次要组织相容性抗原。此外，我们通过鉴定新的HLA-DP4限制性次要组织相容性抗原UTDP4-1，证明了这种新方法的强大功能，尽管此前进行了大量努力，但使用任何先前开发的生化、分子生物学或遗传学策略均无法鉴定出该抗原。因此，基于千人基因组计划鉴定次要组织相容性抗原是一种非常便捷且可靠的方法，可用于鉴定异基因干细胞移植后癌症治疗的新靶点。
