Torikai H, Akatsuka Y, Miyauchi H, Terakura S, Onizuka M, Tsujimura K, Miyamura K, Morishima Y, Kodera Y, Kuzushima K, Takahashi T
Division of Immunology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
Bone Marrow Transplant. 2007 Jul;40(2):165-74. doi: 10.1038/sj.bmt.1705689. Epub 2007 May 28.
HA-1(H) is one of the most attractive minor histocompatibility antigens (mHA) as a target for immunotherapy of hematopoietic malignancies, but HLA-A0201 and HLA-B60 molecules capable of presenting HA-1(H)-derived peptides are less common in eastern Asian populations when compared with Caucasian populations. Therefore, an attempt was made to search for novel epitopes presented by HLA alleles other than those previously reported by generating CTL lines from patients undergoing HLA-identical, HA-1 disparate hematopoietic stem cell transplantation (hematopoietic SCT) by stimulation with a 29-mer HA-1(H) peptide spanning a central polymorphic histidine (His). Two CTL clones established were found to be restricted by HLA-A0206, which is the second or third most common HLA-A2 subtype worldwide. Epitope mapping revealed that the clones recognized the same nonameric peptide as A0201-restricted HA-1(H), VLHDDLLEA. This epitope was unexpected, since it does not contain any preferred anchor motifs for HLA-A0206. However, an HLA peptide binding assay revealed stronger binding of this peptide to A0206 than to A0201. Interestingly, HLA-A0206-restricted CTL clones could lyse both HLA-A0206(+) and HLA-A0201(+) targets (including leukemic blasts) that express HA-1(H) peptide endogenously, whereas an HLA-A0201-restricted, HA-1(H)-specific CTL clone failed to lyse HLA-A*0206(+) targets. This finding will expand the patient population who can benefit from HA-1(H)-based immunotherapy.
HA-1(H)是作为造血系统恶性肿瘤免疫治疗靶点最具吸引力的次要组织相容性抗原（mHA）之一，但与白种人群相比，能够呈递HA-1(H)衍生肽段的HLA-A0201和HLA-B60分子在东亚人群中不太常见。因此，通过用跨越中心多态性组氨酸（His）的29聚体HA-1(H)肽刺激，从接受HLA相同、HA-1不同的造血干细胞移植（造血SCT）的患者中产生CTL系，试图寻找除先前报道的那些HLA等位基因之外呈递的新表位。发现建立起的两个CTL克隆受HLA-A0206限制，HLA-A0206是全球第二或第三常见的HLA-A2亚型。表位作图显示这些克隆识别与A0201限制的HA-1(H)相同的九聚体肽段VLHDDLLEA。这个表位出人意料，因为它不包含任何HLA-A0206的优选锚定基序。然而，HLA肽结合试验显示该肽与A0206的结合比与A0201的结合更强。有趣的是，HLA-A0206限制的CTL克隆能够裂解内源性表达HA-1(H)肽段的HLA-A0206(+)和HLA-A0201(+)靶细胞（包括白血病原始细胞），而HLA-A0201限制的、HA-1(H)特异性的CTL克隆不能裂解HLA-A0206(+)靶细胞。这一发现将扩大能够从基于HA-1(H)的免疫治疗中获益的患者群体。
