High-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease and implication for its molecular mechanism
High-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease and implication for its molecular mechanism
复制标题
DOI：
10.1182/blood-2007-02-072405
复制
发表时间：
2007-10-01
期刊：
影响因子：
20.3
通讯作者：
Sasazuki, Takehiko
中科院分区：
文献类型：
--
作者：
Kawase, Takakazu;Morishima, Yasuo;Sasazuki, Takehiko
在异基因造血干细胞移植中，HLA基因座错配对临床结果的影响已被阐明。然而，每种HLA等位基因错配组合的影响知之甚少，其诱导急性移植物抗宿主病（aGVHD）的分子机制仍有待阐明。共分析了5210例通过日本骨髓捐献者计划接受移植的供体患者对。所有HLA-A、-B、-C、-DRB 1、-DQB 1和-DPB 1等位基因在所有配对中进行回顾性分型。分析HLA等位基因错配组合及6个位点氨基酸替换位置对重度aGVHD的影响。共鉴定了15种严重aGVHD的显著高风险HLA等位基因错配组合和1种HLA-DRB 1-DQB 1连锁错配组合（高风险错配），并且高风险错配的数量与严重aGVHD的发生高度相关，而不管是否存在除高风险错配之外的错配组合。此外，HLA I类中6个特定的氨基酸取代位点被鉴定为导致严重aGVHD的位点。这些结果为从HLA分子水平阐明aGVHD的发病机制提供了依据。此外，识别高风险的错配，即非允许性错配，将有利于选择合适的供体。
In allogenic hematopoietic stem-cell transplantation, an effect of HLA locus mismatch in affele level on clinical outcome has been clarified. However, the effect of each HLA allele mismatch combination is little known, and its molecular mechanism to induce acute graftversus-host disease (aGVHD) remains to be elucidated. A total of 5210 donor patient pairs who underwent transplantation through Japan Marrow Donor Program were analyzed. All HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 alleles were retrospectively typed in all pairs. The impacts of the HLA allele mismatch combinations and amino acid substitution positions in 6 HLA loci on severe aGVHD were analyzed. A total of 15 significant high-risk HLA allele mismatch combinations and 1 HLA-DRBl-DQB1 linked mismatch combinations (high-risk mismatch) for severe aGVHD were identified, and the number of high-risk mismatches was highly associated with the occurrence of severe aGVHD regardless of the presence of mismatch combinations other than high-risk mismatch. Furthermore, 6 specific amino acid substitution positions in HLA class I were identified as those responsible for severe aGVHD. These findings provide evidence to elucidate the mechanism of aGVHD on the basis of HLA molecule. Furthermore, the identification of highrisk mismatch, that is, nonpermissive mismatch, would be beneficial for the selection of a suitable donor.