Morishima Satoko, Kashiwase Koichi, Matsuo Keitaro, Azuma Fumihiro, Yabe Toshio, Sato-Otsubo Aiko, Ogawa Seishi, Shiina Takashi, Satake Masahiro, Saji Hiroh, Kato Shunichi, Kodera Yoshihisa, Sasazuki Takehiko, Morishima Yasuo
Department of Hematology, Fujita Health University School of Medicine, Toyoake, Aichi, Tokyo, Japan
Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.
Haematologica. 2016 Apr;101(4):491-8. doi: 10.3324/haematol.2015.136903. Epub 2016 Jan 14.
HLA molecules play an important role for immunoreactivity in allogeneic hematopoietic stem cell transplantation. To elucidate the effect of specific HLA alleles on acute graft-versus-host disease, we conducted a retrospective analysis using 6967 Japanese patients transplanted with T-cell-replete marrow from an unrelated donor. Using unbiased searches of patient and donor HLA alleles, patient and/or donor HLA-B51:01 (patient: HR, 1.37,P<0.001; donor: HR, 1.35,P<0.001) and patient HLA-C14:02 (HR, 1.35,P<0.001) were significantly associated with an increased risk of severe acute graft-versus-host disease. The finding that donor HLA-C14:02 was not associated with severe acute graft-versus-host disease prompted us to elucidate the relation of these high-risk HLA alleles with patient and donor HLA-C allele mismatches. In comparison to HLA-C allele match, patient mismatched HLA-C14:02 showed the highest risk of severe acute graft-versus-host disease (HR, 3.61,P<0.001) and transplant-related mortality (HR, 2.53,P<0.001) among all patient mismatched HLA-C alleles. Although patient HLA-C14:02 and donor HLA-C15:02 mismatch was usually KIR2DL-ligand mismatch in the graft-versus-host direction, the risk of patient mismatched HLA-C14:02 for severe acute graft-versus-host disease was obvious regardless of KIR2DL-ligand matching. The effect of patient and/or donor HLA-B51:01 on acute graft-versus-host disease was attributed not only to strong linkage disequilibrium of HLA-C14:02 and -B51:01, but also to the effect of HLA-B51:01 itself. With regard to clinical implications, patient mismatched HLA-C14:02 proved to be a potent risk factor for severe acute graft-versus-host disease and mortality, and should be considered a non-permissive HLA-C mismatch in donor selection for unrelated donor hematopoietic stem cell transplantation.
HLA分子在异基因造血干细胞移植的免疫反应中发挥着重要作用。为了阐明特定HLA等位基因对急性移植物抗宿主病的影响，我们对6967例接受无关供体富含T细胞骨髓移植的日本患者进行了回顾性分析。通过对患者和供体HLA等位基因进行无偏搜索，发现患者和/或供体HLA - B51:01（患者：风险比[HR]，1.37，P<0.001；供体：HR，1.35，P<0.001）以及患者HLA - C14:02（HR，1.35，P<0.001）与严重急性移植物抗宿主病风险增加显著相关。供体HLA - C14:02与严重急性移植物抗宿主病不相关这一发现促使我们阐明这些高风险HLA等位基因与患者和供体HLA - C等位基因错配之间的关系。与HLA - C等位基因匹配相比，患者错配的HLA - C14:02在所有患者错配的HLA - C等位基因中显示出严重急性移植物抗宿主病的最高风险（HR，3.61，P<0.001）和移植相关死亡率（HR，2.53，P<0.001）。尽管患者HLA - C14:02和供体HLA - C15:02错配在移植物抗宿主方向上通常是KIR2DL配体错配，但无论KIR2DL配体是否匹配，患者错配的HLA - C14:02发生严重急性移植物抗宿主病的风险都很明显。患者和/或供体HLA - B51:01对急性移植物抗宿主病的影响不仅归因于HLA - C14:02和 - B51:01之间强烈的连锁不平衡，还归因于HLA - B51:01自身的作用。关于临床意义，患者错配的HLA - C14:02被证明是严重急性移植物抗宿主病和死亡率的有力风险因素，在无关供体造血干细胞移植的供体选择中应被视为不允许的HLA - C错配。
