Department of Hematology, Shinko Hospital, Kobe, Japan; Department of Hematology, Medical Research Institute Kitano Hospital, Osaka, Japan.
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Biol Blood Marrow Transplant. 2020 Mar;26(3):431-437. doi: 10.1016/j.bbmt.2019.10.032. Epub 2019 Nov 6.
Natural killer (NK) cells expressing killer cell immunoglobulin-like receptors (KIRs) can recognize specific HLA class I molecules as their ligands. By studying a large Japanese transplant registry, we compared transplant outcomes between patients heterozygous for HLA-C/C (HLA-C1/C2) and those homozygous for HLA-C1 (HLA-C1/C1) among patients who had undergone HLA-matched hematopoietic stem cell transplantation (HSCT). A high frequency of KIR2DL1 with strong HLA-C2 binding capacity and a low frequency of HLA-C2 and KIR haplotype B are characteristic of the Japanese population. In our previous report, HLA-C1/C1 patients with myeloid leukemia were less likely to relapse than HLA-C1/C2 patients. We newly assessed 2884 patients with acute lymphoblastic leukemia (ALL) who received HLA-matched allogeneic HSCT and analyzed their leukemia relapses by using adjusted competing-risk methods. HLA-C1/C1 patients with ALL experienced significantly higher relapse rates than HLA-C1/C2 patients (hazard ratio [HR] = 1.55, P = .003), contrary to our results in patients with myeloid leukemia. We allocated patients with ALL to several subgroups and found a higher frequency of relapse (HR >1.8) in the HLA-C1/C1 group than in the HLA-C1/C2 group among patients with Ph-negative ALL, those who had no cytomegalovirus reactivation, those who received transplants from donors who were aged 41 years or older, and those who experienced acute graft-versus-host disease, especially if it required systemic treatment. One interpretation of our results is that KIR2DL1-positive NK cells disrupt T cells, antigen-presenting cells, or both from working efficiently in transplant immunity in HLA-C1/C1 patients with ALL. Another is that KIR2DS1-positive NK cells directly attack HLA-C2-positive ALL blasts in HLA-C1/C2 patients. Whether HLA-C2 can cause recurrence to decrease or increase in patients depending on the disease (ALL or myeloid leukemia) will be a very important finding. We hope that our results will provide clues to the real mechanisms behind relapse after transplantation in patients with different HLA profiles.
自然杀伤 (NK) 细胞表达杀伤细胞免疫球蛋白样受体 (KIR)，可以识别特定的 HLA Ⅰ类分子作为其配体。通过研究一个大型的日本移植登记处，我们比较了在接受 HLA 匹配造血干细胞移植 (HSCT) 的患者中，HLA-C/C（HLA-C1/C2）杂合子和 HLA-C1 纯合子（HLA-C1/C1）患者之间的移植结果。具有强 HLA-C2 结合能力的 KIR2DL1 高频率和 HLA-C2 和 KIR 单倍型 B 的低频率是日本人群的特征。在我们之前的报告中，患有髓系白血病的 HLA-C1/C1 患者比 HLA-C1/C2 患者复发的可能性更小。我们新评估了 2884 例接受 HLA 匹配同种异体 HSCT 的急性淋巴细胞白血病 (ALL) 患者，并使用调整后的竞争风险方法分析了他们的白血病复发情况。与我们在髓系白血病患者中的结果相反，ALL 患者中 HLA-C1/C1 患者的复发率明显高于 HLA-C1/C2 患者（风险比 [HR] = 1.55，P =.003）。我们将 ALL 患者分配到几个亚组中，并发现 Ph-阴性 ALL 患者、无巨细胞病毒再激活的患者、接受年龄为 41 岁或以上供者移植的患者以及发生急性移植物抗宿主病的患者中 HLA-C1/C1 组的复发率更高（HR >1.8），尤其是需要系统治疗的患者。我们结果的一种解释是，在 ALL 患者中，HLA-C1/C1 患者中 KIR2DL1 阳性 NK 细胞破坏 T 细胞、抗原呈递细胞或两者的工作效率，从而破坏移植免疫。另一种解释是，在 HLA-C1/C2 患者中，KIR2DS1 阳性 NK 细胞直接攻击 HLA-C2 阳性 ALL 白血病细胞。HLA-C2 是导致疾病（ALL 或髓系白血病）患者复发增加还是减少的关键因素。我们希望我们的研究结果能为不同 HLA 谱患者移植后复发的真正机制提供线索。
