Neuchel Christine, Fürst Daniel, Niederwieser Dietger, Bunjes Donald, Tsamadou Chrysanthi, Wulf Gerald, Pfreundschuh Michael, Wagner Eva, Stuhler Gernot, Einsele Hermann, Schrezenmeier Hubert, Mytilineos Joannis
Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttenberg-Hessen and University Hospital of Ulm, Ulm, Germany.
Institute of Transfusion Medicine, University of Ulm, Ulm, Germany.
PLoS One. 2017 Jan 20;12(1):e0169512. doi: 10.1371/journal.pone.0169512. eCollection 2017.
Natural Killer cells (NK) are lymphocytes with the potential to recognize and lyse cells which escaped T-cell mediated lysis due to their aberrant HLA expression profiles. Killer cell immunoglobulin-like receptors (KIR) influence NK-cell activity by mediation of activating or inhibitory signals upon interaction with HLA-C (C1, C2) ligands. Therefore, absence of ligands for donor inhibitory KIRs following hematopoietic stem cell transplantation (HSCT) may have an influence on its outcome. Previous studies showed that C1 negative patients have a decreased HSCT outcome. Our study, based on a cohort of 200 C1-negative patients, confirmed these findings for the endpoints: overall survival (OS: HR = 1.41, CI = 1.14-1.74, p = 0.0012), disease free survival (DFS: HR = 1.27, CI = 1.05-1.53, p = 0.015), treatment related mortality (TRM: HR = 1.41, CI = 1.01-1.96, p = 0.04), and relapse incidence (RI: HR = 1.33, CI = 1.01-1.75, p = 0.04) all being inferior when compared to C1-positive patients (n = 1246). Subsequent analysis showed that these findings applied for patients with myeloid malignancies but not for patients with lymphoproliferative diseases (OS: myeloid: HR = 1.51, CI = 1.15-1.99, p = 0.003; lymphoblastic: HR = 1.26, CI = 0.91-1.75, p = 0.16; DFS: myeloid: HR = 1.31, CI = 1.01-1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90-1.61, p = 0.21; RI: myeloid: HR = 1.31, CI = 1.01-1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90-1.61, p = 0.21). Interestingly, within the C1-negative patient group, transplantation with KIR2DS2 resulted in better OS (9/10 matched: HR = 0.24, CI = 0.08-0.67, p = 0.007) as well as DFS (9/10 matched: HR = 0,26, CI = 0.11-0.60, p = 0.002), and transplantation with KIR2DS1 positive donors was associated with a decreased RI (HR = 0.30, CI = 0.13-0.69, p = 0.005). TRM was increased when the donor was positive for KIR2DS1 (HR = 2.61, CI = 1.26-5.41, p = 0.001). Our findings suggest that inclusion of KIR2DS1/2/5 and KIR3DS1-genotyping in the unrelated donor search algorithm of C1-ligand negative patients with myeloid malignancies may prove to be of clinical relevance.
自然杀伤细胞（NK）是一种淋巴细胞，具有识别和裂解因HLA表达异常而逃避T细胞介导裂解的细胞的潜力。杀伤细胞免疫球蛋白样受体（KIR）通过与HLA-C（C1、C2）配体相互作用介导激活或抑制信号，从而影响NK细胞的活性。因此，造血干细胞移植（HSCT）后供体抑制性KIR的配体缺失可能会对其结果产生影响。先前的研究表明，C1阴性患者的HSCT结果较差。我们基于200例C1阴性患者的队列研究，证实了这些终点指标的结果：总生存期（OS：风险比[HR]=1.41，置信区间[CI]=1.14-1.74，p=0.0012）、无病生存期（DFS：HR=1.27，CI=1.05-1.53，p=0.015）、治疗相关死亡率（TRM：HR=1.41，CI=1.01-1.96，p=0.04）和复发率（RI：HR=1.33，CI=1.01-1.75，p=0.04），与C1阳性患者（n=1246）相比均较差。后续分析表明，这些结果适用于髓系恶性肿瘤患者，但不适用于淋巴增殖性疾病患者（OS：髓系：HR=1.51，CI=1.15-1.99，p=0.003；淋巴细胞性：HR=1.26，CI=0.91-1.75，p=0.16；DFS：髓系：HR=1.31，CI=1.01-1.70，p=0.04；淋巴细胞性：HR=1.21，CI=0.90-1.61，p=0.21；RI：髓系：HR=1.31，CI=1.01-1.70，p=0.04；淋巴细胞性：HR=1.21，CI=0.90-1.61，p=0.21）。有趣的是，在C1阴性患者组中，移植KIR2DS2可带来更好的总生存期（9/10匹配：HR=0.24，CI=0.08-0.67，p=0.007）以及无病生存期（9/10匹配：HR=0.26，CI=0.11-0.60，p=0.002），而移植KIR2DS1阳性供体与复发率降低相关（HR=0.30，CI=0.13-0.69，p=0.005）。当供体KIR2DS1呈阳性时，治疗相关死亡率会升高（HR=2.61，CI=1.26-5.41，p=0.001）。我们的研究结果表明，在C1配体阴性的髓系恶性肿瘤患者的无关供体搜索算法中纳入KIR2DS1/2/5和KIR3DS1基因分型可能具有临床相关性。
