杀伤细胞免疫球蛋白样受体基因及其配体相合或错配对单倍相合骨髓移植效果的影响

本研究分析杀伤细胞免疫球蛋白样受体（killer cell Ig-like receptor,KIR）及其配体分子相合与否对单倍体相合骨髓移植效果的影响。分析了74例KIR基因及其配体分子HLA-Cw的分布频率和特点,同时比较KIR分子配体缺失与否对单倍相合骨髓移植患者总体生存、无病生存、GVHD发生以及复发等的影响。结果表明：19个KIR基因表型中2DL1、2DL4和3DL2-3在所有个体100%分布,其他高频率分布的还有3DP1（98.6%）、2DP1（98.6%）、3DL1（97.3%）、2DL3（97.3%）;抑制型基因分布频次是活化型的1.37倍;所有单倍体都含有2DL1、KIR3DL2、3DL3和2DL4,其中每个单倍体中均含有2DL2和/或2DL3。HLA-C14个等位基因中Cw7分布频率最高为37.8%;KIR2DL2/2DL3识别配体Group2（HLA-Cw1,3,7,8,13,14）组占43.2%。32例单倍相合骨髓移植中KIR基因错配发生比例为43.8%,其中9/14例为2DL不相合、5/14为2DL2或3DL1不相合;46对单倍相合骨髓移植中HLA-Cw全相合者29例,不相合者14例,HLA-Cw发生完全错配比例为30.4%,全相合比例为63.4%。14例KIR基因不相合和13例KIR基因相合移植病例中,KIR基因相合组生存率高于KIR基因不相合者（p=0.032）;17例KIR分子配体HLA-Cw不相合移植患者的DFS明显高于24例相合者（p=0.024）。按供受者KIR配体是缺失的GVHD矢量组生存率高于非GVHD矢量组（p=0.015）。急性重症GVHD发生与活化型KIR2DS1/2DS2有关,2DS1/2DS2不相合组高发急性重症GVHD同时复发减低,而2DS1/2DS2相合组低GVHD但是复发增多。14例KIR配体不相合髓系白血病患者骨髓移植后1例复发死亡,而12例KIR配体相合组患者有4例复发死亡。结论：单倍体相合骨髓移植的主要特点就是HLA不全相合,KIR基因表型不一致性及其配体缺失也是其主要免疫学特征,供者型KIR配体的缺失与移植效果有密切关系,在单倍相合移植中分析KIR基因及其配体对于供者选择和判断预后有重要意义。

Impact of Incompatible Killer Cell Immunoglobulin-like Receptor and Its Ligand on the Outcome of Haploidentical Bone Marrow Transplantation

The purpose of study was to investigate the impact of killer immunoglobulin-like receptor (KIR) and its ligand on haploidentical bone marrow transplantation. 74 cases were analyzed for the distribution frequencies and characteristics of KIR and its ligand as well as the impact of KIR ligand for the haploidentical bone marrow transplantation in terms of the overall survival, disease-free survival (DFS), GVHD and relapse. The results showed that among the 19 KIR genotypes currently nominated KIR2DL1, KIR2DL4 and KIR3DL2-3 could be detected in all the cases. Other high frequency genotypes included KIR3DP1(98.6%), KIR2DP1(98.6%), KIR3DL1(97.3%)and KIR2DL3(97.3%). Inhibitory receptor genotypes were 1.37-fold of activating receptor genotypes. KIR2DL1, KIR3DL2, KIR3DL3 and KIR2DL4 were found in all haplotypes and at least one genotype of KIR2DL2 and/or KIR2DL3 existed in all haplotypes. Among the 14 genotypes found in the test, the HLA-Cw7 was the most popular (37.8%) and the group 2 (HLA-Cw1,3,7,8,13,14) recognized by KIR2DL2/2DL3 counted for 43.2%. The incompatibility of KIR for 32 cases of haploidentical BMT was 43.8%, of which 9/14 were KIR2DL incompatible, 5/14 were KIR2DL2 or KIR3DL1 incompatible. Among the 46 cases of haploidentical BMT, 29 cases were HLA-Cw matched and 14 cases were mismatched. The completed mismatch ratio of HLA-Cw was 30.4% and the match ratio was 63.4%. The survival rate was higher for the 14 cases of KIR genotype compatible group than the 13 cases of KIR genotype incompatible group (p=0.032). The disease-free survival was significantly higher for the 17 cases of mismatched KIR ligands (HLA-Cw) group than the matched group(p=0.024). The survival rate was higher in GVHD group than that in non-GVHD group when the KIR ligand was missing. The acute and severe GVHD was related to the existence of activating receptor of KIR2DS1/2DS2. The incompatibility group was accompanied with frequent acute and severe GVHD and less relapse and vice versa for the compatibility group. One patient died after BMT among the 14 mismatched KIR ligand group suffering from myelogenous leukemia while 4 patients out of 12 patients died in the matched group. It is concluded that the haploidentical BMT is characterized by mismatch between donor and recipient and its immunological reactions also features by the incompatibility of KIR genotype and missing ligand. The missing ligand for the donor KIR has strong effect on the outcome of BMT and it means a lot to analyze the KIR genotype and its ligand for the selection of best donor and prognostic evaluation in haploidentical BMT.