Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan.
Immunogenetics. 2013 Apr;65(4):265-71. doi: 10.1007/s00251-013-0679-8. Epub 2013 Jan 29.
An association between FCGR3A-158 V/F polymorphism and biological responses to infliximab has been reported in Crohn's disease (CD) in Western countries. However, little is known about the mechanism by which gene polymorphism affects the responses to infliximab. The aims of this study were to confirm the association in Japanese CD patients and to reveal the effect of gene polymorphism on biological responses to infliximab. Japanese CD patients were examined retrospectively at weeks 8 and 30. Clinical and biological responses were assessed by the Crohn's disease activity index and C-reactive protein levels, respectively. The infliximab-binding affinity of natural killer (NK) cells from FCGR3A-158 V/V, V/F and F/F donors was examined. Infliximab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) activities were also determined using transmembrane TNF-α-expressing Jurkat T cells as target cells and peripheral blood mononuclear cells (PBMCs) from V/V, V/F and F/F donors as effector cells. Biological responses at week 8 were statistically higher in V/V patients, whereas no significant differences were observed in either clinical responses at weeks 8 and 30 or biological responses at week 30 among the three genotypes. NK cells and PBMCs from V/V patients also showed higher infliximab-binding affinity and infliximab-mediated ADCC activity, respectively. Our results suggest that FCGR3A-158 polymorphism is a predicting factor of biological responses to infliximab in the early phases. FCGR3A-158 polymorphism was also found to affect the infliximab-binding affinity of NK cells and infliximab-mediated ADCC activity in vitro, suggesting that an effect on ADCC activity influences biological responses to infliximab in CD patients.
在西方国家的克罗恩病（CD）中，已经报道了 FCGR3A-158 V/F 多态性与英夫利昔单抗的生物学反应之间存在关联。然而，基因多态性如何影响英夫利昔单抗的反应机制知之甚少。本研究的目的是在日本 CD 患者中证实这种关联，并揭示基因多态性对英夫利昔单抗生物学反应的影响。回顾性检查日本 CD 患者在第 8 周和第 30 周的情况。通过克罗恩病活动指数和 C 反应蛋白水平分别评估临床和生物学反应。检查来自 FCGR3A-158 V/V、V/F 和 F/F 供体的自然杀伤（NK）细胞的英夫利昔单抗结合亲和力。还使用表达跨膜 TNF-α的 Jurkat T 细胞作为靶细胞和来自 V/V、V/F 和 F/F 供体的外周血单核细胞（PBMC）作为效应细胞，测定英夫利昔单抗介导的抗体依赖性细胞介导的细胞毒性（ADCC）活性。第 8 周时，V/V 患者的生物学反应具有统计学意义，而在第 8 周和第 30 周的临床反应或三种基因型的第 30 周的生物学反应中，均未观察到显著差异。V/V 患者的 NK 细胞和 PBMC 也显示出更高的英夫利昔单抗结合亲和力和英夫利昔单抗介导的 ADCC 活性。我们的结果表明，FCGR3A-158 多态性是英夫利昔单抗早期生物学反应的预测因子。还发现 FCGR3A-158 多态性影响 NK 细胞的英夫利昔单抗结合亲和力和英夫利昔单抗介导的 ADCC 活性，这表明 ADCC 活性的影响会影响 CD 患者对英夫利昔单抗的生物学反应。
