Carapito Raphael, Aouadi Ismail, Pichot Angélique, Spinnhirny Perrine, Morlon Aurore, Kotova Irina, Macquin Cécile, Rolli Véronique, Cesbron Anne, Gagne Katia, Oudshoorn Machteld, van der Holt Bronno, Labalette Myriam, Spierings Eric, Picard Christophe, Loiseau Pascale, Tamouza Ryad, Toubert Antoine, Parissiadis Anne, Dubois Valérie, Paillard Catherine, Maumy-Bertrand Myriam, Bertrand Frédéric, von dem Borne Peter A, Kuball Jürgen H E, Michallet Mauricette, Lioure Bruno, Peffault de Latour Régis, Blaise Didier, Cornelissen Jan J, Yakoub-Agha Ibrahim, Claas Frans, Moreau Philippe, Charron Dominique, Mohty Mohamad, Morishima Yasuo, Socié Gérard, Bahram Seiamak
Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, Plateforme GENOMAX, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
Labex TRANSPLANTEX, Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
Bone Marrow Transplant. 2020 Jul;55(7):1367-1378. doi: 10.1038/s41409-020-0886-5. Epub 2020 Apr 14.
Graft-versus-host disease (GVHD) and cytomegalovirus (CMV)-related complications are leading causes of mortality after unrelated-donor hematopoietic cell transplantation (UD-HCT). The non-conventional MHC class I gene MICB, alike MICA, encodes a stress-induced polymorphic NKG2D ligand. However, unlike MICA, MICB interacts with the CMV-encoded UL16, which sequestrates MICB intracellularly, leading to immune evasion. Here, we retrospectively analyzed the impact of mismatches in MICB amino acid position 98 (MICB98), a key polymorphic residue involved in UL16 binding, in 943 UD-HCT pairs who were allele-matched at HLA-A, -B, -C, -DRB1, -DQB1 and MICA loci. HLA-DP typing was further available. MICB98 mismatches were significantly associated with an increased incidence of acute (grade II-IV: HR, 1.20; 95% CI, 1.15 to 1.24; P < 0.001; grade III-IV: HR, 2.28; 95% CI, 1.56 to 3.34; P < 0.001) and chronic GVHD (HR, 1.21; 95% CI, 1.10 to 1.33; P < 0.001). MICB98 matching significantly reduced the effect of CMV status on overall mortality from a hazard ratio of 1.77 to 1.16. MICB98 mismatches showed a GVHD-independent association with a higher incidence of CMV infection/reactivation (HR, 1.84; 95% CI, 1.34 to 2.51; P < 0.001). Hence selecting a MICB98-matched donor significantly reduces the GVHD incidence and lowers the impact of CMV status on overall survival.
移植物抗宿主病（GVHD）和巨细胞病毒（CMV）相关并发症是无关供者造血细胞移植（UD-HCT）后导致死亡的主要原因。非常规的MHC I类基因MICB与MICA一样，编码一种应激诱导的多态性NKG2D配体。然而，与MICA不同的是，MICB与CMV编码的UL16相互作用，后者将MICB隔离在细胞内，导致免疫逃逸。在此，我们回顾性分析了943对在HLA-A、-B、-C、-DRB1、-DQB1和MICA位点等位基因匹配的UD-HCT患者中，MICB氨基酸位置98（MICB98）错配的影响，该位置是参与UL16结合的关键多态性残基。进一步进行了HLA-DP分型。MICB98错配与急性（II-IV级：HR，1.20；95%CI，1.15至1.24；P<0.001；III-IV级：HR，2.28；95%CI，1.56至3.34；P<0.001）和慢性GVHD（HR，1.21；95%CI，1.10至1.33；P<0.001）的发生率增加显著相关。MICB98匹配显著降低了CMV状态对总死亡率的影响，危险比从1.77降至1.16。MICB98错配显示出与CMV感染/再激活的较高发生率存在不依赖于GVHD的关联（HR，1.84；95%CI，1.34至2.51；P<0.001）。因此，选择MICB98匹配的供者可显著降低GVHD发生率，并降低CMV状态对总生存的影响。
