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Compatibility at amino acid position 98 of MICB reduces the incidence of graft-versus host disease in conjunction with the CMV status

Raphaël Carapito 1, 2, 3, 4, 5 Ismaïl Aouadi 1, 2, 3, 4 Angelique Pichot 1, 2, 3, 4 Perrine Spinnhirny 1, 2, 3, 4 Aurore Morlon 2, 6 Irina Kotova 2, 6 Cécile Macquin 1, 2, 3, 4 Véronique Rolli 1, 2, 3, 4 Anne Cesbron 2, 7, 8 Katia Gagne 9, 2, 7 Machteld Oudshoorn 10, 11 Bronno van der Holt 12 Myriam Labalette 13, 14 Eric Spierings 15 Christophe Picard 16 Pascale Loiseau 2, 8, 17 Ryad Tamouza 2, 17 Antoine Toubert 2, 8, 17 Anne Parissiadis 8, 18 Valérie Dubois 19 Catherine Paillard 1, 2, 8, 20 Myriam Maumy-Bertrand 21 Frédéric Bertrand 21 Peter von Dem Borne 11 Jürgen Kuball 15 Mauricette Michallet 8, 22 Bruno Lioure 8, 20 Régis Peffault de Latour 2, 8, 23 Didier Blaise 8, 24 Jan J. Cornelissen 25 Ibrahim Yakoub Agha 8, 14 Frans H.J. Claas 11 Philippe Moreau 8, 26 Dominique Charron 1, 2, 17 Mohamad Mohty 8, 27, 28, 29 Yasuo Morishima 30 Gérard Socié 2, 8, 20 Seiamak Bahram 1, 2, 3, 4, 5
1 Inserm U1109 - Equipe Plate-forme GENOMAX
Fédération Hospitalo-Universitaire OMICARE, FMTS - Fédération de Médecine Translationnelle de Strasbourg, Immuno-Rhumatologie Moléculaire
9 CRCINA-ÉQUIPE 1 - Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications
CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers
Abstract : 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.
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Raphaël Carapito, Ismaïl Aouadi, Angelique Pichot, Perrine Spinnhirny, Aurore Morlon, et al.. Compatibility at amino acid position 98 of MICB reduces the incidence of graft-versus host disease in conjunction with the CMV status. Bone Marrow Transplantation, Nature Publishing Group, 2020, 15, Online ahead of print. ⟨10.1038/s41409-020-0886-5⟩. ⟨inserm-02545513⟩

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