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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Acknowledgements
We would like to thank Prof. Robert Zeiser (University of Freiburg/Germany) for critical reading of this manuscript. We thank Martin Verniquet for critical review of statistical analyses. We would also like to thank Nicole Raus (SFGM-TC, Lyon, France) for retrieving the clinical data from the ProMISe database. This work was supported by grants from the Agence Nationale de la Recherche (ANR) (ANR-11-LABX-0070_TRANSPLANTEX), and the INSERM (UMR_S 1109), the Institut Universitaire de France (IUF), all to SB; from the University of Strasbourg (IDEX UNISTRA) to CP and SB; from the European regional development fund (European Union) INTERREG V program (project n°3.2 TRIDIAG) to RC and SB; and from MSD-Avenir grant AUTOGEN to SB.
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RC performed the experiments, designed the study, analyzed the data, and wrote the manuscript. SB designed the study, analyzed the data and wrote the manuscript. PS, AM, IK, CM, APi, and VR performed the experiments and analyzed the data. IA performed the statistics. PAB, DB, AC, DC, FC, KG, JK, JC, ML, PL, MMi, PM, MOu, APa, RPL, CPi, GS, ES, RT, AT, IY, VD and BH provided samples and clinical data, interpreted the clinical data and discussed the results. BL, MMo, AN, YM and CPa interpreted the clinical data and discussed results. FB, MMB, and BH analyzed the data and reviewed statistics. All authors contributed to the writing of the report and approved the final version of the manuscript.
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SB is the scientific founder and a (minority) shareholder of BIOMICA SAS. JK is the co-founder and chief scientific officer of Gadeta. He received personal fees from Gadeta. In addition, JK has a patent issued/pending. ES is the inventor of a patent application filed by the University Medical Center Utrecht on the prediction of an alloimmune response against mismatched HLA (PCT/EPT2013/073386). All other authors declare no conflict of interests.
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Carapito, R., Aouadi, I., Pichot, A. 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 Transplant 55, 1367–1378 (2020). https://doi.org/10.1038/s41409-020-0886-5
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DOI: https://doi.org/10.1038/s41409-020-0886-5