Three-dimensional structure discrepancy between HLA alleles for effective prediction of aGVHD severity and optimal selection of recipient-donor pairs: a proof-of-concept study

// Hongxing Han 1, * , Fang Yuan 1, * , Yuying Sun 1, * , Jinfeng Liu 1 , Shuguang Liu 1 , Yuan Luo 1 , Fei Liang 1 , Nan Liu 1 , Juan Long 1 , Xiao Zhao 1 , Fanhua Kong 1 , Yongzhi Xi 1 1 Department of Immunology and National Center for Biomedicine Analysis, Beijing 307 Hospital Affiliated to Academy of Military Medical Sciences, Beijing, China * These authors have contributed equally to this work Correspondence to: Yongzhi Xi, e-mail: xiyz@yahoo.com Fanhua Kong, e-mail: k.fanhua@yahoo.com Keywords: acute graft-versus-host disease, HLA alleles, three-dimensional structure discrepancy, optimizing recipient-donor selection, allogeneic CTLs reaction Received: July 05, 2015      Accepted: October 05, 2015      Published: October 16, 2015 ABSTRACT The optimal selection of recipient-donor pair and accurate prediction of acute graft-versus-host disease (aGVHD) severity are always the two most crucial works in allogeneic hematopoietic stem cell transplantation (allo-HSCT), which currently rests mostly with HLA compatibility, the most polymorphic loci in the human genome, in clinic. Thus, there is an urgent need for a rapid and reliable quantitative system for optimal recipient-donor pairs selection and accurate prediction of aGVHD severity prior to allo-HSCT. For these reasons, we have developed a new selection/prediction system for optimal recipient-donor selection and effective prediction of aGVHD severity based on HLA three-dimensional (3D) structure modeling (HLA-TDSM) discrepancy, and applied this system in a pilot randomized clinical allo-HSCT study. The 37 patient-donor pairs in the study were typed at low- and high-resolution levels for HLA-A/-B/-DRB1/-DQB1 loci. HLA-TDSM system covering the 10000 alleles in HLA class I and II consists of the revised local and coordinate root-mean-square deviation (RMSD) values for each locus. Its accuracy and reliability were confirmed using stably transfected Hmy2.CIR–HLA-B cells, TCR Vβ gene scan, and antigen-specific alloreactive cytotoxic lymphocytes. Based on the preliminary results, we theoretically defined all HLA acceptable versus unacceptable mismatched alleles. More importantly, HLA-TDSM enabled a successful retrospective verification and prospective prediction for aGVHD severity in a pilot randomized clinical allo-HSCT study of 32 recipient-donor transplant pairs. There was a strong direct correlation between single/total revised RMSD and aGVHD severity (92% in retrospective group vs 95% in prospective group). These results seem to be closely related to the 3D structure discrepancy of mismatched HLA-alleles, but not the number or loci of mismatched HLA-alleles. Our data first provide the proof-of-concept that HLA-TDSM is essential for optimal selection of recipient-donor pairs and effective prediction of aGVHD severity before allo-HSCT.