Clinical Research Papers:

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, Fang Yuan, Yuying Sun, Jinfeng Liu, Shuguang Liu, Yuan Luo, Fei Liang, Nan Liu, Juan Long, Xiao Zhao, Fanhua Kong and Yongzhi Xi _

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Oncotarget. 2015; 6:40337-40359. https://doi.org/10.18632/oncotarget.5378

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Hongxing Han1,*, Fang Yuan1,*, Yuying Sun1,*, Jinfeng Liu1, Shuguang Liu1, Yuan Luo1, Fei Liang1, Nan Liu1, Juan Long1, Xiao Zhao1, Fanhua Kong1, Yongzhi Xi1

1Department 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: [email protected]

Fanhua Kong, e-mail: [email protected]

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


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.

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