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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2235-2241.
Prepublished online as a Blood First Edition Paper on June 6, 2007; DOI 10.1182/blood-2007-02-072405.
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Submitted February 6, 2007
Accepted June 4, 2007
High-risk HLA allele mismatch combinations responsible for severe acute graft versus host disease and implication for its molecular mechanism
Takakazu Kawase, Yasuo Morishima*, Keitaro Matsuo, Koichi Kashiwase, Hidetoshi Inoko, Hiroh Saji, Shunichi Kato, Takeo Juji, Yoshihisa Kodera, and Takehiko Sasazuki
Division of Immunology, Aichi Cancer Center, Nagoya, Japan
Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan
Division of Epidemiology and Prevention, Aichi Cancer Center, Nagoya, Japan
Japanese Red Cross Tokyo Metropolitan Blood Center, Tokyo, Japan
Division of Molecular Science, Tokai University School of Medicine, Isehara, Japan
HLA Laboratory, NPO, Kyoto, Japan
Department of Cell Transplantation & Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan
Japanese Red Cross Central Blood Institute, Tokyo, Japan
Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan
International Medical Center of Japan, Tokyo, Japan
* Corresponding author; email: ymorisim{at}aichi-cc.jp.
In allogenic hematopoietic stem cell transplantation, an effect of HLA locus mismatch in allele level on clinical outcome has been clarified. However, the effect of each HLA allele mismatch combination is little known, and its molecular mechanism to induce acute graft-versus-host disease (aGVHD) remains to be elucidated. Total 5210 donor-patient pairs transplanted through Japan Marrow Donor Program were analyzed. All HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 alleles were retrospectively typed in all pairs. The impacts of the HLA allele mismatch combinations and amino acid substitution positions in six HLA loci on severe aGVHD were analyzed. Total 15 significant high-risk HLA allele mismatch combinations and one HLA-DRB1-DQB1 linked mismatch combinations (high-risk mismatch) for severe aGVHD were identified, and the number of high-risk mismatches was highly associated with the occurrence of severe aGVHD regardless of the presence of mismatch combinations other than high-risk mismatch. Furthermore, 6 specific amino acid substitution positions in HLA class I were identified as those responsible for severe aGVHD. These findings provide evidence to elucidate the mechanism of aGVHD on the basis of HLA molecule. Furthermore, the identification of high-risk mismatch, that is, nonpermissive mismatch, would be beneficial for the selection of a suitable donor.
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