Submitted August 4, 2008
Accepted October 31, 2008
HLA mismatch combinations associated with decreased risk of relapse: Implications for molecular mechanism
Takakazu Kawase, Keitaro Matsuo, Koichi Kashiwase, Hidetoshi Inoko, Hiroh Saji, Seishi Ogawa, Shunichi Kato, Takehiko Sasazuki, Yoshihisa Kodera, and Yasuo Morishima*
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, 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
The 21st Century COE Program, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
Department of Cell Transplantation & Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan
International Medical Center of Japan, Tokyo, Japan
Japanese Red Cross Nagoya First Hospital, Nagoya, Japan
Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya, Japan
* Corresponding author; email: ymorisim{at}aichi-cc.jp.
The finding that the risk of relapse in hematological malignancy decreases after allogeneic hematopoietic stem cell transplantation (HSCT) has lead to the concept of a graft-versus-leukemia effect (GVL). This beneficial effect is considered often offset, however, by graft-versus-host disease (GVHD). Thus, improving HSCT outcomes by separating GVL from GVHD is considered a key clinical issue. This cohort study registered 4643 patients transplanted for hematological malignancy from an unrelated donor. 6 major HLA loci were retrospectively genotyped. We identified 4 HLA-Cw and 6 HLA-DPB1 mismatch combinations responsible for a decreased risk of relapse; of these, 8 of 10 combinations were different from those responsible for severe acute GVHD, including all 6 of the HLA-DPB1 combinations. Pairs with these combinations of HLA-DPB1 had a significantly improved overall survival compared to completely matched pairs. Moreover, several amino acid substitutions on specific positions responsible for a decreased risk of relapse were identified in HLA-Cw, but not in HLA-DPB1. These findings might be key to elucidating the mechanism of the decreased risk of relapse on the basis of HLA molecule. Donor selection made in consideration of these results might allow the separation of GVL from acute GVHD, especially in HLA-DPB1 mismatch combinations.
