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Morishima S.,Aichi University | Kashiwase K.,Red Cross | Matsuo K.,Aichi Cancer Center Research Institute | Azuma F.,Red Cross | And 10 more authors.
Haematologica | Year: 2016

HLA molecules play an important role for immunoreactivity in allogeneic hematopoietic stem cell transplantation. To elucidate the effect of specific HLA alleles on acute graft-versus-host disease, we conducted a retrospective analysis using 6967 Japanese patients transplanted with T-cell-replete marrow from an unrelated donor. Using unbiased searches of patient and donor HLA alleles, patient and/or donor HLA-B*51:01 (patient: HR, 1.37, P<0.001; donor: HR, 1.35, P<0.001) and patient HLA-C*14:02 (HR, 1.35, P<0.001) were significantly associated with an increased risk of severe acute graft-versus- host disease. The finding that donor HLA-C*14:02 was not associated with severe acute graft-versus-host disease prompted us to elucidate the relation of these high-risk HLA alleles with patient and donor HLAC allele mismatches. In comparison to HLA-C allele match, patient mismatched HLA-C*14:02 showed the highest risk of severe acute graft-versus- host disease (HR, 3.61, P<0.001) and transplant-related mortality (HR, 2.53, P<0.001) among all patient mismatched HLA-C alleles. Although patient HLA-C*14:02 and donor HLA-C*15:02 mismatch was usually KIR2DL-ligand mismatch in the graft-versus-host direction, the risk of patient mismatched HLA-C*14:02 for severe acute graft-versushost disease was obvious regardless of KIR2DL-ligand matching. The effect of patient and/or donor HLA-B*51:01 on acute graft-versus-host disease was attributed not only to strong linkage disequilibrium of HLAC* 14:02 and -B*51:01, but also to the effect of HLA-B*51:01 itself. With regard to clinical implications, patient mismatched HLA-C*14:02 proved to be a potent risk factor for severe acute graft-versus-host disease and mortality, and should be considered a non-permissive HLA-C mismatch in donor selection for unrelated donor hematopoietic stem cell transplantation. © 2016 Ferrata Storti Foundation. Source

Ito A.,Oita University | Shimada H.,Oita University | Ishikawa K.,Oita University | Takeo N.,Oita University | And 9 more authors.
Journal of Affective Disorders | Year: 2015

Background Human leukocyte antigen (HLA) genotypes in lamotrigine -induced (LTG-induced) cutaneous adverse drug reactions (cADRs) have been described in several reports but controversy remains even for a given ethnic group. We attempted to clarify a possible association between LTG-induced cADRs and HLA alleles in Japanese patients. Method Sixteen subjects, including eight patients with LTG-induced cADRs and eight LTG-tolerant controls were included in this study. All eight patients with LTG-induced cADRs gave positive results in a drug-induced lymphocyte stimulation test (DLST) with LTG. We performed HLA-typing for HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1, using PCR with sequence-specific oligonucleotide probes and multiple analyte profiling (xMAP) technology (Luminex System; Luminex Corporation, Austin, TX). We examined differences between allele frequencies in our two groups of subjects and the allele frequencies in the general Japanese population. Results The frequencies of HLA-DRB1∗0405, and HLA-DQB1∗0401 alleles were higher in our LTG-cADRs patients than the reference frequencies in the general Japanese population. We also detected HLA-DQA1∗0303 frequently in our LTG-cADRs patients, but data for this allele in the Japanese population was not available. Our observation was presumably due to the linkage disequilibrium among the three alleles. The haplotype frequency of HLA-DRB1∗0405, DQB1∗0401 and DQA1∗0303 in our LTG-cADRs subjects was also different from the corresponding haplotype frequency in the database for the Japanese population and the difference was statistically significant. One patient with the HLA-DRB1∗0405, -DQB1∗0401 and DQA1∗0303 haplotype was safely re-treated with LTG after results of a DLST with LTG ceased to be positive about 4 months after discontinuation of LTG. Limitations Our analysis included only 16 patients. Associations between LTG-induced cADRs and specific HLA loci will have to be confirmed in larger studies. Conclusions LTG-induced cADRs are associated with HLA-DRB1∗0405, -DQB1∗0401 and -DQA1∗0303. © 2015 Published by Elsevier B.V. Source

Yamakawa N.,Center for Genomic Medicine | Fujimoto M.,Center for Genomic Medicine | Kawabata D.,Center for Genomic Medicine | Terao C.,Center for Genomic Medicine | And 18 more authors.
Journal of Rheumatology | Year: 2014

Objective. Methotrexate-associated lymphoproliferative disorders (MTX-LPD) often regress spontaneously during MTX withdrawal, but the prognostic factors remain unclear. The aim of our study was to clarify the clinical, histological, and genetic factors that predict outcomes in patients with MTX-LPD. Methods. Patients with MTX-LPD diagnosed between 2000 and 2012 were analyzed retrospectively regarding their clinical course, site of biopsy, histological typing, Epstein-Barr virus (EBV) in situ hybridization and immunostaining, and HLA type. Results. Twenty-one patients, including 20 with rheumatoid arthritis (RA) and 1 with polymyositis, were analyzed. The mean dose of MTX was 6.1 mg/week and the mean duration of treatment was 71.1 months. Clinically, 5 patients were diagnosed with EBV-positive mucocutaneous ulcer (EBVMCU) and had polymorphic histological findings. The proportion of those patients successfully treated solely by withdrawal of MTX was significantly greater than that of those without EBVMCU (75% vs 7.7%, p = 0.015). The HLA-B15:11 haplotype was more frequent in patients with EBV+ RA with MTX-LPD than in healthy Japanese controls (p = 0.0079, Bonferroni's method). EBV latency classification and HLA typing were not associated with the prognosis of MTX-LPD in our cohort. Conclusion. Our data demonstrate that patients in the EBVMCU, a specific clinical subgroup of MTX-LPD, had a better clinical outcome when MTX was withdrawn than did other patients with MTX-LPD. (First Release Dec 15 2013; J Rheumatol 2014;41:293-9; doi:10.3899/jrheum.130270). © The Journal of Rheumatology Copyright 2014. All rights reserved. Source

Sato-Otsubo A.,University of Tokyo | Sato-Otsubo A.,Japan Science and Technology Agency | Sato-Otsubo A.,Kyoto University | Nannya Y.,Japan Science and Technology Agency | And 21 more authors.
Blood | Year: 2015

Acute graft-versus-host disease (aGVHD) represents one of the major complications in allogeneic stem cell transplantation and is primarily caused by genetic disparity between the donor and recipient. In HLA-matched transplants, the disparity is thought to be determined by loci encoding minor histocompatibility antigens (minorHantigens), which are presented by specific HLA molecules. We performed a genome-wide association study (GWAS) to identify minor H antigen loci associated with aGVHD. A total of 500 568 single nucleotide polymorphisms (SNPs) were genotyped for donors and recipients from 1589 unrelated bone marrow transplants matched for HLA-A,-B,-C,-DRB1, and-DQB1, followed by the imputation of unobserved SNPs. We interrogated SNPs whose disparity between the donor and recipient was significantly associated with aGVHD development. Without assuming HLA unrestriction, we successfully captured a known association between HLA-DPB1 disparity (P = 4.50 × 10-9) and grade II-IV aGVHD development, providing proof of concept for the GWAS design aimed at discovering genetic disparity associated with aGVHD. In HLA-restricted analyses, whereby association tests were confined to major subgroups sharing common HLA alleles to identify putative minor H antigen loci, we identified 3 novel loci significantly associated with grade III-IV aGVHD. Among these, rs17473423 (P = 1.20 × 10-11) at 12p12.1 within the KRAS locus showed the most significant association in the subgroup, sharing HLA-DQB1∗06:01. Our result suggested that a GWAS can be successfully applied to identify allele mismatch associated with aGVHD development, contributing to the understanding of the genetic basis of aGVHD. © 2015 by The American Society of Hematology. Source

Inaguma Y.,Fujita Health University Hospital | Akahori Y.,Health Science University | Murayama Y.,Fujita Health University Hospital | Shiraishi K.,Aichi Cancer Center Research Institute | And 14 more authors.
Gene Therapy | Year: 2014

The genetic transfer of T-cell receptors (TCRs) directed toward target antigens into T lymphocytes has been used to generate antitumor T cells efficiently without the need for the in vitro induction and expansion of T cells with cognate specificity. Alternatively, T cells have been gene-modified with a TCR-like antibody or chimeric antigen receptor (CAR). We show that immunization of HLA-A2 transgenic mice with tetramerized recombinant HLA-A2 incorporating HA-1 H minor histocompatibility antigen (mHag) peptides and β2- microglobulin (HA-1 H/HLA-A2) generate highly specific antibodies. One single-chain variable region moiety (scFv) antibody, #131, demonstrated high affinity (K D =14.9 nM) for the HA-1 H/HLA-A2 complex. Primary human T cells transduced with #131 scFV coupled to CD28 transmembrane and CD3ζ domains were stained with HA-1 H/HLA-A2 tetramers slightly more intensely than a cytotoxic T lymphocyte (CTL) clone specific for endogenously HLA-A2-and HA-1 H-positive cells. Although #131 scFv CAR-T cells required >100-fold higher antigen density to exert cytotoxicity compared with the cognate CTL clone, they could produce inflammatory cytokines against cells expressing HLA-A2 and HA-1 H transgenes. These data implicate that T cells with high-affinity antigen receptors reduce the ability to lyse targets with low-density peptide/MHC complexes (∼100 per cell), while they could respond at cytokine production level. © 2014 Macmillan Publishers Limited. Source

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