High-risk HLA alleles for severe acute graft-
            <i>versus</i>
            -host disease and mortality in unrelated donor bone marrow transplantation

Kashiwase, Koichi; Matsuo, Keitaro; Azuma, Fumihiro; Yabe, Toshikazu; Sato‐Otsubo, Aiko; Ogawa, Seishi; Shiina, Takashi; Satake, Masahiro; Saji, Hiroh; Kato, Shingo; Kodera, Yoshihisa; Sasazuki, Takehiko; Morishima, Yasuo

doi:10.3324/haematol.2015.136903

Cited by 28 publications

(26 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are indications for such constellations. [31][32][33] Environmental factors might as well influence presence or absence of graftversus-host disease; the microbiome of the gut has long been in focus and regained most recent interest. 33,34 If successful, a 'no graft-versus-host disease' constellation might favor an early low cost transplant with no need for immunosuppression post grafting, and save costs and suffering.…”

Section: Alloreactivity In Hsct a Gratwohl Et Almentioning

confidence: 99%

Alloreactivity: the Janus-face of hematopoietic stem cell transplantation

et al. 2017

View full text Add to dashboard Cite

Differences in major and minor histocompatibility antigens between donor and recipient trigger powerful graft-versus-host reactions after allogeneic hematopoietic stem cell transplantation (HSCT). The clinical effects of alloreactivity present a Janus-face: detrimental graft-versus-host disease increases non-relapse mortality, beneficial graft-versus-malignancy may cure the recipient. The ultimate consequences on long-term outcome remain a matter of debate. We hypothesized that increasing donor-recipient antigen matching would decrease the negative effects, while preserving antitumor alloreactivity. We analyzed retrospectively a predefined cohort of 32 838 such patients and compared it to 59 692 patients with autologous HSCT as reference group. We found a significant and systematic decrease in non-relapse mortality with decreasing phenotypic and genotypic antigen disparity, paralleled by a stepwise increase in overall and relapse-free survival (Spearman correlation coefficients of cumulative excess event rates at 5 years 0.964; P o 0.00; respectively 0.976; P o0.00). We observed this systematic stepwise effect in all main disease and disease-stage categories. The results suggest that detrimental effects of alloreactivity are additive with each step of mismatching; the beneficial effects remain preserved. Hence, if there is a choice, the best match should be donor of choice. The data support an intensified search for predictive genomic and environmental factors of 'no-graft-versus-host disease'.

show abstract

Section: Alloreactivity In Hsct a Gratwohl Et Almentioning

confidence: 99%

Alloreactivity: the Janus-face of hematopoietic stem cell transplantation

et al. 2017

View full text Add to dashboard Cite

show abstract

“…20 In this retrospective analysis of 6967 Japanese transplant recipients of T-replete unrelated donor bone marrow, patients and/or donors who possessed the HLA-B*51:01 allotype had significantly higher post-transplant risks (patient HR 1.37, P < .001; donor HR 1.35, P < .001). Furthermore, patients who were HLA-C*14:02-positive had increased risk of severe acute GVHD (HR 1.35, P < .001).…”

Section: Choosing Among Hla-mismatched Donorsmentioning

confidence: 88%

Mismatched unrelated donor transplantation

Petersdorf

2016

Seminars in Hematology

View full text Add to dashboard Cite

There are now over 25 million volunteer donors registered worldwide for patients in need of a life-saving hematopoietic cell transplant to cure blood disorders. Although an HLA-matched donor remains the preferred stem cell source for transplantation, the use of a donor with limited HLA mismatching may be considered. Significant advances in clinical and basic research have been instrumental in furthering the understanding of donor-recipient HLA mismatches that are better tolerated than other mismatches. An increased appreciation of the role of regulatory region variation that affects the level of HLA expression provides new approaches for the selection of HLA-mismatched donors.

show abstract

“…For patients with less common HLA haplotypes, 9/10-matched donors with a single HLA-C MM can represent the best option, but such incompatible transplants are characterized by increased risk of posttransplant complications (15, 16, 28). Some clinical studies have proposed that the alloresponse may vary with the nature of the HLA-C MM (12–14), although reliable prediction of less detrimental MMs remains a difficult task.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, a wide distribution of expression levels was observed among the negative MLR combinations. For comparison purposes with previous clinical studies (15, 16), we also analyzed the alloresponses measured in the 63 MLRs on the basis of MFIs taken as proxies of HLA-C expression levels (5, 15). In accordance with the results of the Japan Marrow Donor Program study (16), we did not find any correlation with HLA-C expression using these proxies (Figure 3), although, again, C*14:02 MMs were indeed recognized more efficiently.…”

Section: Discussionmentioning

confidence: 99%

“…Using 1,975 9/10-matched HSCT of the International Histocompatibility Working Group in HCT, Petersdorf et al (15) compared patients with low expression mismatched C*03 and C*07 allotypes and high expression C*01 and C*14 allotypes and found that high expression mismatched HLA-C alleles were associated with increased mortality. On the other hand, analyzing 1,965 pairs with single HLA-C MMs, Morishima et al (16) did not find any correlation between increasing level of expression of patient’s mismatched HLA-C allele and aGVHD or TRM risk, although patients’ HLA-C*14:02 was significantly associated with poor outcome. The same MFI values have also been applied to analyze a possible correlation with in vitro CTLp frequency to single HLA-C MMs.…”

Section: Introductionmentioning

confidence: 96%

See 1 more Smart Citation

Allorecognition of HLA-C Mismatches by CD8+ T Cells in Hematopoietic Stem Cell Transplantation Is a Complex Interplay between Mismatched Peptide-Binding Region Residues, HLA-C Expression, and HLA-DPB1 Disparities

2016

View full text Add to dashboard Cite

HLA-C locus mismatches (MMs) are the most frequent class I disparities in unrelated hematopoietic stem cell transplantation (HSCT) and have a detrimental impact on clinical outcome. Recently, a few retrospective clinical studies have reported some variability in the immunogenicity of HLA-C incompatibilities. To get better insight into presumably permissive HLA-C MMs, we have developed a one-way in vitro mixed lymphocyte reaction (MLR) assay allowing to quantify activated CD56−CD137+CD8+ lymphocytes in HLA-C incompatible combinations. T cell-mediated alloresponses were correlated with genetic markers such as HLA-C mRNA expression and the number of amino acid (aa) MMs in the α1/α2 domains (peptide-binding region). Because of the high rate of HLA-DPB1 incompatibilities in HLA-A-, B-, C-, DRB1-, and DQB1-matched unrelated HSCT patient/donor pairs, the impact of HLA-DPB1 mismatching, a potential bystander of CD4+ T cell activation, was also considered. Heterogeneous alloresponses were measured in 63 HLA-C-mismatched pairs with a positive assay in 52% of the combinations (2.3–18.6% activated CTLs), representing 24 different HLA-A~B~DRB1~DQB1 haplotypes. There was no correlation between measured alloresponses and mRNA expression of the mismatched HLA-C alleles. The HLA-C*03:03/03:04 MM did not induce any positive alloresponse in five MLRs. We also identified HLA-C*02:02 and HLA-C*06:02 as mismatched alleles with lower immunogenicity, and HLA-C*14:02 as a more immunogenic MM. A difference of at least 10 aa residues known to impact peptide/T cell receptor (TCR) binding and a bystander HLA-DPB1 incompatibility had a significant impact on CTL alloreactivity (p = 0.021). The same HLA-C MM, when recognized by two different responders with the same HLA haplotypes, was recognized differently, emphasizing the role of the T-cell repertoire of responding cells. In conclusion, mismatched HLA-C alleles differing by 10 or more aas in the peptide/TCR-binding region, when occurring together with HLA-DPB1 incompatibilities, should be considered as high-risk MMs in unrelated HSCT.

show abstract

High-risk HLA alleles for severe acute graft- versus -host disease and mortality in unrelated donor bone marrow transplantation

Cited by 28 publications

References 36 publications

Alloreactivity: the Janus-face of hematopoietic stem cell transplantation

Alloreactivity: the Janus-face of hematopoietic stem cell transplantation

Mismatched unrelated donor transplantation

Allorecognition of HLA-C Mismatches by CD8+ T Cells in Hematopoietic Stem Cell Transplantation Is a Complex Interplay between Mismatched Peptide-Binding Region Residues, HLA-C Expression, and HLA-DPB1 Disparities

Contact Info

Product

Resources

About