Translating in vitro prediction of cytotoxic T cell alloreactivity to hematopoietic stem cell transplantation outcome

Jöris, Monique; Lankester, A.; Borne, Peter A. von dem; Kuball, Jürgen; Bierings, Marc; Cornelissen, J.J.; Sijnke, M.E. Groenendijk; Rood, Jon J. van; Oudshoorn, Machteld; Claas, Frans H.J.

doi:10.1016/j.trim.2013.08.006

Cited by 13 publications

(16 citation statements)

References 14 publications

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“…4,9,16,17 Considerable attention has also been given to the association between specific amino acid (AA) substitutions in mismatched HLA class I alleles and adverse outcome, 11,[18][19][20] resulting in a number of bio-informatic models for in silico outcome prediction. [21][22][23][24][25] For HLA class II, structural variability has been extensively studied in the context of solid organ transplantation, with some in silico models predictive of antibody formation and/or kidney transplant outcome already entered into clinical use. 26, 27 These models did not prove equally valid for HCT outcome prediction, 23,28 probably reflecting the more complex nature of HLA-peptide recognition by the T-cell receptor (TCR) compared with allo-antibodies.…”

Section: Introductionmentioning

confidence: 99%

“…[21][22][23][24][25] For HLA class II, structural variability has been extensively studied in the context of solid organ transplantation, with some in silico models predictive of antibody formation and/or kidney transplant outcome already entered into clinical use. 26, 27 These models did not prove equally valid for HCT outcome prediction, 23,28 probably reflecting the more complex nature of HLA-peptide recognition by the T-cell receptor (TCR) compared with allo-antibodies. 29,30 Here, we have addressed the functional role of AA polymorphism in HLA class II for clinical outcome of HCT in the context of nonpermissive TCE mismatches at HLA-DPB1, shown by some 4,9 but not all 31 multicenter studies to be associated with mortality after 10/10 HLA-matched unrelated HCT.…”

Section: Introductionmentioning

confidence: 99%

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Functional distance between recipient and donor HLA-DPB1 determines nonpermissive mismatches in unrelated HCT

Crivello¹,

Heinold

Rebmann

et al. 2016

Blood

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Key Points• Nonpermissive mismatches associated with survival after HCT reflect FD between recipient-donor HLA-DPB1.• FD within HLA-DPB1 is determined by the combined impact of nonconservative peptide-binding AA substitutions.The role of HLA amino acid (AA) polymorphism for the outcome of hematopoietic cell transplantation (HCT) is controversial, in particular for HLA class II. Here, we investigated this question in nonpermissive HLA-DPB1 T-cell epitope (TCE) mismatches reflected by numerical functional distance (FD) scores, assignable to all HLA-DPB1 alleles based on the combined impact of 12 polymorphic AAs. We calculated the difference in FD scores (DFD) of mismatched HLA-DPB1 alleles in patients and their 10/10 HLA-matched unrelated donors of 379 HCTs performed at our center for acute leukemia or myelodysplastic syndrome. Receiver-operator curve-based stratification into 2 DFD subgroups showed a significantly higher percentage of nonpermissive TCE mismatches for DFD >2.665, compared with DFD £2.665 (88% vs 25%, P < .0001). In multivariate analysis, DFD >2.665 was significantly associated with overall survival (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.05-1.87; P < .021) and event-free survival (HR, 1.39; 95% CI, 1.05-1.82; P < .021), compared with DFD £2.665. These associations were stronger than those observed for TCE mismatches. There was a marked but not statistically significant increase in the hazards of relapse and nonrelapse mortality in the high DFD subgroup, whereas no differences were observed for acute and chronic graft-versus-host disease. Seven nonconservative AA substitutions in peptide-binding positions had a significantly stronger impact on DFD compared with 5 others (P 5 .0025), demonstrating qualitative differences in the relative impact of AA polymorphism in HLA-DPB1. The novel concept of DFD sheds new light onto nonpermissive HLA-DPB1 mismatches in unrelated HCT. (Blood. 2016;128(1):120-129)

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional distance between recipient and donor HLA-DPB1 determines nonpermissive mismatches in unrelated HCT

Crivello¹,

Heinold

Rebmann

et al. 2016

Blood

View full text Add to dashboard Cite

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“…36,37 However it was not possible to reliably predict this lack of recognition by looking at the structural differences between the mismatched alleles. 38 It seems reasonable to predict that HLA disparities characterized by substitutions in the peptide binding site which significantly alter the set of pepHow to select the best available donor haematologica | 2016; 101(6) 683 tides presented by the HLA molecules will be more efficiently recognized by alloreactive T cells, whereas mismatches involving residues outside the peptide binding site are not expected to be recognized. Indeed a semiquantitative, in vitro measurement of CD8 + CD137 + alloreactive T cells in mixed lymphocyte reactions demonstrated that such a mismatch in the B44 serotype (i.e.…”

Section: Searching For 'Permissive' Mismatchesmentioning

confidence: 99%

How to select the best available related or unrelated donor of hematopoietic stem cells?

2016

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“…A model to predict cytotoxic T-cell alloreactivity was based on an amino acid mismatch score depending on the position and physicochemical properties of the mismatched residues (40). After testing the model on 171 9/10 and 168 10/10 matched HSCT patients, these authors found out that the aa mismatch score did not predict clinical outcome (41). …”

Section: Recognition Of Hla-c Incompatibilities By Alloreactive T Cellsmentioning

confidence: 99%

HLA-C Incompatibilities in Allogeneic Unrelated Hematopoietic Stem Cell Transplantation

Tiercy

2014

Front. Immunol.

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An increasingly larger fraction of patients with hematological diseases are treated by hematopoietic stem cells transplantation (HSCT) from HLA matched unrelated donors. Polymorphisms of HLA genes represent a major barrier to HSCT because HLA-A, -B, -C and DRB1 incompatibilities confer a higher risk of acute graft-versus-host disease (aGVHD) and mortality. Although >22 million volunteer HLA-typed donors are available worldwide, still a significant number of patients do not find a highly matched HSC donor. Because of the large haplotypic diversity in HLA-B–C associations, incompatibilities occur most frequently at HLA-C, so that unrelated donors with a single HLA-C mismatch often represent the only possible choice. The ratio of HLA-C-mismatched HSCT over the total number of transplants varies from 15 to 30%, as determined in 12 multicenter studies. Six multicenter studies involving >1800 patients have reported a 21–43% increase in mortality risk. By using in vitro cellular assays, a large heterogeneity in T-cell allorecognition has been observed. Yet the permissiveness of individual HLA-C mismatches remains poorly defined. It could be linked to the position and nature of the mismatched residues on HLA-C molecules, but also to variability in the expression levels of the mismatched alleles. The permissive C*03:03–03:04 mismatch is characterized by full compatibility at residues 9, 97, 99, 116, 152, 156, and 163 reported to be key positions influencing T-cell allorecognition. With a single difference among these seven key residues the C*07:01–07:02 mismatch might also be considered by analogy as permissive. High variability of HLA-C expression as determined by quantitative RT-PCR has been observed within individual allotypes and shows some correlation with A–B–C–DRB1 haplotypes. Thus in addition to the position of mismatched amino acid residues, expression level of patient’s mismatched HLA-C allotype might influence T-cell allorecognition, with patients low expression-C alleles representing possible permissive mismatches.

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Translating in vitro prediction of cytotoxic T cell alloreactivity to hematopoietic stem cell transplantation outcome

Cited by 13 publications

References 14 publications

Functional distance between recipient and donor HLA-DPB1 determines nonpermissive mismatches in unrelated HCT

Functional distance between recipient and donor HLA-DPB1 determines nonpermissive mismatches in unrelated HCT

How to select the best available related or unrelated donor of hematopoietic stem cells?

HLA-C Incompatibilities in Allogeneic Unrelated Hematopoietic Stem Cell Transplantation

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