Significantly higher frequencies of alloreactive CD4+ T cells responding to nonpermissive than to permissive HLA-DPB1 T-cell epitope disparities

Sizzano, Federico; Zito, Laura; Crivello, Pietro; Crocchiolo, Roberto; Vago, Luca; Zino, Elisabetta; Fleischhauer, Katharina

doi:10.1182/blood-2010-05-284687

Cited by 27 publications

(27 citation statements)

References 10 publications

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“…However, our results are compatible with an emerging picture that HLA-DPB1 TCE groups, and in turn their respective FD allele scores, reflect structural differences that are correlated with the strength of the alloreactive T cell response. In fact, we and others have shown that the median magnitude of the MLR response is higher against mismatched HLA-DPB1 alleles from different TCE groups, compared with the MLR response against mismatched HLA-DPB1 alleles from the same TCE group [39][40][41]. Although TCE groups 1 and 2 are characterized by relatively narrow FD allele score ranges of 0.0 to 0.5 and 0.6 to 1.9, respectively, TCE group 3 included a broader range of FD allele scores from 2.0 to 5.5, raising the possibility of further functional heterogeneity of HLA-DPB1 alleles from this group.…”

Section: Discussionmentioning

confidence: 92%

The Impact of Amino Acid Variability on Alloreactivity Defines a Functional Distance Predictive of Permissive HLA-DPB1 Mismatches in Hematopoietic Stem Cell Transplantation

Crivello

Zito

Sizzano

et al. 2015

Biology of Blood and Marrow Transplantation

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111

104

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A major challenge in unrelated hematopoietic stem cell transplantation (HSCT) is the prediction of permissive HLA mismatches, ie, those associated with lower clinical risks compared to their nonpermissive counterparts. For HLA-DPB1, a clinically prognostic model has been shown to be matching for T cell epitope (TCE) groups assigned by cross reactivity of T cells alloreactive to HLA-DPB1∗09:01; however, the molecular basis of this observation is not fully understood. Here, we have mutated amino acids (aa) in 10 positions of HLA-DPB1∗09:01 to other naturally occurring variants, expressed them by lentiviral vectors in B cell lines, and quantitatively measured allorecognition by 17 CD4(+) T cell effectors from 6 unrelated individuals. A significant impact on the median alloresponse was observed for peptide contact positions 9, 11, 35, 55, 69, 76, and 84, but not for positions 8, 56, and 57 pointing away from the groove. A score for the "functional distance" (FD) from HLA-DPB1∗09:01 was defined as the sum of the median impact of polymorphic aa in a given HLA-DPB1 allele on T cell alloreactivity. Established TCE group assignment of 23 alleles correlated with FD scores of ≤0.5, 0.6 to 1.9 and ≥2 for TCE groups 1, 2, and 3, respectively. Based on this, prediction of TCE group assignment will be possible for any given HLA-DPB1 allele, including currently 367 alleles encoding distinct proteins for which T cell cross reactivity patterns are unknown. Experimental confirmation of the in silico TCE group classification was successfully performed for 7 of 7 of these alleles. Our findings have practical implications for the applicability of TCE group matching in unrelated HSCT and provide new insights into the molecular mechanisms underlying this model. The innovative concept of FD opens new potential avenues for risk prediction in unrelated HSCT.

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Section: Discussionmentioning

confidence: 92%

The Impact of Amino Acid Variability on Alloreactivity Defines a Functional Distance Predictive of Permissive HLA-DPB1 Mismatches in Hematopoietic Stem Cell Transplantation

Crivello

Zito

Sizzano

et al. 2015

Biology of Blood and Marrow Transplantation

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111

104

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“…24 The frequency of alloreactive CD4 + T cells responding to nonpermissive than to permissive HLA-DPB1 T-cell epitope disparities was significantly higher in vitro. 25 Unfortunately, PBMC of donors, patients and recipients post HSCT were not available in our National study and thus this hypothesis could not have been tested. No significant effect of TCE3 or TCE4 nonpermissive disparities on relapse incidence were highlighted in other studies.…”

Section: Resultsmentioning

confidence: 97%

Is there any impact of HLA-DPB1 disparity in 10/10 HLA-matched unrelated hematopoietic SCT? Results of a French multicentric retrospective study

Gagne¹,

Loiseau²,

Dubois³

et al. 2014

Bone Marrow Transplant

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We retrospectively analyzed the impact of HLA-DPB1 mismatches in a large cohort of 1342 French patients who underwent 10/10 HLA-matched unrelated HSCT. A significant impact of HLA-DPB1 allelic mismatches (2 vs 0) was observed in severe acute GVHD (aGVHD III-IV) (risk ratio (RR) = 1.73, confidence interval (CI) 95% 1.09-2.73, P = 0.019) without impact on OS, TRM, relapse and chronic GVHD (cGVHD). According to the T-cell epitope 3 (TCE3)/TCE4 HLA-DPB1 disparity algorithm, 37.6% and 58.4% pairs had nonpermissive HLA-DPB1, respectively. TCE3 and TCE4 disparities had no statistical impact on OS, TRM, relapse, aGVHD and cGVHD. When TCE3/TCE4 disparities were analyzed in the graft-vs-host or host-vs-graft (HVG) direction, only a significant impact of TCE4 nonpermissive disparities in the HVG direction was observed on relapse (RR = 1.34, CI 95% 1.00-1.80, P = 0.048). In conclusion, this French retrospective study shows an adverse prognosis of HLA-DPB1 mismatches (2 vs 0) on severe aGVHD and of nonpermissive TCE4 HVG disparities on relapse after HLA-matched 10/10 unrelated HSCT.

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“…It was predicted that mismatches between HLA-DPB1 alleles from the same TCE group (designated permissive) would elicit less vigorous T-cell alloreactivity compared with alleles from different TCE groups (designated nonpermissive). This hypothesis was proven correct, both experimentally 65 and clinically, with nonpermissive HLA-DPB1 mismatches in either GVH or HVG direction resulting in worse survival after HLA-matched UD-HCT. 4,39,62,63 The survival disadvantage of nonpermissive mismatches is the net result of a greater risk of severe acute GVHD without a significant change in relapse risk compared with permissive mismatches.…”

Section: 55-58mentioning

confidence: 93%

HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities

Fleischhauer

Shaw

2017

Blood

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When considering HLA-matched hematopoietic cell transplantation (HCT), sibling and unrelated donors (UDs) are biologically different because UD-HCT is typically performed across HLA-DP disparities absent in sibling HCT. Mismatched HLA-DP is targeted by direct alloreactive T cell responses with important implications for graft-versus-host disease and graft-versus-leukemia. This concise review details special features of HLA-DP as model antigens for clinically permissive mismatches mediating limited T-cell alloreactivity with minimal toxicity, and describes future avenues for their exploitation in cellular immunotherapy of malignant blood disorders.

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Significantly higher frequencies of alloreactive CD4+ T cells responding to nonpermissive than to permissive HLA-DPB1 T-cell epitope disparities

Cited by 27 publications

References 10 publications

The Impact of Amino Acid Variability on Alloreactivity Defines a Functional Distance Predictive of Permissive HLA-DPB1 Mismatches in Hematopoietic Stem Cell Transplantation

The Impact of Amino Acid Variability on Alloreactivity Defines a Functional Distance Predictive of Permissive HLA-DPB1 Mismatches in Hematopoietic Stem Cell Transplantation

Is there any impact of HLA-DPB1 disparity in 10/10 HLA-matched unrelated hematopoietic SCT? Results of a French multicentric retrospective study

HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities

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