Immunobiology of HLA Class-Ib Molecules in Transplantation

Jucaud, Vadim

doi:10.15226/2372-0948/3/4/00137

Cited by 8 publications

(9 citation statements)

References 101 publications

(238 reference statements)

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“…It is known that peptide/HLA-E complexes serve as ligands to a restricted albeit functionally variable repertoire of receptors found on NK-, NKT-, and CD8 + T cells. Through their multifaceted interactions with those cells, they accordingly tune innate as well as adaptive immune responses in a series of distinct conditions such as infection, pregnancy, cancer, transplantation, and autoimmune disease [5,12,[33][34][35][36][37]. It has also been repeatedly demonstrated that the 2 basic HLA-E allelic variants (namely, 01:01 and 01:03) exhibit remarkably different surface expression levels, which are most likely attributed to post-transcriptional regulation factors such as peptide binding affinity and thermal stability [6,7,9,38,39].…”

Section: Discussionmentioning

confidence: 99%

Donor HLA-E Status Associates with Disease-Free Survival and Transplant-Related Mortality after Non In Vivo T Cell-Depleted HSCT for Acute Leukemia

Tsamadou

Fürst

Wang

et al. 2019

Biology of Blood and Marrow Transplantation

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Previous studies have suggested that HLA-E may have a significant role in the outcome of matched unrelated hematopoietic stem cell transplantation (HSCT), especially for patients with acute leukemia. We used Center for International Blood and Marrow Transplant Research data and samples of 1840 adult patients with acute leukemia and their 10/10 HLA-matched unrelated donors to investigate the impact of HLA-E matching status as well as of donor/recipient (D/R) HLA-E genotype on post-HSCT outcome. Both patients and donors were HLA-E genotyped by next-generation sequencing. All patients received their first transplant in complete remission between 2000 and 2015. Median follow-up time was 90 months. Overall survival, disease-free survival (DFS), transplant-related mortality (TRM), and relapse incidence were primary endpoints with statistical significance set at .01. D/R HLA-E genotype analysis revealed a significant association of donor HLA-E*01:03/01:03 genotype with DFS (hazard ratio [HR] = 1.35, P = .0006) and TRM (HR = 1.41, P = .0058) in patients who received T cell replete (ie, without in vivo T cell depletion) transplants (n = 1297). As for D/R HLA-E matching, we did not identify any significant effect on any of the clinical outcome endpoints. In conclusion, this is the largest study to date reporting an improvement of DFS and TRM after matched unrelated HSCT by avoidance of HLA-E*01:03 homozygous donors in patients transplanted with T cell replete grafts for acute leukemia.

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Section: Discussionmentioning

confidence: 99%

Donor HLA-E Status Associates with Disease-Free Survival and Transplant-Related Mortality after Non In Vivo T Cell-Depleted HSCT for Acute Leukemia

Tsamadou

Fürst

Wang

et al. 2019

Biology of Blood and Marrow Transplantation

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“…Finally, besides protein modifications and differential levels of expression that could impact their respective interaction and affinity with their specific receptors, non-classical HLA polymorphisms could also influence antibody production. Non-native forms of HLA-Ib, caused by alternative splicing or loss of β-2 microglobulin, may expose immunogenic cryptic epitopes and trigger an immune response [ 67 ]. Naturally occurring anti-HLA-E antibodies were shown to mimic anti-HLA-Ia antibodies and such cross-reactive binding was reported to affect the screening of anti-HLA-Ia antibodies in renal and liver transplant recipients [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

Association of HLA-A and Non-Classical HLA Class I Alleles

et al. 2016

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The HLA-A locus is surrounded by HLA class Ib genes: HLA-E, HLA-H, HLA-G and HLA-F. HLA class Ib molecules are involved in immuno-modulation with a central role for HLA-G and HLA-E, an emerging role for HLA-F and a yet unknown function for HLA-H. Thus, the principal objective of this study was to describe the main allelic associations between HLA-A and HLA-H, -G, -F and -E. Therefore, HLA-A, -E, -G, -H and -F coding polymorphisms, as well as HLA-G UnTranslated Region haplotypes (referred to as HLA-G UTRs), were explored in 191 voluntary blood donors. Allelic frequencies, Global Linkage Disequilibrium (GLD), Linkage Disequilibrium (LD) for specific pairs of alleles and two-loci haplotype frequencies were estimated. We showed that HLA-A, HLA-H, HLA-F, HLA-G and HLA-G UTRs were all in highly significant pairwise GLD, in contrast to HLA-E. Moreover, HLA-A displayed restricted associations with HLA-G UTR and HLA-H. We also confirmed several associations that were previously found to have a negative impact on transplantation outcome. In summary, our results suggest complex functional and clinical implications of the HLA-A genetic region.

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“…The monoclonal antibody (mAb) TFL-033 has a unique specificity and selectivity, which allows differentiating between the trimeric complex consisting of the HLA-E α-chain, the presented and loaded peptide and β 2 -m microglobulin (β 2 -m) and the β 2 -m-free, unloaded HLA-E monomer [23]. The diagnostic potential of the TFL-033 mAb has been recently described by analyzing HLA-E expression in normal gastric mucosa, primary as well as metastatic gastric cancer [24].…”

Section: Introductionmentioning

confidence: 99%

HLA-E expression and its clinical relevance in human renal cell carcinoma

et al. 2016

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The non-classical human leukocyte antigen E (HLA-E) expression is frequently overexpressed in tumor diseases, transplants and virus-infected cells and represents an immunomodulatory molecule by binding to the receptors CD94/NKG2A, -B and –C on NK and T cells. Due to its immune suppressive features HLA-E expression might represent an important mechanism of tumors to escape immune surveillance.While an aberrant expression of the non-classical HLA-G antigen in human renal cell carcinoma (RCC) has been demonstrated to be associated with a worse outcome of patients and reduced sensitivity to immune effector cell-mediated cytotoxicity, the expression and function of HLA-E has not yet been analyzed in this tumor entity.Higher levels of HLA-E transcripts were detected in all RCC cell lines and tumor lesions, which were tested in comparison to normal kidney epithelium. Immunohistochemical staining of a tissue microarray (TMA) using the HLA-E-specific monoclonal antibody TFL-033 recognizing the cytoplasmic HLA-E α-chain as monomer revealed a heterogeneous HLA-E expression in RCC lesions with the highest frequency in chromophobe RCC when compared to other RCC subtypes. HLA-E expression did not correlate with the frequency of CD3+, CD4+, CD8+ and FoxP3+ immune cell infiltrations, but showed an inverse correlation with infiltrating CD56+ cells. In contrast to HLA-G, HLA-E expression in RCCs was not statistically significant associated with a decreased disease specific survival. These data suggest that HLA-E overexpression frequently occurs in RCC and correlates with reduced immunogenicity.

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Immunobiology of HLA Class-Ib Molecules in Transplantation

Cited by 8 publications

References 101 publications

Donor HLA-E Status Associates with Disease-Free Survival and Transplant-Related Mortality after Non In Vivo T Cell-Depleted HSCT for Acute Leukemia

Donor HLA-E Status Associates with Disease-Free Survival and Transplant-Related Mortality after Non In Vivo T Cell-Depleted HSCT for Acute Leukemia

Association of HLA-A and Non-Classical HLA Class I Alleles

HLA-E expression and its clinical relevance in human renal cell carcinoma

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