Denatured Class I Human Leukocyte Antigen Antibodies in Sensitized Kidney Recipients

Visentin, Jonathan; Guidicelli, Gwendaline; Bachelet, Thomas; Jacquelinet, Christian; Audry, Benoît; Nong, Thoa; Dubois, Valérie; Moreau, Jean-François; Lee, Jar-How; Couzi, Lionel; Merville, Pierre; Taupin, Jean‐Luc

doi:10.1097/tp.0000000000000229

Cited by 76 publications

(107 citation statements)

References 30 publications

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“…A few of them behaved like the majority of anti-dHLAs, suggesting that some anti-dHLAs could have been misclassified in our seminal work [14]. The second pattern showed a dissociated behavior between nontreated and acid-treated LSAB, as expected in the presence of a mix of antibodies recognizing different epitopes located on the same allele, some of them being restricted to nHLAs and the others to dHLAs.…”

Section: Discussionmentioning

confidence: 84%

“…We established a threshold for the ratio between mean fluorescence intensity (MFI) with acid-treated (D condition) and nontreated (N condition) LSAB, in order to differentiate anti-dHLAs (D ࣙ1.2N) from anti-nHLAs (D <1.2N) [14]. We validated this threshold by using the T-lymphocyte flow cytometry crossmatch (FCXM) assay, as resting T-lymphocytes are known to express negligible levels of FHC [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

“…We recently demonstrated with a large cohort of HLAsensitized recipients awaiting kidneys that anti-dHLA antibodies defined by LSAB acid treatment are also highly prevalent in these patients and cover a wide array of alleles/antigens [14]. We established a threshold for the ratio between mean fluorescence intensity (MFI) with acid-treated (D condition) and nontreated (N condition) LSAB, in order to differentiate anti-dHLAs (D ࣙ1.2N) from anti-nHLAs (D <1.2N) [14].…”

Section: Introductionmentioning

confidence: 99%

“…Exposure of LSAB to low pH, which dissociates the class I HLA heterotrimer and leaves the beads covered with dHLA only, was used by El-Awar et al to identify dHLA epitopes recognized by natural antibodies. Most of them were cryptic epitopes involving hidden residues, i.e., not surface-exposed and therefore not accessible to antibody on nHLA, but some were only partially cryptic or were even surface-exposed [13].We recently demonstrated with a large cohort of HLAsensitized recipients awaiting kidneys that anti-dHLA antibodies defined by LSAB acid treatment are also highly prevalent in these patients and cover a wide array of alleles/antigens [14]. We established a threshold for the ratio between mean fluorescence intensity (MFI) with acid-treated (D condition) and nontreated (N condition) LSAB, in order to differentiate anti-dHLAs (D ࣙ1.2N) from anti-nHLAs (D <1.2N) [14].…”

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confidence: 99%

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Deciphering allogeneic antibody response against native and denatured HLA epitopes in organ transplantation

et al. 2015

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Anti-HLA donor-specific antibodies are deleterious for organ transplant survival. Class I HLA donor-specific antibodies are identified by using the Luminex single antigen beads (LSAB) assay, which also detects anti-denatured HLA antibodies (anti-dHLAs). Anti-dHLAs are thought to be unable to recognize native HLA (nHLA) on the cell surface and therefore to be clinically irrelevant. Acid denaturation of nHLA on LSAB allows anti-dHLAs to be discriminated from anti-nHLAs. We previously defined a threshold for the ratio between mean fluorescence intensity against acid-treated (D for denaturation) and nontreated (N) LSAB, D ࣙ 1.2 N identifying the anti-dHLAs. However, some anti-dHLAs remained able to bind nHLA on lymphocytes in flow cytometry crossmatches, and some anti-nHLAs conserved significant reactivity toward acid-treated LSAB. After depleting serum anti-nHLA reactivity with HLA-typed cells, we analyzed the residual LSAB reactivity toward nontreated and acid-treated LSABs, and then evaluated the ability of antibodies to recognize nHLA alleles individually. We observed that sera can contain mixtures of anti-nHLAs and anti-dHLAs, or anti-nHLAs recognizing acid-resistant epitopes, all possibly targeting the same allele(s). Therefore, the anti-HLA antibody response can be highly complex and subtle, as is the accurate identification of pathogenic anti-HLA antibodies in human serum.Keywords: Anti-denatured HLA antibodiesHLA antibodiesHLA epitopesLuminex single antigen bead assay Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionTypically produced following exposure to foreign HLAs during pregnancy, after transfusion or upon organ transplantation, alloCorrespondence: Prof. Jean-Luc Taupin e-mail: jean-luc.taupin@chu-bordeaux.fr geneic anti-HLA antibodies are deleterious for the function and survival of transplanted organs when they are donor-specific (the so-called anti-HLA donor-specific antibodies or DSA) [1][2][3][4][5][6]. Understanding of the alloantibody response at antigen and epitope levels has been hampered since the origins of histocompatibility testing owing to the lack of sensitivity and resolution of the available tools. A major step forward was the release of the Luminex single antigen beads (LSAB) assays, which made possiblewww.eji-journal.eu 2112 J. Visentin et al. Eur. J. Immunol. 2015. 45: 2111-2121 the simultaneous analysis of nearly a hundred different class I or class II HLA alleles with a highly sensitive flow cytometric readout [7,8]. Using this tool with monoclonal anti-HLA antibodies or alloantibodies eluted after binding on cell lines expressing a single recombinant HLA allele, Terasaki's group indexed about two hundred distinct HLA epitopes accessible for antibody recognition [9]. The same task was achieved by Duquesnoy's group using a theoretical algorithm that predicts HLA epitopes on the molecular surface and relies on stereochemical modeling of the epitope-paratope interfaces of antigen-antibody complexes [10]. O...

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Deciphering allogeneic antibody response against native and denatured HLA epitopes in organ transplantation

et al. 2015

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“…Interpreting HLA or other antibodies as pathogenic requires expert opinion and is moving toward probabilistic assessment (28)(29)(30)(31), but this will often preclude the simple designation as ''positive versus negative'' specified in the Banff guidelines. For example, preexisting class I DSA has ABMR, antibody-mediated rejection; DSA, donor-specific antibody; NDSA, non-donor-specific HLA antibody.…”

Section: Discussionmentioning

confidence: 99%

Identifying Subphenotypes of Antibody-Mediated Rejection in Kidney Transplants

Halloran

Lopez

Pereira

2016

American Journal of Transplantation

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The key lesions in antibody-mediated kidney transplant rejection (ABMR) are microcirculation inflammation (peritubular capillaritis and/or glomerulitis lesions, abbreviated ''pg'') and glomerular double contours (cg lesions). We used these features to explore subphenotypes in 164 indication biopsies with ABMR-related diagnoses: 137 ABMR (109 pure and 28 mixed with T cellmediated rejection [TCMR]) and 27 transplant glomerulopathy (TG), identified from prospective multicenter studies. The lesions indicated three ABMR subphenotypes: pgABMR, cgABMR, and pgcgABMR. Principal component analysis confirmed these subphenotypes and showed that TG can be reclassified as pgcgABMR (n ¼ 17) or cgABMR (n ¼ 10). ABMR-related biopsies included 45 pgABMR, 90 pgcgABMR, and 25 cgABMR, with four unclassifiable. Dominating all time intervals was the subphenotype pgcgABMR. The pgABMR subphenotype presented earliest (median <2 years), frequently mixed with TCMR, and was most associated with nonadherence. The cgABMR subphenotype presented late (median 9 years). Subphenotypes differed in their molecular changes, with pgABMR having the most histologic-molecular discrepancies (i.e. potential errors). Donor-specific antibody (DSA) was not identified in 29% of pgcgABMR and 46% of cgABMR, but failure rates and molecular findings were similar to cases where DSA was known to be positive. Thus, ABMR presents distinct subphenotypes, early pg-dominant, late cg-dominant, and combined pgcg phenotype, differing in time, molecular features, accompanying TCMR, HLA antibody, and probability of nonadherence.

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The Histocompatibility Lab: Alloantibodies, Sensitization, and the Virtual Crossmatch

Fitch,

Jackson

2023

Textbook of Transplantation and Mechanical Support for End‐Stage Heart and Lung Disease

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Denatured Class I Human Leukocyte Antigen Antibodies in Sensitized Kidney Recipients

Cited by 76 publications

References 30 publications

Deciphering allogeneic antibody response against native and denatured HLA epitopes in organ transplantation

Deciphering allogeneic antibody response against native and denatured HLA epitopes in organ transplantation

Identifying Subphenotypes of Antibody-Mediated Rejection in Kidney Transplants

The Histocompatibility Lab: Alloantibodies, Sensitization, and the Virtual Crossmatch

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