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Impact of allele-specific anti-human leukocyte antigen class I antibodies on organ allocation.

ABSTRACT: Technological advances in the field of histocompatibility have allowed us to define anti-human leukocyte antigen (HLA) antibody specificity at the allelic level. However, how allele-specific antibodies affect organ allocation is poorly studied. We examined allelic specificities of class I HLA antibodies in 6726 consecutive serum samples from 2953 transplant candidates and evaluated their impact on the corresponding crossmatch and organ allocation. Out of 17 class I HLA antigens represented by >1 allele in the LABScreen single antigen bead assay, 12 had potential allele-specific reactivity. Taking advantage of our unbiased cohort of deceased donor-candidate testing (123,135 complement-dependent cytotoxicity crossmatches between 2014 and 2017), we estimated that the presence of allele-specific antibody detected using a single antigen bead assay (median fluorescence intensity, >3000) against only the rare allele was a poor predictor of a positive complement-dependent cytotoxicity crossmatch, with a positive predictive value of 0% to 7%, compared with 52.5% in allele-concordant class I HLA antibodies against A or B locus antigens. Further, we confirmed allele-specific reactivity using flow crossmatch in 3 scenarios: A11:01/A11:02, A68:01/A68:02, and B44:02/B44:03. Our results suggest that allele-specific antibodies may unnecessarily exclude transplant candidates (up to 10%) from organ offers by overcalling unacceptable antigens; incorporation of selective reactivity pattern in allocation may promote precision matching and more equitable allocation.

SUBMITTER: Yeung MY

PROVIDER: S-EPMC10756661 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Impact of allele-specific anti-human leukocyte antigen class I antibodies on organ allocation.

Yeung Melissa Y MY Murakami Naoka N Kafetzi Maria L ML Simmons Daimon P DP Wood Isabelle I Macaskill Peter P Towle Matthew M DellaGatta Jamie J Stevens Jonathan J Comeau Edward E Baronas Jane J Mohsin Nabil N Chen Mike M Lee Jar-How JH Lane William J WJ Milford Edgar L EL Guleria Indira I

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20230529 9

Technological advances in the field of histocompatibility have allowed us to define anti-human leukocyte antigen (HLA) antibody specificity at the allelic level. However, how allele-specific antibodies affect organ allocation is poorly studied. We examined allelic specificities of class I HLA antibodies in 6726 consecutive serum samples from 2953 transplant candidates and evaluated their impact on the corresponding crossmatch and organ allocation. Out of 17 class I HLA antigens represented by >1 ...[more]

PMID: 37257653

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Project description:The consolidation of single antigen beads (SAB-panIgG) assay in the detection of preformed anti-human leukocyte antigen (HLA) antibodies has improved transplantation success. However, its high sensitivity has limited the allograft allocation for sensitized patients, increasing their waiting time. A modification of the standard SAB-panIgG assay allows the detection of that subset of antibodies capable of binding C1q (SAB-C1q assay). However, the clinical usefulness of SAB-C1q assay for determining the unacceptable mismatches is under discussion. We retrospectively analyzed the impact of preformed donor-specific anti-HLA antibodies (DSA) according to the C1q-binding ability on allograft outcome, examining 389 single-kidney transplanted patients from deceased donors. Recipients with preformed C1q-binding DSA showed the lowest allograft survival up to 7 years (40.7%) compared to patients with preformed non-C1q-binding DSA (73.4%; p = 0.001) and without DSA (79.1%; p < 0.001). Allograft survival rate was similar between patients with preformed non-C1q-binding DSA and patients without preformed DSA (p = 0.403). Interestingly, among the high-mean fluorescence intensity DSA (≥10,000) population (n = 46), those patients whose DSA were further capable of binding C1q showed a poorer allograft outcome (38.4 vs. 68.9%; p = 0.041). Moreover, in our multivariate predictive model for assessing the risk of allograft loss, the presence of C1q-binding DSA (HR 4.012; CI 95% 2.326-6.919; p < 0.001) but not of non-C1q-binding DSA (HR 1.389; CI 95% 0.784-2.461; p = 0.260) remained an independent predictor after stratifying the DSA population according to the C1q-binding ability and adjusting the model for other pre-transplantation predictive factors including donor age, cold-ischemia time, and HLA-DR mismatches. In conclusion, the unacceptable mismatch definition according to the SAB-C1q assay would improve the risk stratification of allograft loss and increase the limited allograft allocation of highly sensitized patients, shortening their waiting time.

Project description:Histocompatibility in solid-organ transplantation has a strong impact on long-term graft survival. Although recent advances in matching of both B-cell epitopes and T-cell epitopes have improved understanding of allorecognition, the immunogenic determinants are still not fully understood. We hypothesized that HLA solvent accessibility is allele-specific, thus supporting refinement of HLA B-cell epitope prediction. We developed a computational pipeline named Snowflake to calculate solvent accessibility of HLA Class I proteins for deposited HLA crystal structures, supplemented by constructed HLA structures through the AlphaFold protein folding predictor and peptide binding predictions of the APE-Gen docking framework. This dataset trained a four-layer long short-term memory bidirectional recurrent neural network, which in turn inferred solvent accessibility of all known HLA Class I proteins. We extracted 676 HLA Class-I experimental structures from the Protein Data Bank and supplemented it by 37 Class-I alleles for which structures were predicted. For each of the predicted structures, 10 known binding peptides as reported by the Immune Epitope DataBase were rendered into the binding groove. Although HLA Class I proteins predominantly are folded similarly, we found higher variation in root mean square difference of solvent accessibility between experimental structures of different HLAs compared to structures with identical amino acid sequence, suggesting HLA's solvent accessible surface is protein specific. Hence, residues may be surface-accessible on e.g. HLA-A*02:01, but not on HLA-A*01:01. Mapping these data to antibody-verified epitopes as defined by the HLA Epitope Registry reveals patterns of (1) consistently accessible residues, (2) only subsets of an epitope's residues being consistently accessible and (3) varying surface accessibility of residues of epitopes. Our data suggest B-cell epitope definitions can be refined by considering allele-specific solvent-accessibility, rather than aggregating HLA protein surface maps by HLA class or locus. To support studies on epitope analyses in organ transplantation, the calculation of donor-allele-specific solvent-accessible amino acid mismatches was implemented as a cloud-based web service.

Dataset Information

Impact of allele-specific anti-human leukocyte antigen class I antibodies on organ allocation.

Publications

Impact of allele-specific anti-human leukocyte antigen class I antibodies on organ allocation.

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