Mapping the Human Leukocyte Antigen Diversity among Croatian Regions: Implication in Transplantation.
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ABSTRACT:
SUBMITTER: Grubic Z
PROVIDER: S-EPMC8051524 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recent studies have suggested that plasma-derived proteins may be potential biomarkers relevant for graft-versus-host disease and/or non-relapse mortality occurring after allogeneic blood or marrow transplantation. However, none of these putative biomarkers have been assessed in patients treated either with human leukocyte antigen-haploidentical blood or marrow transplantation or with post-transplantation cyclophosphamide, which has been repeatedly associated with low rates of severe acute graft-versus-host disease, chronic graft-versus-host disease, and non-relapse mortality. We explored whether seven of these plasma-derived proteins, as measured by enzyme-linked immunosorbent assays, were predictive of clinical outcomes in post-transplantation cyclophosphamide-treated patients using plasma samples collected at serial predetermined timepoints from patients treated on prospective clinical studies of human leukocyte antigen-haploidentical (n=58; clinicaltrials.gov Identifier: 00796562) or human leukocyte antigen-matched-related or -unrelated (n=100; clinicaltrials.gov Identifiers: 00134017 and 00809276) T-cell-replete bone marrow transplantation. Day 30 levels of interleukin-2 receptor ?, tumor necrosis factor receptor 1, serum STimulation-2 (IL1RL1 gene product), and regenerating islet-derived 3-? all had high areas under the curve of 0.74-0.97 for predicting non-relapse mortality occurrence by 3 months post-transplant in both the human leukocyte antigen-matched and human leukocyte antigen-haploidentical cohorts. In both cohorts, all four of these proteins were also predictive of subsequent non-relapse mortality occurring by 6, 9, or 12 months post-transplant and were significantly associated with non-relapse mortality in univariable analyses. Furthermore, day 30 elevations of interleukin-2 receptor ? were associated with grade II-IV and III-IV acute graft-versus-host disease occurring after day 30 in both cohorts. These data confirm that plasma-derived proteins previously assessed in other transplantation platforms appear to retain prognostic and predictive utility in patients treated with post-transplantation cyclophosphamide.
| S-EPMC5477612 | biostudies-literature
Project description:Despite the increasingly well-documented evidence of high genetic, ethnic, and linguistic diversity amongst African populations, there is limited data on human leukocyte antigen (HLA) diversity in these populations. HLA is part of the host defense mechanism mediated through antigen presentation to effector cells of the immune system. With the high disease burden in southern Africa, HLA diversity data is increasingly important in the design of population-specific vaccines and the improvement of transplantation therapeutic interventions. This review highlights the paucity of HLA diversity data amongst southern African populations and defines a need for information of this kind. This information will support disease association studies, provide guidance in vaccine design, and improve transplantation outcomes.
| S-EPMC4549606 | biostudies-literature
Project description:The current state-of-the-art technology employed to assess anti-human leukocyte antigen antibodies (Anti-HLA Ab) for donor-recipient matching and patient risk stratification in renal transplantation is the single antigen bead (SAB) assay. However, there are limitations to the SAB assay as it is not quantitative and due to variations in techniques and reagents, there is no standardization across laboratories. In this study, a structurally-defined human monoclonal alloantibody was employed to provide a mechanistic explanation for how fundamental alloantibody biology influences the readout from the SAB assay. Performance of the clinical SAB assay was evaluated by altering Anti-HLA Ab concentration, subclass, and detection reagents. Tests were conducted in parallel by two internationally accredited laboratories using standardized protocols and reagents. We show that alloantibody concentration, subclass, laboratory-specific detection devices, subclass-specific detection reagents all contribute to a significant degree of variation in the readout. We report a significant prozone effect affecting HLA alleles that are bound strongly by the test alloantibody as opposed to those bound weakly and this phenomenon is independent of complement. These data highlight the importance for establishing international standards for SAB assay calibration and have significant implications for our understanding of discordance in previous studies that have analyzed its clinical relevance.
| S-EPMC7591533 | biostudies-literature
Project description:Introduction: The impact of preformed donor-specific anti-human leukocyte antigen (HLA) antibodies (pDSAs) after combined liver-kidney transplantation (CLKT) is still uncertain.Methods: We conducted a retrospective study in 8 European high-volume transplant centers and investigated the outcome of 166 consecutive CLKTs, including 46 patients with pDSAs.Results: Patient survival was lower in those with pDSAs (5-year patient survival rate of 63% and 78% with or without pDSA, respectively; P = 0.04). The presence of pDSAs with a mean fluorescence intensity (MFI) ? 5000 (hazard ratio 4.96; 95% confidence interval: 2.3-10.9; P < 0.001) and the presence of 3 or more pDSAs (hazard ratio 6.5; 95% confidence interval: 2.5-18.8; P = 0.05) were independently associated with death. The death-censored liver graft survival was similar in patients with or without pDSAs. Kidney graft survival was comparable in both groups. (The 1- and 5-year death-censored graft survival rates were 91.6% and 79.5%, respectively, in patients with pDSAs and 93% and 88%, respectively, in the donor-specific antibody [DSA]-negative group, P = not significant). Despite a higher rate of kidney graft rejection in patients with pDSAs (5-year kidney graft survival rate without rejection of 87% and 97% with or without pDSAs, respectively; P = 0.04), kidney function did not statistically differ between both groups at 5 years post-transplantation (estimated glomerular filtration rate 45 ± 17 vs. 57 ± 29 ml/min per 1.73 m2, respectively, in patients with and without pDSAs). Five recipients with pDSAs (11.0%) experienced an antibody-mediated kidney rejection that led to graft loss in 1 patient.Conclusion: Our results suggest that CLKT with pDSAs is associated with a lower patients' survival despite good recipients', liver and kidney grafts' outcome.
| S-EPMC7710847 | biostudies-literature
Project description:BackgroundBecause the development of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) after lung transplantation has been associated with acute and chronic rejection, we implemented a clinical protocol to screen all transplant recipients for DSA and preemptively treat those who developed DSA with rituximab and intravenous immune globulin (IVIG), or IVIG alone.MethodsWe conducted a prospective observational study of this protocol and used the LABScreen Single Antigen assay to detect DSA after transplantation. We compared the incidence of acute rejection, lymphocytic bronchiolitis, and bronchiolitis obliterans syndrome (BOS) between those who developed DSA and those who did not using Cox proportional hazards models. We used the Kaplan-Meier method to compare freedom from BOS and survival between those who had persistent DSA and those who had successful depletion of DSA.ResultsAmong 116 recipients screened, DSA developed in 65 during the study period. Those who developed DSA and received antibody-directed therapy had a similar incidence of acute rejection, lymphocytic bronchiolitis, and BOS as those who did not develop DSA. Furthermore, recipients who had successful depletion of DSA had greater freedom from BOS and better survival than those who had persistent DSA. Finally, those treated for DSA had a similar incidence of infectious complications as those who did not develop DSA.ConclusionsThe development of DSA is surprisingly common after lung transplantation. Antibody-directed therapy may reduce the risk of rejection associated with DSA, but a randomized controlled trial is necessary to critically evaluate the efficacy of this treatment protocol.
| S-EPMC2926224 | biostudies-literature
Project description:BackgroundNatural immunity against cytomegalovirus (CMV) can control virus replication after solid organ transplantation; however, it is not known which components of the adaptive immune system mediate this protection. We investigated whether this protection requires human leukocyte antigen (HLA) matching between donor and recipient by exploiting the fact that, unlike transplantation of other solid organs, liver transplantation does not require HLA matching, but some donor and recipient pairs may nevertheless be matched by chance.MethodsTo further investigate this immune control, we determined whether chance HLA matching between donor (D) and recipient (R) in liver transplants affected a range of viral replication parameters.ResultsIn total, 274 liver transplant recipients were stratified according to matches at the HLA A, HLA B, and HLA DR loci. The incidence of CMV viremia, kinetics of replication, and peak viral load were similar between the HLA matched and mismatched patients in the D+/R+ and D-/R+ transplant groups. D+/R- transplants with 1 or 2 mismatches at the HLA DR locus had a higher incidence of CMV viremia >3000 genomes/mL blood compared to patients matched at this locus (78% vs. 17%; P = 0.01). Evidence was seen that matching at the HLA A locus had a small effect on peak viral loads in D+/R- patients, with median peak loads of 3540 and 14,706 genomes/mL in the 0 and combined (1 and 2) mismatch groups, respectively (P = 0.03).ConclusionOverall, our data indicate that, in the setting of liver transplantation, prevention of CMV infection and control of CMV replication by adaptive immunity is minimally influenced by HLA matching of the donor and recipient. Our data raise questions about immune control of CMV in the liver and also about the cells in which the virus is amplified to give rise to CMV viremia.
| S-EPMC4345424 | biostudies-literature
Project description:The human leukocyte antigen class II genes DRB1, DQB1, and DQA1 are associated with Graves disease (GD), but, because of strong linkage disequilibrium within this region, the primary etiological variant(s) remains unknown. In the present study, 871 patients with GD and 621 control subjects were genotyped at the DRB1, DQB1, and DQA1 loci. All three loci were associated with GD (P=1.45 x 10(-12), P=3.20 x 10(-5), and P=9.26 x 10(-12), respectively). Stepwise logistic-regression analysis showed that the association could be explained by either DRB1 or DQA1 but not by DQB1. To extend previous results, the amino acid sequence of the exon 2-encoded peptide-binding domain of DRB1 was predicted for each subject, and, by use of logistic regression, each position was analyzed for association with GD. Of 102 amino acids, 70 were uninformative; of the remaining 32 amino acids, 13 were associated with GD (P values ranged from 2.20 x 10(-4) to 1.2 x 10(-12)). The strongest association was at position beta 74. This analysis is consistent with the possibility that position beta 74 of exon 2 of the DRB1 molecule may have a specific and central role in autoantigen presentation by DRB1 to T lymphocytes. However, we cannot yet exclude a primary role for DQA1 or for other polymorphisms that affect DRB1 function or expression.
| S-EPMC1196419 | biostudies-literature
Project description:We studied the effect of HLA-C matching in 515 patients after double umbilical cord blood (UCB) transplantation. After HLA matching HLA-A, -B, and -DRB1 at the allele level, we scored patients according to number of donor-recipient HLA-C matches at 4 possible loci: 2 from each donor unit, at the allele level. Given a direct interaction between HLA-A, -B, and -DRB1 matching and HLA-C score, we analyzed HLA-C matching in those receiving at least 1 2/6 to 4/6 HLA-matched unit (n = 389) versus those receiving only 5/6 or 6/6-matched units (n = 126). In those with at least 1 2/6 to 4/6 HLA-matched unit, a better HLA-C matching score was associated with significantly lower risk of death of any cause and nonrelapse mortality and better disease-free survival. There was no association with the risk of relapse, acute and chronic graft-versus-host disease, and hematopoietic recovery. In contrast, among patients receiving only allele-level 5/6 or 6/6 HLA-matched UCB units, HLA-C match had no demonstrable effect on any outcome. For patients receiving at least 1 allele-level 2/6 to 4/6 HLA-matched UCB unit, matching at HLA-C reduces nonrelapse mortality and improves survival.
| S-EPMC5510875 | biostudies-literature
Project description:Donor-recipient human leukocyte antigen (HLA) compatibility has not been considered to significantly affect liver transplantation (LT) outcomes; however, its significance in living-donor LT (LDLT), which is mostly performed between blood relatives, remains unclear. This retrospective cohort study included 1954 LDLTs at our institution (1990-2020). The primary and secondary endpoints were recipient survival and the incidence of T cell-mediated rejection (TCMR) after LDLT, respectively, according to the number of HLA mismatches at all five loci: HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ. Subgroup analyses were also performed in between-siblings that characteristically have widely distributed 0-10 HLA mismatches. A total of 1304 cases of primary LDLTs were finally enrolled, including 631 adults (recipient age at LT ≥18 years) and 673 children (<18 years). In adult-to-adult LDLT, the more HLA mismatches at each locus, the significantly worse the recipient survival was (p = 0.03, 0.01, 0.03, 0.001, and <0.001 for HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ, respectively). This trend was more pronounced when multiple loci were combined (all p < 0.001 for A + B + DR, A + B + C, DR + DQ, and A + B + C + DR + DQ). Notably, a total of three or more HLA-B + DR mismatches was an independent risk factor for both TCMR (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.21-5.87; p = 0.02) and recipient survival (HR 2.44, 95% CI 1.11-5.35; p = 0.03) in between-siblings. By contrast, HLA mismatch did not affect pediatric LDLT outcomes at any locus or in any combinations; however, it should be noted that all donor-recipient relationships are parent-to-child that characteristically possesses one or less HLA mismatch at each locus and maximally five or less mismatches in total. In conclusion, HLA mismatch significantly affects not only TCMR development but also recipient survival in adult LDLT, but not in children.
| S-EPMC9796617 | biostudies-literature
Project description:Humanized mouse models have contributed significantly to human immunology research. In transplant immunity, human immune cell responses to donor grafts have not been reproduced in a humanized animal model. To elicit human T-cell immune responses, we generated immune-compromised nonobese diabetic/Shi-scid, IL-2RγKO Jic (NOG) with a homozygous expression of human leukocyte antigen (HLA) class I heavy chain (NOG-HLA-A2Tg) mice. After the transplantation of HLA-A2 human hematopoietic stem cells into NOG-HLA-A2Tg, we succeeded in achieving alloimmune responses after the HLA-mismatched human-induced pluripotent stem cell (hiPSC)-derived liver-like tissue transplantation. This immune response was inhibited by administering tacrolimus. In this model, we reproduced allograft rejection after the human iPSC-derived liver-like tissue transplantation. Human tissue transplantation on the humanized mouse liver surface is a good model that can predict T-cell-mediated cellular rejection that may occur when organ transplantation is performed.
| S-EPMC7927063 | biostudies-literature