Establishment of Human Leukocyte Antigen-Mismatched Immune Responses after Transplantation of Human Liver Bud in Humanized Mouse Models.
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ABSTRACT:
SUBMITTER: Mori A
PROVIDER: S-EPMC7927063 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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: Not available
| S-EPMC5053847 | 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: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: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:In transplantation, direct allorecognition is a complex interplay between T-cell receptors (TCR) and HLA molecules and their bound peptides expressed on antigen-presenting cells. In analogy to HLA mismatched hematopoietic stem cell transplantation (HSCT), the TCR CDR3β repertoires of alloreactive cytotoxic CD8+ responder T cells, defined by the cell surface expression of CD137 and triggered in vitro by HLA mismatched stimulating cells, were analyzed in different HLA class I mismatched combinations. The same HLA mismatched stimulatory cells induced very different repertoires in distinct but HLA identical responders. Likewise, stimulator cells derived from HLA identical donors activated CD8+ cells expressing very different repertoires in the same mismatched responder. To mimic in vivo inflammation, expression of HLA class l antigens was upregulated in vitro on stimulating cells by the inflammatory cytokines TNFα and IFNβ. The repertoires differed whether the same responder cells were stimulated with cells treated or not with both cytokines. In conclusion, the selection and expansion of alloreactive cytotoxic T-cell clonotypes expressing a very diverse repertoire is observed repeatedly despite controlling for HLA disparities and is significantly influenced by the inflammatory status. This makes prediction of alloreactive T-cell repertoires a major challenge in HLA mismatched HSCT.
| S-EPMC7856301 | biostudies-literature
Project description:Primary sclerosing cholangitis (PSC) is well characterized in European populations. We aimed to characterize clinical characteristics and human leukocyte antigen (HLA) associations in a population of European American, Hispanic, and African American PSC patients listed for liver transplantation (LT). Population-stratified demographic, clinical, and HLA data from 6767 LT registrants of the United Network for Organ Sharing who had a diagnosis of PSC (4.7% of the registrants) were compared to data from registrants with other diagnoses. Compared to European Americans and Hispanics, African Americans were significantly younger (46.6 ± 13.7, 42.3 ± 15.9, and 39.7 ± 13.1 years, respectively; P = 0.002) and were listed with a higher Model for End-Stage Liver Disease score (15.2 ± 7.5, 14.9 ± 7.6, and 18.1 ± 9.3, respectively; P = 0.001); they were also less frequently noted to have inflammatory bowel disease in comparison with European Americans (71.4% versus 60.5%, P < 0.01). In multivariate analysis, African origin was a significant factor associated with listing for LT with PSC (odds ratio with respect to European Americans = 1.325, 95% confidence interval = 1.221-1.438). HLA associations in European Americans, Hispanics, and African Americans with PSC versus alcoholic liver disease were detected for HLA-B8, HLA-DR13, and protective HLA-DR4. However, HLA-DR3, which is in linkage disequilibrium with HLA-B8, showed associations only in European Americans and Hispanics. In conclusion, African Americans with PSC who are listed for LT differ clinically from European Americans and Hispanics. The association with HLA-B8 but not HLA-DR3 in African Americans should make possible the refinement of the HLA associations in PSC.
| S-EPMC2967453 | biostudies-literature
Project description:In organ transplantation, human leukocyte antigen (HLA)-mismatch grafts not only induce the activation of cellular mediated immune response but also the development of chronic antibody-mediated rejection due to the donor-specific anti-HLA antibody (DSA) produced by B cells and plasma cells interacting with the graft endothelium. Significant improvement in long-term survival after transplantation can be expected if antibody-mediated rejection due to the DSA can be overcome. However, the mechanism of producing or controlling the DSA remains to be elucidated. In recent decades, "humanized" mouse models have been widely used for the basic research of human immune systems, but a humanized mouse model to analyze the mechanism of DSA production has not been established yet. Thus, we aimed to create a humanized mouse using a severe immunodeficiency mouse (NSG mouse) administered with human peripheral blood mononuclear cells (PBMCs). Initially, we detected a very low level of human total-IgG and no anti-HLA antibodies (Abs) in these mice. In our next attempt, we mixed PBMCs of various HLA antigenic combinations with or without regulatory T cells and preconditioned them by culturing on feeder cells stably transfected with human CD40 ligand (h-CD40L) alone or with h-CD40L and human B cell activating factor (h-BAFF). They were subsequently co-cultured with the corresponding irradiated stimulator PBMCs, and all cells were administered into naïve NSG mice. Although all three humanized models had sufficient human total-IgG and anti-HLA antibody production, allospecific anti-HLA Ab production was prominently suppressed whereas non-specific anti-HLA Abs were sufficiently detected. Therefore, this novel humanized mouse model might be useful for analyzing the mechanism of anti-allogeneic human B cell tolerance induction.
| S-EPMC7864411 | biostudies-literature
Project description:In the present study, HLA allele and haplotype frequencies were studied using the HLA data of 9277 Croatian unrelated individuals, typed using high-resolution methods for the HLA-A, -B, -C, and -DRB1 loci. The total numbers of observed alleles were 47 for HLA-A, 88 for HLA-B, 34 for HLA-C, and 53 for HLA-DRB1. HLA-A∗02:01 (29.5%), B∗51:01 (10.5%), C∗04:01 (15.8%), and DRB1∗16:01 (10.4%) were the most frequent alleles in the Croatian general population. The three most frequent haplotypes were HLA-A∗01:01~C∗07:01~B∗08:01~DRB1∗03:01 (4.7%), HLA-A∗03:01~C∗07:02~B∗07:02~DRB1∗15:01 (1.7%), and HLA-A∗02:01~C∗07:01~B∗18:01~DRB1∗11:04 (1.5%). Allele and haplotype frequencies were compared between national and regional data, and differences were observed, particularly in the North Croatia region. The data has potential use in refining donor recruitment strategies for national registries of volunteer hematopoietic stem cell donors, solid organ allocation schemes, and the design of future disease and anthropological studies.
| S-EPMC8051524 | 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