Anti-HLA Antibody: The Role of Epitopes in Organ Transplantation

Argani, Hassan

doi:10.6002/ect.mesot2018.l41

Cited by 13 publications

(5 citation statements)

References 6 publications

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“…The number of mismatched eplets is defined using HLAMatchmaker ™ 3.1, a computer-based matching program that compares the HLA amino acid sequences between the donor and recipient using high-resolution HLA typing. 19,20,21 Building on our prior studies, 1 we quantified molecular eplet DR/DQ mismatch to classify patients into low-and high-mismatch or low-and highrisk categories. These risk categories were then correlated with primary alloimmune events and clinical outcomes (i.e., dnDSA development and T-cell-mediated rejection (TCMR)).…”

Section: Introductionmentioning

confidence: 99%

“…An eplet consists of one or more amino acids that are in the accessible locations on the HLA molecular surface and is an essential component of the HLA epitope to which an individual antibody binds. The number of mismatched eplets is defined using HLAMatchmaker ™ 3.1, a computer‐based matching program that compares the HLA amino acid sequences between the donor and recipient using high‐resolution HLA typing 19,20,21 . Building on our prior studies, 1 we quantified molecular eplet DR/DQ mismatch to classify patients into low‐ and high‐mismatch or low‐ and high‐risk categories.…”

Section: Introductionmentioning

confidence: 99%

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Mismatch epitope load predicts de novo‐DSA‐free survival in pediatric liver transplantation

Shin

Lee

Dente

et al. 2022

Pediatric Transplantation

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Background: Our knowledge of de novo anti-HLA donor-specific antibodies (dnDSA) in liver transplantation continues to be defined. We hypothesized that differences of HLA-DR/DQ mismatches can improve precision in alloimmune risk categorization and be applied to tailor immunosuppression. Methods:A retrospective chart review of 244 pediatric patients consecutively transplanted at our center between 2003 and 2019 was performed to identify patients tested for dnDSA. Records were queried for: demographics, pre-transplant diagnosis, biopsy-proven T-cell-mediated rejection (TCMR), radiology proven biliary complications, tacrolimus trough levels, dnDSA characteristics, and HLA typing. The eplet mismatch analyses were performed using HLAMatchmaker ™ 3.1. All statistical analyses were conducted using R software version 3.40.Results: There were 99 dnDSA-negative patients and 73 dnDSA-positive patients (n = 70 against class II and n = 3 against class I and II). ROC analysis identified optimal cutoff of eplet mismatch load for dnDSA and defined risk groups for an alloimmune outcome. Kaplan-Meier curves and log-rank tests showed high eplet mismatch load was associated with shorter dnDSA-free survival (log-rank p = .001). Multivariable Cox regression models showed that tacrolimus coefficient of variation and tacrolimus mean levels were significantly associated with dnDSA-free survival (p < .001 and p = .036). Fisher's exact test showed that dnDSA was associated with an increased likelihood of TCMR (OR 14.94;; p < .001). Patients without TCMR were more likely to have dnDSA to HLA-DQ7 and less likely to have dnDSA to HLA-DQ2 (p = .03, p = .080). Conclusions:Mismatched epitope load predicts dnDSA-free survival in pediatric liver transplant, while dnDSA specificity may determine alloimmune outcome.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mismatch epitope load predicts de novo‐DSA‐free survival in pediatric liver transplantation

Shin

Lee

Dente

et al. 2022

Pediatric Transplantation

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“…The immunological reaction to the grafted organ is both lymphocyte and antibody-mediated. Nevertheless, the central player in transplant rejection is the T cell/lymphocyte [68]. There are 2 phases in transplant rejection (Figure 3): a sensitization phase and an effector phase [50].…”

Section: Mechanisms Of Rejection In Tissue Transplantationmentioning

confidence: 99%

Classic and Current Opinions in Human Organ and Tissue Transplantation

Oli¹,

Rowaiye²,

Adejumo³

et al. 2022

Cureus

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Graft tolerance is a pathophysiological condition heavily reliant on the dynamic interaction of the innate and adaptive immune systems. Genetic polymorphism determines immune responses to tissue/organ transplantation, and intricate humoral and cell-mediated mechanisms control these responses. In transplantation, the clinician's goal is to achieve a delicate equilibrium between the allogeneic immune response, undesired effects of the immunosuppressive drugs, and the existing morbidities that are potentially life-threatening. Transplant immunopathology involves sensitization, effector, and apoptosis phases which recruit and engages immunological cells like natural killer cells, lymphocytes, neutrophils, and monocytes. Similarly, these cells are involved in the transfer of normal or genetically engineered T cells. Advances in tissue transplantation would involve a profound knowledge of the molecular mechanisms that underpin the respective immunopathology involved and the design of precision medicines that are safe and effective.

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“…An eplet or functional HLA epitope—a concept introduced by Duquesnoy 19 —is defined as a cluster of polymorphic amino acid configurations within a 3.0–3.5 Å radius that is needed to induce an antibody response, and that these epitopes may be identical on different HLA molecules 20,21 . Literature showed that the number of HLA epitope mismatches has been associated with poor graft function in different types of solid organ transplantation 22,23 . However, the clinical relevance of DESAs recognizing epitopes shared between different HLA molecules, compared with DSA, has not been defined yet.…”

Section: Introductionmentioning

confidence: 99%

“…20,21 Literature showed that the number of HLA epitope mismatches has been associated with poor graft function in different types of solid organ transplantation. 22,23 However, the clinical relevance of DESAs recognizing epitopes shared between different HLA molecules, compared with DSA, has not been defined yet.…”

Section: Introductionmentioning

confidence: 99%

Determination of the clinical relevance of donor epitope‐specific HLA‐antibodies in kidney transplantation

Kardol‐Hoefnagel,

Senejohnny,

Kamburova

et al. 2024

HLA

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In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex‐defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope‐specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan–Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre‐transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p < 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA‐DR, and 1 of HLA‐DQ, and most antibodies were directed to HLA‐B (47%). Fifty‐three patients (69.7%) had DESA against one donor epitope (range 1–5). Long‐term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84–3.25) in deceased donation, and 2.22 (1.25–3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA‐based risk analysis on antigen level.

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Anti-HLA Antibody: The Role of Epitopes in Organ Transplantation

Cited by 13 publications

References 6 publications

Mismatch epitope load predicts de novo‐DSA‐free survival in pediatric liver transplantation

Mismatch epitope load predicts de novo‐DSA‐free survival in pediatric liver transplantation

Classic and Current Opinions in Human Organ and Tissue Transplantation

Determination of the clinical relevance of donor epitope‐specific HLA‐antibodies in kidney transplantation

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