Molecular Disparity of HY Antigen Affects Chronic Graft-Versus-Host Disease and Relapse in Female-to-Male Stem Cell Transplants.

Background: Minor histocompatibility antigens play an important role in eliciting an alloimmune response in allogeneic hematopoietic stem cell transplantation (allo-HSCT). HY antigens, minor histocompatibility antigens originating from distinct regions of the Y chromosome, serve as immunogenic targets in female-to-male (FtoM) allo-HSCT, potentially increasing the risk of graft-versus-host disease (GVHD) and the development of allogeneic HY antibodies. Moreover, extensive HLA polymorphism and diverse peptide-binding specificities of HLA molecules can lead to varying alloimmunity and subsequent clinical risks/benefits among patients upon exposure to the HY antigen.

Impact of HLA evolutionary divergence and donor-recipient molecular mismatches on antibody-mediated rejection of kidney allografts.

Several in-silico methods emerge to assess HLA immunogenicity and stratify immunological risk, including HLA molecular mismatches and HLA evolutionary divergence (HED). However, their added value in risk-stratifying antibody-mediated rejection (AMR) remains uncertain. We include 5159 kidney transplant recipients from four centers.

Swine Xenografts Share Few Predicted Indirectly Recognisable SLA-Derived Epitopes With HLA-Derived Epitopes From Human Kidney Grafts.

Swine-derived kidneys are a promising alternative organ source for transplantation, but compatibility in the major histocompatibility complex remains an immunological barrier. Furthermore, in repeat transplantations, CD4+ memory T cells can lead to a more rapid immune response against repeated exposure to the same antigens. Several studies have shown that HLA and SLA proteins share overlapping B cell epitopes due to structural or electrostatic similarities, but the role of overlapping T cell epitopes has not been fully explored.

donor-specific anti-HLA antibody risk stratification in kidney transplantation using a combination of B cell and T cell molecular mismatch assessment.

Introduction: The presence of donor-specific antibody (dnDSA) has detrimental effect on allograft outcomes in kidney transplantation. As humoral responses in transplantation are elicited targeting non-self-epitopes on donor HLA proteins, assessing HLA mismatches at the molecular level provides a refined means for immunological risk stratification.

Methods: In the present study, we utilized three HLA molecular mismatch assessment algorithms, Snow, HLAMatchmaker, and PIRCHE-II, to evaluate the independent and synergistic association of B cell and T cell epitope mismatches with dnDSA development in a cohort of 843 kidney transplant recipients.

Indirect presentation of mismatched human leukocyte antigen-B associates with outcomes of cord blood transplantation.

Cord blood transplantation (CBT) is a valuable donor source for patients without human leukocyte antigen (HLA)-matched donors. While CBT has a lower risk of graft-versus-host disease and requires less stringent histocompatibility, it is associated with a higher transplantation-related mortality (TRM) compared to other donor sources. We hypothesized that assessing the immunogenicity of mismatched HLA could reveal non-permissive mismatches contributing to increased TRM.

Advancing risk stratification in kidney transplantation: integrating HLA-derived T-cell epitope and B-cell epitope matching algorithms for enhanced predictive accuracy of HLA compatibility.

Introduction: The immune-mediated rejection of transplanted organs is a complex interplay between T cells and B cells, where the recognition of HLA-derived epitopes plays a crucial role. Several algorithms of molecular compatibility have been suggested, each focusing on a specific aspect of epitope immunogenicity.

Methods: Considering reported death-censored graft survival in the SRTR dataset, we evaluated four models of molecular compatibility: antibody-verified Eplets, Snow, PIRCHE-II and amino acid matching.

Predicted Indirectly Recognizable T-cell Epitope (PIRCHE) Load Correlates With Rejection Events After Simultaneous Pancreas-Kidney Transplantation.

Background: Given the lack of specificity of current blood and urine testing and the resistance/inability to perform pancreas allograft biopsies, additional noninvasive investigational tools to assess the risk for rejection are needed. This study examines the clinical impact of molecular HLA matching in a large single-center simultaneous pancreas-kidney (SPK) transplant program.

Methods: The study cohort comprised 238 SPK recipients between 2012 and 2021.

Molecular matching tools for allocation and immunosuppression optimization. Ready for primetime?

Purpose Of Review: Molecular matching continues to be an important topic in organ transplantation. Over the years, several studies - larger and smaller - supported correlations of molecular incompatibility loads and clinical outcomes. However, their practical utility for clinical decision making remains controversial and there is no consensus on the context in which they should be used.

Donor-derived cell-free DNA monitoring for early diagnosis of antibody-mediated rejection after kidney transplantation: a randomized trial.

Background: Donor-derived cell-free DNA (dd-cfDNA) shows good diagnostic performance for the detection of antibody-mediated rejection (AMR) in kidney transplant recipients (KTR). However, the clinical benefits of dd-cfDNA monitoring need to be established. Early diagnosis of AMR at potentially reversible stages may be increasingly important due to emerging treatment options for AMR.

Which is more important for predicting de novo DSA production in donor-sensitized kidney transplant recipients, B-cell epitope or T-cell epitope analysis?

De novo donor-specific antibodies (dnDSA), particularly those against human leukocyte antigen (HLA) class II, can cause kidney allograft rejection, resulting in poor prognosis. Recently, HLA matching at both B-cell and T-cell epitopes, assessed by eplet mismatches and predicted indirectly recognizable HLA epitopes (PIRCHE) score, respectively, has been reported to be associated with dnDSA production. It remains unclear how these epitopes are involved in transplant immunology and how the results of the analysis can be applied in clinical practice.

Combined Molecular Mismatch Approaches to Predict Immunological Events Within the First Year After Renal Transplantation.

Several molecular mismatch assessment approaches exist, but data on their combined use are limited. In this study, we aimed to define distinct risk groups for rejection based on the combination of three molecular mismatch assessment approaches (i.e.

PIRCHE-II Risk and Acceptable Mismatch Profile Analysis in Solid Organ Transplantation.

To optimize outcomes in solid organ transplantation, the HLA genes are regularly compared and matched between the donor and recipient. However, in many cases a transplant cannot be fully matched, due to widespread variation across populations and the hyperpolymorphism of HLA alleles. Mismatches of the HLA molecules in transplanted tissue can be recognized by immune cells of the recipient, leading to immune response and possibly organ rejection.

Positive Long-Term Outcome of Kidney Allocation via Acceptable Mismatch Program in Highly Sensitized Patients.

Introduction: Eurotransplant established the acceptable mismatch (AM) program to facilitate timely kidney transplantations of highly sensitized patients, but long-term granular clinical and immunological outcomes regarding overall graft survival and de novo DSA (dnDSA) formation are still intensively researched. The right choice of induction therapy in patients with differing immunological risk is not conclusively determined, as well as the impact of human leukocyte antigen (HLA) epitope matching on dnDSA formation.

Methods: This monocentric, retrospective study analyzed 94 patients transplanted within the AM program between 2000 and 2019 compared to case-control matched cohorts of non- (PRA 0-5%; PRA-0) and intermediately sensitized (PRA 6-84%; PRA-6/84) patients transplanted through Eurotransplant Kidney Allocation System.

High-resolution HLA genotyping improves PIRCHE-II assessment of molecular mismatching in kidney transplantation.

HLA matching in solid organ transplant is performed with the aim of assessing immunologic compatibility in order to avoid hyperacute rejection and assess the risk of future rejection events. Molecular mismatch algorithms are intended to improve granularity in histocompatibility assessment and risk stratification. PIRCHE-II uses HLA genotyping to predict indirectly presented mismatched donor HLA peptides, though most clinical validation studies rely on imputing high resolution (HR) genotypes from low resolution (LR) typing data.

PIRCHE application major versions 3 and 4 lead to equivalent T cell epitope mismatch scores in solid organ and stem cell transplantation modules.

PIRCHE scores in organ and stem cell transplantation have been shown to correlate with increased risk of donor-specific HLA antibodies and graft-versus-host disease, respectively. With advancements of the PIRCHE application server, it is critical to compare the predicted scores with previous versions. This manuscript compares the newly introduced PIRCHE version 4.

NephroCAGE-German-Canadian Consortium on AI for Improved Kidney Transplantation Outcome: Protocol for an Algorithm Development and Validation Study.

Background: Recent advances in hardware and software enabled the use of artificial intelligence (AI) algorithms for analysis of complex data in a wide range of daily-life use cases. We aim to explore the benefits of applying AI to a specific use case in transplant nephrology: risk prediction for severe posttransplant events. For the first time, we combine multinational real-world transplant data, which require specific legal and technical protection measures.

Repeated local ellipsoid protrusion supplements HLA surface characterization.

Allorecognition of donor HLA is a major risk factor for long-term kidney graft survival. Although several molecular matching algorithms have been proposed that compare physiochemical and structural features of the donors' and recipients' HLA proteins in order to predict their compatibility, the exact underlying mechanisms are still not fully understood. We hypothesized that the ElliPro approach of single ellipsoid fitting and protrusion ranking lacks sensitivity for the characteristic shape of HLA molecules and developed a prediction pipeline named Snowball that is fitting smaller ellipsoids iteratively to substructures.

Using cloud infrastructure to facilitate data collection and conversion of HLA diagnostic data for the 18th International HLA and Immunogenetics Workshop.

The International HLA and Immunogenetics Workshop (IHIW) is a recurring gathering of researchers, technologists and clinicians where participants contribute to collaborative projects with a variety of goals, and come to consensus on definitions and standards for representing HLA and immunogenic determinants. The collaborative and international nature of these workshops, combined with the multifaceted goals of several specific workshop components, necessitates the collection and curation of a wide assortment of data, as well as an adaptable platform for export and analysis. With the aim of ensuring data quality and creation of reusable datasets, specific standards and nomenclature conventions are continuously being developed, and are an integral part of IHIW.

Dissecting the impact of molecular T-cell HLA mismatches in kidney transplant failure: A retrospective cohort study.

Introduction: Kidney transplantation is the optimal treatment in end-stage kidney disease, but donor specific antibody development continues to negatively impact patients undergoing kidney transplantation. One of the recent advances in solid organ transplantation has been the definition of molecular mismatching between donors and recipients' Human Leukocyte Antigens (HLA). While not fully integrated in standard clinical care, cumulative molecular mismatch at the level of eplets (EMM) as well as the PIRCHE-II score have shown promise in predicting transplant outcomes.

Snowflake epitope matching correlates with child-specific antibodies during pregnancy and donor-specific antibodies after kidney transplantation.

Development of donor-specific human leukocyte antigen (HLA) antibodies (DSA) remains a major risk factor for graft loss following organ transplantation, where DSA are directed towards patches on the three-dimensional structure of the respective organ donor's HLA proteins. Matching donors and recipients based on HLA epitopes appears beneficial for the avoidance of DSA. Defining surface epitopes however remains challenging and the concepts underlying their characterization are not fully understood.

Snowflake: A deep learning-based human leukocyte antigen matching algorithm considering allele-specific surface accessibility.

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.

Formation of donor-specific antibodies depends on the epitope load of mismatched HLAs in lung transplant recipients: A retrospective single-center study.

The development of donor-specific antibodies (DSA) has a significant impact on graft outcome in solid organ transplantation. Mismatched HLAs are recognized directly and indirectly by the recipient immune system. Both pathways occur in parallel and result in the generation of plasma cells, DSA, cytotoxic and T helper lymphocytes.

Immunologic risk stratification of pediatric heart transplant patients by combining HLAMatchmaker and PIRCHE-II.

Background: Molecular-level human leukocyte antigen (HLA) mismatch is a powerful biomarker of rejection; however, few studies have explored its use in heart transplant recipients, and none have attempted to use the results of separate algorithms synergistically. Here we tested the hypothesis that a combination of HLAMatchmaker and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) can be used to identify more patients at low risk of rejection.

Methods: We studied 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC) performing class I and II HLA genotyping by next-generation sequencing to determine eplet mismatch (epMM) load and PIRCHE-II score.