Epitope-Level Matching—A Review of the Novel Concept of Eplets in Transplant Histocompatibility

The development of de novo donor-specific antibodies is related to the poor matching of the human leukocyte antigen (HLA) between donor and recipient, which leads to dismal clinical outcomes and graft loss. However, new approaches that stratify the risks of long-term graft failure in solid organ transplantation have emerged, changing the paradigm of HLA compatibility. In addition, advances in software development have given rise to a new structurally based algorithm known as HLA Matchmaker, which determines compatibility at the epitope rather than the antigen level. Although this technique still has limitations, plenty of research maintains that this assessment represents a more complete and detailed definition of HLA compatibility. This review summarizes recent aspects of eplet mismatches, highlighting the most recent advances and future research directions.

Maternal-Fetal HLA Compatibility in Uncomplicated and Preeclamptic Naturally Conceived Pregnancies

IntroductionIn pregnancy, the mother and fetus differ in HLA antigens, and yet the maternal immune system generally tolerates the fetus. KIR receptors expressed by maternal uterine NK cells at the maternal-fetal interface directly interact with HLA-C on extravillous trophoblast cells for optimal placental development. In this study, we aimed to determine whether there is a preferential selection for HLA compatibility and specific KIR/HLA-C combinations in uncomplicated and preeclamptic naturally conceived pregnancies compared to what would be expected by chance.MethodsGenotyping for maternal and fetal HLA-A, -B, -C, -DR, and -DQ, and maternal KIR was performed for 451 uncomplicated pregnancies and 77 pregnancies complicated with preeclampsia. The number of HLA antigen (mis)matches between mother and fetus was calculated and compared to expected values obtained by randomization of the HLA haplotype, inherited from the father, over the existing maternal haplotype of the fetuses. A similar methodology was executed for analysis of the KIR/HLA-C data (n=309).ResultsIn uncomplicated pregnancies, the degree of maternal-fetal HLA matching was not different than expected-by-chance values. In preeclamptic pregnancies, the degree of maternal-fetal HLA matching was different in observed compared to expected-by-chance values (p=0.012). More specifically, the degree of maternal-fetal matching of HLA-C was higher in the actual preeclamptic pregnancies than was expected-by-chance (p=0.007). Preeclamptic pregnancies showed an overall tendency towards higher maternal-fetal HLA compatibility, for total HLA matches (p=0.021), HLA class I (p=0.038) and HLA-C (p=0.025) compared to uncomplicated pregnancies.ConclusionThe data suggest that there is no preferential selection of maternal-fetal HLA compatibility in uncomplicated pregnancies. In contrast, increased total HLA, HLA class I and, especially, HLA-C compatibility is associated with preeclampsia, suggestive for a role of HLA mismatches in immune regulation leading to uncomplicated pregnancy.

ASSESSMENT OF HLA-COMPATIBILITY AND REQUIREMENTS FOR HLA-TYPING OF PATIENT AND DONOR IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

Introduction. Unification of guidelines and standards concerning requirements for HLA typing and assessment of the degree of HLA match between the recipient and the donor for different types of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is of a great importance.Aim. To present contemporary requirements for the HLA typing of a recipient and a donor for allo-HSCT, to generalize recom mendations for assessing a required match degree of a recipient and a donor and to provide data on additional immunogenetic factors capable of improving the results of allogeneic hematopoietic stem cell transplantation.General findings. Allo-HSCT appears to be an effective, and, in some cases, non-alternative treatment for many diseases of the blood system. The number of allo-HSCT types is constantly growing globally. Currently, an allogeneic hematopoietic stem cell donor can be selected for almost every recipient having indication for this type of therapy. Such a transplantation can be performed from an HLA-identical sibling, an HLA-match unrelated donor, a partially HLA-match unrelated donor, a relative haploidentical donor or cord blood. HLA match between the recipient and the donor present itself as an important factor affecting the results of allo-HSCT. The choice of a donor should involve a correct assessment the HLA match degree between the recipient and the donor, as well as consideration of additional factors that may affect the results of allo-HSCT.

Biomarkers for posttransplantation outcomes

During the last decade, the development of biomarkers for the complications seen after allogeneic hematopoietic stem cell transplantation has expanded tremendously, with the most progress having been made for acute graft-versus-host disease (aGVHD), a common and often fatal complication. Although many factors are known to determine transplant outcome (including the age of the recipient, comorbidity, conditioning intensity, donor source, donor-recipient HLA compatibility, conditioning regimen, posttransplant GVHD prophylaxis), they are incomplete guides for predicting outcomes. Thanks to the advances in genomics, transcriptomics, proteomics, and cytomics technologies, blood biomarkers have been identified and validated for us in promising diagnostic tests, prognostic tests stratifying for future occurrence of aGVHD, and predictive tests for responsiveness to GVHD therapy and nonrelapse mortality. These biomarkers may facilitate timely and selective therapeutic intervention. However, such blood tests are not yet available for routine clinical care. This article provides an overview of the candidate biomarkers for clinical evaluation and outlines a path from biomarker discovery to first clinical correlation, to validation in independent cohorts, to a biomarker-based clinical trial, and finally to general clinical application. This article focuses on biomarkers discovered with a large-scale proteomics platform and validated with the same reproducible assay in at least 2 independent cohorts with sufficient sample size according to the 2014 National Institutes of Health consensus on biomarker criteria, as well as on biomarkers as tests for risk stratification of outcomes, but not on their pathophysiologic contributions, which have been reviewed recently.

The mechanism of humoral immune response to allogeneic organ transplantation

The problem of antibody-mediated rejection of donor organ remains extremely relevant. The main targets of the antibodies are mainly donor HLA-antigens (Human Leucocyte Antigens), expressed, in particular, by the cells of graft vascular endothelium. This review describes the mechanisms of the development of humoral alloimmunity which are based on B-cell recognition of epitopes of donor HLA-molecules and affinity maturation of B-cell receptors in the germinal centers of peripheral lymphatic system. Monitoring of epitope load and cross-reactivity indicators to evaluate HLA-compatibility of donor and recipient plays an important role in the prevention of allograft humoral rejection.