Search

Prolonging the lifespan of transplanted organs is critical to combat the shortage of this life‐saving resource. Chronic rejection, with irreversible demise of the allograft, is often caused by the development of donor‐specific HLA antibodies. Currently, enumerating molecular (amino acid) mismatches between recipient and donor is promoted to identify patients at higher risk of developing HLA antibodies, for use in organ allocation, and immunosuppression‐minimization strategies. We have counseled against the incorporation of such approaches into clinical use and hypothesized that not all molecular mismatches equally contribute to generation of donor‐specific immune responses. Herein, we document statistical shortcomings in previous study design: for example, use of individuals who lack the ability to generate donor‐specific‐antibodies (HLA identical) as part of the negative cohort. We provide experimental evidence, using CRISPR‐Cas9‐edited cells, to rebut the claim that the HLAMatchmaker eplets represent "functional epitopes." We further used unique sub‐cohorts of patients, those receiving an allograft with two HLA‐DQ mismatches yet developing antibodies only to one mismatch (2MM1DSA), to interrogate differential immunogenicity. Our results demonstrate that mismatches of DQα05‐heterodimers exhibit the highest immunogenicity. Additionally, we demonstrate that the DQα chain critically contributes to the overall qualities of DQ molecules. Lastly, our data proposes that an augmented risk to develop donor‐specific HLA‐DQ antibodies is dependent on qualitative (evolutionary and functional) divergence between recipient and donor, rather than the mere number of molecular mismatches. Overall, we propose an immunological mechanistic rationale to explain differential HLA‐DQ immunogenicity, with potential ramifications for other pathological processes such as autoimmunity and infections. [ABSTRACT FROM AUTHOR]

Summary: Young adults (YA) represent a minority among recipients of allogeneic haematopoietic stem cell transplantation (HSCT). In order to describe the outcome of YA following HSCT in Germany, 9299 patients who were registered with the German Registry for Stem Cell Transplantation were included in this retrospective analysis of the years 1998–2019. The impact of the variables, such as patient age and sex, sex differences, stem cell source, donor type, conditioning, year of HSCT, the diagnosis, and the achieved remission status were tested in univariable and multivariable analysis for overall, event‐free and relapse‐free survival as well as for the cumulative incidences of non‐relapse and therapy‐related mortality. Altogether, the outcome of YA after HSCT improved over time and was determined by the underlying disease, the age at disease onset, stem cell source, and donor type. Patients were most likely to die from relapse, and survival of HSCT recipients after 10 years was reduced by more than half in comparison to the general population of YA. Deeper understanding of modifiable risk factors may be gained by studies comparing the outcome of YA post‐HSCT with that of children, adolescents and elderly patients. A deliberate and strong patient selection may further improve mortality rates. [ABSTRACT FROM AUTHOR]

Summary: High genetic heterogeneity in the human leukocyte antigen (HLA) increases the likelihood of efficient immune response to pathogens and tumours. As measure of HLA diversity, HLA evolutionary divergence (HED) has been shown to predict the response of tumours to immunotherapy and haematopoietic stem cell transplantation (HSCT) in adults. We retrospectively investigated the association of HED with outcomes of 153 paediatric/young adults patients, treated for malignant disorders with HSCT from 9–10/10 HLA‐matched unrelated donors. HED was calculated as pairwise genetic distance between alleles in patient HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1 and ‐DPB1, using the locus median to stratify patients with 'high' or 'low' HED. Patients with high HED‐B and ‐DRB1 showed significantly improved disease‐free survival (DFS), especially when combined (70.8% vs 53.7% p = 0.008). High HED‐B + ‐DRB1 was also associated with improved overall survival (OS) (82.1 vs 66.4% p = 0.014), and concomitant reduction of non‐relapse‐mortality (5.1% vs 21.1% p = 0.006). The impact on OS and DFS of combined HED‐B + ‐DRB1 was confirmed in multivariate analysis [hazard ratio (HR) 0.39, p = 0.009; and HR 0.45, p = 0.007 respectively]. Only high HED scores for HLA‐DPB1 were associated, in univariate analysis, with reduced incidence of relapse (15.9% vs 31.1%, p = 0.03). These results support HED as prognostic marker in allogeneic HSCT and, if confirmed in larger cohorts, would allow its use to inform clinical risk and potentially influence clinical practice. [ABSTRACT FROM AUTHOR]

We present a catalog of common and well‐documented (CWD) alleles of the German population for the six HLA loci A, B, C, DRB1, DQB1, and DPB1. This study is based on a sample of over 5 million volunteer adult hematopoietic stem cell donors from the 26 German donor centers. To establish the catalog, allele and haplotype frequencies were estimated with a validated implementation of the expectation‐maximization algorithm. CWD criteria similar to existing CWD catalogs were applied in order to be able to put our findings into the context of relevant existing references. Overall, 2155 HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1, and ‐DPB1 alleles were identified as CWD in the German donor population representing about 20% of the HLA alleles at two‐field resolution in the IPD‐IMGT/HLA Database release v3.25.0 from July 2016 for these six loci. We found a substantial concordance of CWD alleles between the three catalogs and showed the contribution of the German donor population to the CWD alleles domain. In conclusion, the definition of CWD criteria that allow interoperability, scalability, and flexibility will be crucial for the development of a worldwide CWD catalog. [ABSTRACT FROM AUTHOR]

Recently, novel strategies to control graft-versus-host disease and facilitate engraftment have allowed an increasing number of human leukocyte antigen ( HLA)-haploidentical hematopoietic stem cell transplantation (haplo HSCT) to be performed. A meeting was convened to review the biological rationale and the clinical results of various T-cell-depleted ( TCD) and T-cell-replete ( TCR) HLA-haploidentical 'transplant platforms'. The objective of the meeting was to promote discussion and consent among leading researchers in the field on three main crucial issues for haplo HSCT: (i) eligibility criteria, (ii) choice of the most suitable donor, and (iii) choice of the most appropriate transplant platform. The experts in attendance agreed that a patient who is eligible for an allogeneic transplant and lacks an HLA-identical sibling or an HLA-matched unrelated donor should be considered for an alternative donor transplant. Together with the experience of the individual center, the most important decision criteria in choosing an alternative donor source should be the rapidity of transplantation so as to avoid disease relapse/progression. The choice of the mismatched donor should be driven by younger age, ABO blood group compatibility, and Cytomegalovirus status. If a TCD transplant is planned, NK-alloreactive donors and/or the mother should be preferred. Prospective comparative studies are needed to establish the relative efficacy of different transplant platforms. However, expertise in stem cell manipulation and in adoptive immunotherapy is essential if a TCD transplant platform is chosen. [ABSTRACT FROM AUTHOR]

Marktel S, Napolitano S, Zino E, Cappelli B, Chiesa R, Poli F, Crocchiolo R, Ronchi P, Rossini S, Ciceri F, Roncarolo MG, Fleischhauer K. Platelet transfusion refractoriness in highly immunized beta thalassemia children undergoing stem cell transplantation. Pediatr Transplantation 2010: 14:393–401. © 2010 John Wiley & Sons A/S. Immune-mediated refractoriness to platelet transfusion is a major problem in patients undergoing HSCT. In a cohort of 50 pediatric patients affected by beta thalassemia coming from Middle East countries, we experienced a high incidence of refractoriness because of anti-HLA antibodies during post-HSCT aplasia. In a risk factors analysis, factors predicting a negative transfusion outcome were presence of spleen and the number of anti-HLA antibodies. We adopted a policy to select platelet donors by avoiding HLA antigens against which the patient had specific antibodies. Transfusion of dedicated units resulted in 26% refractoriness compared to 74% to random units (p < 0.0001). When dedicated transfusions were used, the presence of spleen did not influence transfusion outcome. Analyzing transfusion outcome depending on the degree of HLA match and ABO compatibility, 76% successful transfusions were obtained with HLA-matched- ABO compatible followed by 67% in HLA-1mismatch- ABO compatible or HLA-matched- ABO incompatible and by 46% in HLA-1mismatch- ABO incompatible. In conclusion, we provide evidence that the selection of platelet donors according to patient characteristics, anti-HLA antibodies and ABO matching, is successful in reducing platelet refractoriness in heavily alloimmunized thalassemia patients undergoing transplantation. [ABSTRACT FROM AUTHOR]

Interleukin-10 (IL-10)-secreting T regulatory type 1 (Tr1) cells are defined by their specific cytokine production profile, which includes the secretion of high levels of IL-10 and transforming growth factor-β(TGF-β), and by their ability to suppress antigen-specific effector T-cell responses via a cytokine-dependent mechanism. In contrast to the naturally occurring CD4+CD25+ T regulatory cells (Tregs) that emerge directly from the thymus, Tr1 cells are induced by antigen stimulation via an IL-10-dependent process in vitro and in vivo. Specialized IL-10-producing dendritic cells, such as those in an immature state or those modulated by tolerogenic stimuli, play a key role in this process. We propose to use the term Tr1 cells for all IL-10-producing T-cell populations that are induced by IL-10 and have regulatory activity. The full biological characterization of Tr1 cells has been hampered by the difficulty in generating these cells in vitro and by the lack of specific marker molecules. However, it is clear that Tr1 cells play a key role in regulating adaptive immune responses both in mice and in humans. Further work to delineate the specific molecular signature of Tr1 cells, to determine their relationship with CD4+CD25+ Tregs, and to elucidate their respective role in maintaining peripheral tolerance is crucial to advance our knowledge on this Treg subset. Furthermore, results from clinical protocols using Tr1 cells to modulate immune responses in vivo in autoimmunity, transplantation, and chronic inflammatory diseases will undoubtedly prove the biological relevance of these cells in immunotolerance. [ABSTRACT FROM AUTHOR]

Summary Specific CD8- T-lymphocyte (CTL) activity against Plasmodium pre-erythrocytic stages (P-ES) derived antigens is considered one of the most important mechanisms for malaria protection. Plasmodium vivax is the second most prevalent human malaria parasite species distributed worldwide. Although several CTL epitopes have been identified in Plasmodium falciparum P-ES derived antigens, none has been described for P. vivax to date. In this study, we analysed HLA-A*0201 specific CD8- T-lymphocyte responses to the P. vivax circumsporozoite (CS) protein in both malaria exposed and non-exposed populations from the Colombian Pacific Coast. First, we analysed the prevalence of HLA-A2 allele in the study populations and found that approximately 38% of the individuals expressed this molecule and that 50% of them were HLA-A*0201. We then selected, on the P. vivax CS, five peptide sequences containing the HLA-A*0201 binding motifs and used the corresponding synthetic peptides to evaluate the CD8- T-lymphocyte interferon (IFN)-γ response. Peripheral blood mononuclear cells from the HLA-A*0201 donors were in vitro stimulated with these peptides and IFN-γ production was determined by an ELISPOT assay. Specific CD8- T-lymphocyte responses were detected for three peptides located in the C-terminal region of the protein. Specific responses to these peptides were also detected in several individuals expressing different HLA-A*02 subtypes. The potential of these peptides to induce specific cytolysis and that of long synthetic peptides comprising these epitopes as P. vivax malaria vaccine subunits are being studied. [ABSTRACT FROM AUTHOR]