De novo donor-specific human leucocyte antigen (HLA) antibodies (dnDSA) are associated with increased risk of rejection and mortality in solid organ transplantation. Such dnDSA is produced in some recipients upon allorecognition of mismatched HLA posttransplant. HLA matching is not currently considered in the allocation of deceased donor hearts and lungs and pre-transplant immunological risk stratification is based entirely on the mean fluorescence intensity (MFI) of circulating donor-directed HLA antibodies. HLA epitope-based matching tools predict B-cell or T-cell HLA epitopes that are present in the donor's HLA but absent in the recipient's HLA. We hypothesized that patients with higher epitope mismatch loads would be at increased risk of dnDSA development. We retrospectively analysed 73 heart and/or lung transplant recipients who were tested for DSA between 2015 and 2020. HLAMatchmaker, PIRCHE-II and HLA epitope mismatch algorithm (HLA-EMMA) were used to calculate eplet mismatch (EpMM) loads, T-cell epitope mismatch (TEpMM) loads and solvent accessible amino acid mismatch (SAMM) loads, respectively. Multivariate analyses showed that HLA-EMMA was the only tool with a significant association between the total score for all HLA loci and dnDSA production [odds ratio (OR) 1.021, 95% confidence interval (CI) 1.003-1.042, p = .0225] though this increased risk was marginal. The majority of dnDSA were directed against HLA-DQ and patients with higher HLA-DQ TEpMM loads (OR = 1.008, CI = 1.002-1.014, p = .007), and HLA-DR+DQ SAMM loads (OR = 1.035, CI = 1.010-1.064, p = .0077) were most at risk of producing dnDSA.We also showed that patients with a risk epitope within the HLA molecule encoded for by HLA-DQA1*05 + HLA-DQB1*02/03:01 were significantly more likely to produce dnDSA. The use of HLA epitope-based matching tools could be used for cardiothoracic transplant risk stratification to enable early intervention and monitoring of patients at increased risk of producing dnDSA.

Summary Acute graft versus host disease (aGvHD) is a major cause of early morbidity post‐haematopoietic stem cell transplantation with minor histocompatibility antigens being a contributing factor. One mHA encoded by the UDP glycosyltransferase 2 family polypeptide B17 (UGT2B17) gene has been shown to be immunogenic because of differential expression in the donor and recipient. We investigated the effects of a homozygous gene deletion of UGT2B17 on the severity of acute aGvHD post‐HSCT in HLA‐matched related donors. 115 donor and recipient HLA and UGT2B17 genotypes were determined using PCR‐SSO and PCR‐SSP, respectively. aGvHD grading was determined using routine criteria and dichotomized into either nonclinically significant (0–I) or clinically significant (II–IV). For all analyses, P‐values of ≤ 0.05 were considered significant. The frequency of the gene deletion within the total cohort tested was 29.1%. A significant increase in aGvHD severity (grades II‐IV) was seen in UGT2B17 recipients expressing the protein when transplanted with a UGT2B17 disparate donor (P = 0.011). We observed a significant association between UGT2B17 expressing recipients and UGT2B17 deficient donors with the severity of aGvHD. This study provides additional evidence that genomic variations may predispose to more severe aGvHD, but are not a mechanism for GvHD.

Introduction: Kidney dysfunction is a highly significant disease, both in the United Kingdom and globally. Many previous studies have reported associations between human leukocyte antigens (HLA) and renal function; this systematic review attempts to identify, summarize and appraise all published studies of these associations.Methods: A literature search was performed using Medline, Embase and Cochrane Central Register of Controlled Trials to identify papers whose keywords included each of the following concepts: HLA, renal failure and genetic association. A total of 245 papers were identified and assessed for eligibility; 35 of these were included in the final study.Results: A total of 95 HLA types and 14 three-locus haplotypes were reported to be associated with either increased or decreased renal function. A number of these findings were replicated by independent studies that reported 16 types were protective against renal dysfunction and 15 types were associated with reduced renal function.A total of 20 HLA types were associated with both increased risk of renal disease and decreased risk by independent studies. Discussion: There is very little consensus on which HLA types have a protective or deleterious effect on renal function. Ethnicity may play a role, with HLA types possibly having different effects among different populations, and it is possible that the different primary diseases that lead to ESRD may have different HLA associations. Some of the studies may contain type I and type II errors caused by insufficient sample sizes, cohort selection and statistical methods. Although we have compiled a comprehensive list of published associations between renal function and HLA, in many cases, it is unclear which associations are reliable. Further studies are required to confirm or refute these findings.