HLA-DPB1 matching status has significant implications for recipients of unrelated donor stem cell transplants.

Studies in unrelated donor (UD) hematopoietic stem cell transplantations (HSCT) show an effect of the matching status of HLA-DPB1 on complications. We analyzed 423 UD-HSCT pairs. Most protocols included T-cell depletion (TCD). All pairs had high-resolution tissue typing performed for 6 HLA loci. Two hundred eighty-two pairs were matched at 10 of 10 alleles (29% were DPB1 matched). In 141 HILA-mismatched pairs, 28% were matched for DPB1. In the 10 of 10 matched pairs (n = 282), the 3-year probability of relapse was 61%. This was significantly higher in DPB1-matched pairs (74%) as compared with DPB1-mismatched pairs (56%) (log rank, P = .001). This finding persisted in multivariate analysis. In the group overall (n = 423), relapse was also significantly increased if DPB1 was matched (log rank; P < .001). These results were similar in chronic myeloid leukemia (CML; P < .001) and acute lymphoblastic leukemia (ALL; P = .013). In ALL, DPB1-matched pairs had a significantly worse overall survival (log rank; P = .025). Thus, in recipients of TCD UD-HSCT, a match for DPB1 is associated with a significantly increased risk of disease relapse, irrespective of the matching status for the other HILA molecules. It is possible that this effect is especially apparent following TCD transplantations and invites speculation about the function of DPB1 within the immune system

The novel HLA-C*03:04:01:47 allele sequence identified using Pacific biosciences SMRT sequencing

A novel variant of HLA-C*03:04:01:47 was identified using Pacific Biosciences SMRT sequencing platform

The HLA diversity of the Anthony Nolan register

While the success of allogeneic stem cell transplantation depends on a high degree of HLA compatibility between donor and patient, finding a suitable donor remains challenging due to the hyperpolymorphic nature of HLA genes. We calculated high‐resolution allele, haplotype and phenotype frequencies for HLA‐A, ‐C, ‐B, ‐DRB1 and ‐DQB1 for 10 subpopulations of the Anthony Nolan (AN) register using an in‐house expectation‐maximisation (EM) algorithm run on mixed resolution HLA data, covering 676 155 individuals. Sample sizes range from 599 410 for British/Irish North West European (BINWE) individuals, the largest subpopulation in the United Kingdom to 1105 for the British Bangladeshi population. Calculation of genetic distance between the subpopulations based on haplotype frequencies shows three broad clusters, each following a major continental group: European, African and Asian. We further analysed the HLA haplotype and phenotype diversity of each subpopulation, and found that 35.52% of BINWE individuals ranging to 98.34% of Middle Eastern individuals on the register had a unique phenotype within their subpopulation. These analyses and the allele, haplotype and phenotype frequency data of the subpopulation on the AN register are a valuable resource in understanding the HLA diversity in the United Kingdom and can be used to improve the accuracy of match likelihoods and to inform future donor recruitment strategies

Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles

HLA class I glycoproteins contain the functional sites that bind peptide antigens and engage lymphocyte receptors. Recently, clinical application of sequence-based HLA typing has uncovered an unprecedented number of novel HLA class I alleles. Here we define the nature and extent of the variation in 3,489 HLA-A, 4,356 HLA-B and 3,111 HLA-C alleles. This analysis required development of suites of methods, having general applicability, for comparing and analyzing large numbers of homologous sequences. At least three amino-acid substitutions are present at every position in the polymorphic α1 and α2 domains of HLA-A, -B and -C. A minority of positions have an incidence >1% for the 'second' most frequent nucleotide, comprising 70 positions in HLA-A, 85 in HLA-B and 54 in HLA-C. The majority of these positions have three or four alternative nucleotides. These positions were subject to positive selection and correspond to binding sites for peptides and receptors. Most alleles of HLA class I (>80%) are very rare, often identified in one person or family, and they differ by point mutation from older, more common alleles. These alleles with single nucleotide polymorphisms reflect the germ-line mutation rate. Their frequency predicts the human population harbors 8-9 million HLA class I variants. The common alleles of human populations comprise 42 core alleles, which represent all selected polymorphism, and recombinants that have assorted this polymorphism

Haplobanking induced pluripotent stem cells for clinical use

The development of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka and colleagues in 2006 has led to a potential new paradigm in cellular therapeutics, including the possibility of producing patient-specific, disease-specific and immune matched allogeneic cell therapies. One can envisage two routes to immunologically compatible iPSC therapies: using genetic modification to generate a ‘universal donor’ with reduced expression of Human Leukocyte Antigens (HLA) and other immunological targets or developing a haplobank containing iPSC lines specifically selected to provide HLA matched products to large portions of the population. HLA matched lines can be stored in a designated physical or virtual global bank termed a ‘haplobank’. The process of ‘iPSC haplobanking’ refers to the banking of iPSC cell lines, selected to be homozygous for different HLA haplotypes, from which therapeutic products can be derived and matched immunologically to patient populations. By matching iPSC and derived products to a patient’s HLA class I and II molecules, one would hope to significantly reduce the risk of immune rejection and the use of immunosuppressive medication. Immunosuppressive drugs are used in several conditions (including autoimmune disease and in transplantation procedures) to reduce rejection of infused cells, or transplanted tissue and organs, due to major and minor histocompatibility differences between donor and recipient. Such regimens can lead to immune compromise and pathological consequences such as opportunistic infections or malignancies due to decreased cancer immune surveillance. In this article, we will discuss what is practically involved if one is developing and executing an iPSC haplobanking strategy

The frequency of HLA-B*57:01 and the risk of Abacavir hypersensitivity reactions in the Costa Rica Central Valley Population

HLA-B*57:01 is a pharmacogenetic marker for abacavir hypersensitivity among HIV+ individuals. The utility and cost-effectiveness of the typing of this allele as a prospective marker has been confirmed to decrease or abolish abacavir hypersensitivity reactions in these patients. However, as for other HLA alleles, there is widespread variation in its frequency across populations. Thus, characterisation of the frequency of this marker in a given population is the first step towards the evaluation of the feasibility and need of pharmacogenetic screening for this drug. The Costa Rica Central Valley Population (CCVP) is the major population in this country. The frequency of HLA-B*57:01 in this population has not been described yet. Consequently, in an exploratory study, we set out to determine the frequency of this allele in a sample of unrelated healthy blood donors. We genotyped 153 samples from CCVP inhabitants. The samples were typed to intermediate resolution by SSO or SSP methods, and samples that were HLA-B*57-positve were further typed by sequence- based typing in order to define the alleles to four-digit resolution. An HLA-B*57:01 carrier frequency of 5.23% (allele frequency of 2.61%) was determined in this sample. This frequency is relatively high in comparison to reports from other populations in Latin America. These results suggest that there is a considerable frequency of HLA-B*57:01 in the CCVP and that pharmacogenetic testing for HIV+ patients who are going to receive abacavir-based treatment schemes is likely to benefit the security of this therapy. According to WHO data, we hypothesize that some 200,000 persons in this country would be susceptible to abacavir- induced hypersensitivity, and that some 15,000 HIV+ people living in Costa Rica could benefit from prospective HLA-B*57:01 genotyping

HFE gene polymorphism defined by sequence based typing of the Brazilian population and a standardized nomenclature for HFE allele sequences

The HFE molecule controls iron uptake from gut, and defects in the molecule have been associated with iron overload, particularly in hereditary hemochromatosis. The HFE gene including both coding and boundary intronic regions were sequenced in 304 Brazilian individuals, encompassing healthy individuals and patients exhibiting hereditary or acquired iron overload. Six sites of variation were detected: i) H63D C > G in exon 2, ii) IVS2 (+4) T > C in intron 2, iii) a C > G transversion in intron 3, iv) C282Y G > A in exon 4, v) IVS4 (-44) T > C in intron 4, and vi) a new Guanine deletion (G > del) in intron 5, which were used for haplotype inference. Nine HFE alleles were detected and six of these were officially named on the basis of the HLA Nomenclature, defined by the WHO Nomenclature Committee for Factors of the HLA System, and published via the IPD-IMGT/HLA website. Four alleles, HFE*001, 002, 003 and 004 exhibited variation within their exon sequences

High-throughput sequencing defines donor and recipient HLA B-cell epitope frequencies for prospective matching in transplantation

Compatibility for human leukocyte antigen (HLA) genes between transplant donors and recipients improves graft survival but prospective matching is rarely performed due to the vast heterogeneity of this gene complex. To reduce complexity, we have combined next-generation sequencing and in silico mapping to determine transplant population frequencies and matching probabilities of 150 antibody-binding eplets across all 11 classical HLA genes in 2000 ethnically heterogeneous renal patients and donors. We show that eplets are more common and uniformly distributed between donors and recipients than the respective HLA isoforms. Simulations of targeted eplet matching shows that a high degree of overall compatibility, and perfect identity at the clinically important HLA class II loci, can be obtained within a patient waiting list of approximately 250 subjects. Internal epitope-based allocation is thus feasible for most major renal transplant programs, while regional or national sharing may be required for other solid organs