Showing papers by "Anthony Nolan published in 2010"

Nomenclature for factors of the HLA system, 2010.

Abstract: The WHO Nomenclature Committee for Factors of the HLA System met following the 14th International HLA and Immunogenetics Workshop in Melbourne, Australia in December 2005 and Buzios, Brazil during the 15th International HLA and Immunogenetics Workshop in September 2008. This report documents the additions and revisions to the nomenclature of HLA specificities following the principles established in previous reports (1–18).

Different Patterns of Evolution in the Centromeric and Telomeric Regions of Group A and B Haplotypes of the Human Killer Cell Ig-Like Receptor Locus

Abstract: The fast evolving human KIR gene family encodes variable lymphocyte receptors specific for polymorphic HLA class I determinants. Nucleotide sequences for 24 representative human KIR haplotypes were determined. With three previously defined haplotypes, this gave a set of 12 group A and 15 group B haplotypes for assessment of KIR variation. The seven gene-content haplotypes are all combinations of four centromeric and two telomeric motifs. 2DL5, 2DS5 and 2DS3 can be present in centromeric and telomeric locations. With one exception, haplotypes having identical gene content differed in their combinations of KIR alleles. Sequence diversity varied between haplotype groups and between centromeric and telomeric halves of the KIR locus. The most variable A haplotype genes are in the telomeric half, whereas the most variable genes characterizing B haplotypes are in the centromeric half. Of the highly polymorphic genes, only the 3DL3 framework gene exhibits a similar diversity when carried by A and B haplotypes. Phylogenetic analysis and divergence time estimates, point to the centromeric gene-content motifs that distinguish A and B haplotypes having emerged ~6 million years ago, contemporaneously with the separation of human and chimpanzee ancestors. In contrast, the telomeric motifs that distinguish A and B haplotypes emerged more recently, ~1.7 million years ago, before the emergence of Homo sapiens. Thus the centromeric and telomeric motifs that typify A and B haplotypes have likely been present throughout human evolution. The results suggest the common ancestor of A and B haplotypes combined a B-like centromeric region with an A-like telomeric region.

The impact of HLA genotyping on survival following unrelated donor haematopoietic stem cell transplantation.

Abstract: One of the major factors that have contributed to improving the outcomes of Stem Cell Transplantation is progress made in the field of human leucocyte antigen(s) (HLA). This is evident not only in developing techniques for rapid and accurate tissue typing, but also in the greatly improved understanding of the HLA system and the impact of HLA matching on transplant complications. It is now accepted that high-resolution HLA matching for transplant recipients and unrelated donors is associated with the best clinical outcomes. The most important HLA determinants are the six 'classical' polymorphic HLA loci: HLA-A, -B, -C, -DRB1,-DQB1, -DPB1. For several years, based on the outcome of numerous studies, a 10/10 matched donor (HLA-A, -B, -C, -DRB1, -DQB1) was considered the ideal. The impact of HLA-DPB1 has been less clear, in view of reduced likelihood of patient/donor matching for this locus. More recently, several large studies have questioned the importance of HLA-DQB1 matching on outcome. Based on the findings of recent studies, the current gold standard unrelated donor is believed to be one matched for 8/8 alleles at high resolution i.e. matched for HLA-A, -B, -C, -DRB1, however, in certain circumstances, mismatches may be tolerated and/or permissive.

Quality rather than quantity: the cord blood bank dilemma.

Abstract: Growing inventories of cord blood units have facilitated access to umbilical cord cell transplantation for many patients lacking conventional stem cell donors. They are in principle 'off-the-shelf', 'fit-for-use', as well as safe and effective therapy products. Cellular enumeration is used as a surrogate of graft potency, and users rely on the rigorous assessment carried out in banks to avoid poor engraftment after thawing (loss of cells or poor function), when the patient's situation is critical. However, in practice, when units are selected, initially on the basis of HLA matching and cell dose assessment, their absolute quality remains uncertain. Unfortunately, quality-related issues (particularly related to viability) are not uncommon in cord blood transplantation. The reasons for potency failures are diverse, but a lack of thorough validation during critical steps of the process and of appropriate use of quality-control tools for timely detection of problematic units are significant contributors. Moreover, incongruence between different sets of standards and regulations, and lack of common quality systems between banks result in a highly heterogeneous international inventory. Therefore, this complicates the matter for the end user of the product. To ameliorate this situation, it is essential to improve quality at each of the critical manufacturing steps wherein potency can be threatened, thereby creating homogeneous inventories of units with excellent quality and quantity.

Diverging effects of HLA–DPB1 matching status on outcome following unrelated donor transplantation depending on disease stage and the degree of matching for other HLA alleles

Abstract: Disease stage and recipient/donor human leukocyte antigen (HLA) matching are important determinants of outcome in transplantation using volunteer-unrelated donors (VUD). Matching for HLA-A, -B, -C, -DRB1, -DQB1 is beneficial, whereas the importance of DPB1 matching is more controversial. The impact of HLA matching status may differ dependent on disease stage. We investigated the outcome according to the degree of HLA matching at 6 loci, in 488 recipients of predominantly T-cell depleted bone marrow VUD transplants for leukaemia. Survival was significantly better in 12/12-matched transplants in those with early leukaemia (5 years: 63 versus 41% in 10/10 matched, P=0.006), but not late stage disease. Conversely, within the HLA-mismatched group (< or =9/10), there was a significant survival advantage to DPB1 mismatching (5 years: 39 versus 21% in DPB1 matched, P=0.008), particularly in late leukaemia (P=0.01), persisting in multivariate analysis (odds ratio 0.478; 95% confidence interval 0.30, 0.75; P=0.001). These novel findings suggest that the best outcome for patients with early leukaemia, with a 10/10-matched donor, is achieved by matching for DPB1. Conversely, our results suggest that in patients receiving an HLA-mismatched graft, the outcome is significantly better if they are also mismatched for DPB1. We recommend validation of these results in independent datasets.

Diverging effects of HLA-DPB1 matching status on outcome following unrelated donor transplantation depending on disease stage and the degree of matching for other HLA alleles

Abstract: Disease stage and recipient/donor human leukocyte antigen (HLA) matching are important determinants of outcome in transplantation using volunteer-unrelated donors (VUD) Matching for HLA-A, -B, -C, -DRB1, -DQB1 is beneficial, whereas the importance of DPB1 matching is more controversial The impact of HLA matching status may differ dependent on disease stage We investigated the outcome according to the degree of HLA matching at 6 loci, in 488 recipients of predominantly T-cell depleted bone marrow VUD transplants for leukaemia Survival was significantly better in 12/12-matched transplants in those with early leukaemia (5 years: 63 versus 41% in 10/10 matched, P=0006), but not late stage disease Conversely, within the HLA-mismatched group (< or =9/10), there was a significant survival advantage to DPB1 mismatching (5 years: 39 versus 21% in DPB1 matched, P=0008), particularly in late leukaemia (P=001), persisting in multivariate analysis (odds ratio 0478; 95% confidence interval 030, 075; P=0001) These novel findings suggest that the best outcome for patients with early leukaemia, with a 10/10-matched donor, is achieved by matching for DPB1 Conversely, our results suggest that in patients receiving an HLA-mismatched graft, the outcome is significantly better if they are also mismatched for DPB1 We recommend validation of these results in independent datasets

Family donor care management: principles and recommendations.

Abstract: The World Marrow Donor Association (WMDA) is an international organization fostering collaboration in clinical transplantation and promoting the interests of unrelated stem cell donors. The WMDA has developed standards for the recruitment, counseling, work-up and subsequent donations to protect the interests of donors. Although the care of family donors has been carefully considered and managed in transplant centers (TCs) internationally over numerous years (and increasingly TCs are facing accreditation programs, which address this issue) there is currently a lack of standardized guidelines for the management of family donors. The underlying principles of family donor care are in many ways identical to those concerning unrelated donors, although key ethical considerations differ. Although the WMDA is primarily involved in the field of unrelated donors, we believe that it is important to collaborate with those involved with family donors, to standardize the care. This document hopes to encourage increased collaboration between those caring for related and unrelated donors, and build on the extensive work, which has already been undertaken in this field to homogenize care. We recognize that there will be financial, regulatory and logistic differences in different countries and that the manner in which these principles are achieved may vary.

An update to HLA nomenclature, 2010.

Abstract: The WHO Nomenclature Committee for Factors of the HLA System met during the 15th International Histocompatibility and Immunogenetics Workshop in Buzios, Brazil in September 2008. This update is an extract of the main report that documents the additions and revisions to the nomenclature of human leukocyte antigen (HLA) specificities following the principles established in previous reports.

Cytomegalovirus-specific CD8+ T cells targeting different HLA/peptide combinations correlate with protection but at different threshold frequencies.

Abstract: Summary Cytomegalovirus (CMV) causes significant morbidity and mortality in patients after haematopoietic stem cell transplantation (HSCT). Due to limitations of current antiviral therapies, alternative approaches, involving transfer of donor-derived CMV-specific CD8 + T cells, have been considered. Levels of such cells correlating with protection against CMV infection and disease have only been reported in patients expressing HLA-A*0201 and HLA-B*0702. This is despite an increasing number of reports describing cells targeting CMV peptides presented by other human leucocyte antigens (HLAs). Considering several frequent HLA alleles, our findings suggest that HLA-A*2402/pp65 (341-349)- and HLA-B*3501/pp65 (123-131)-specific CD8 + T cells correlate with protection from CMV reactivation at significantly lower cell levels than HLA-A*0101/pp50 (245-253)- and HLAA*0201/pp65 (495-503)-specific CD8 + T cells, both in HSCT recipients posttransplant and in healthy CMV seropositive volunteers. This may result from a differing efficiency of the responses restricted by the two sets of HLA alleles. These findings add to the knowledge of immunodominance and differences in antigen processing that are coordinated in individuals with different HLA alleles and have direct implications for therapy and monitoring in patients.

Association of functional polymorphisms of the transforming growth factor B1 gene with survival and graft-versus-host disease after unrelated donor hematopoietic stem cell transplantation.

Abstract: Background Many genetic factors play major roles in the outcome of hematopoietic stem cell transplants from unrelated donors. Transforming growth factor β1 is a member of a highly pleiotrophic family of growth factors involved in the regulation of numerous immunomodulatory processes. Design and Methods We investigated the impact of single nucleotide polymorphisms at codons 10 and 25 of TGFB1 , the gene encoding for transforming growth factor β1, on outcomes in 427 mye-loablative-conditioned transplanted patients. In addition, transforming growth factor β1 plasma levels were measured in 263 patients and 327 donors. Results Patients homozygous for the single nucleotide polymorphism at codon 10 had increased non-relapse mortality (at 3 years: 46.8% versus 29.4%, P =0.014) and reduced overall survival (at 5 years 29.3% versus 42.2%, P =0.013); the differences remained statistically significant in multivariate analysis. Donor genotype alone had no impact, although multiple single nucleotide polymorphisms within the pair were significantly associated with higher non-relapse mortality (at 3 years: 44% versus 29%, P =0.021) and decreased overall survival (at 5 years: 33.8% versus 41.9%, P =0.033). In the 10/10 HLA matched transplants (n=280), recipients of non-wild type grafts tended to have a higher incidence of acute graft- versus -host disease grades II-IV ( P =0.052). In multivariate analysis, when analyzed with patients’ genotype, the incidences of both overall and grades II-IV acute graft- versus -host disease were increased ( P =0.025 and P =0.009, respectively) in non-wild-type pairs. Conclusions We conclude that increasing numbers of single nucleotide polymorphisms in codon 10 of TGFB1 in patients and donors are associated with a worse outcome following hematopoietic stem cell transplantation from unrelated donors.