In celebration of Ruggero Ceppellini: HLA in transplantation.

The availability of hematopoietic cell transplantation as curative therapy for blood disorders has been dramatically improved through a better understanding of the human leukocyte antigen (HLA) barrier. Although a fully compatible unrelated donor is preferable, transplantation from donors with a limited degree of HLA mismatching is associated with acceptable outcomes in many cases. Research on the limits of HLA mismatching, and the features that define permissible HLA mismatches will continue to enable transplantation to be more broadly available to patients in need.

16th IHIW: international histocompatibility working group in hematopoietic cell transplantation.

The International Histocompatibility Working Group is a collaborative international effort to understand the HLA and non-HLA genetics of the transplantation barrier. The Working Group is comprised of experts in the fields of histocompatibility and immunogenetics, hematopoietic cell transplantation and outcomes research. Data for 25 855 unrelated donor transplants were submitted in support of research studies for the 16th International Histocompatibility Workshop. Active investigation is in progress in seven key areas: the impact of HLA matching, role of race and ethnicity, identification of permissible HLA mismatches, haplotype-associated determinants, minor histocompatibility antigens, immune response genes and KIR genetics. New hypotheses for the 16th workshop were developed for immunogenetic studies in cord blood and haploidentical-related donor transplantation.

Identification of the MICA*070 allele by sequencing and phasing.

A novel MICA allele, MICA*070, was defined by sequencing. The new allele differs from the MICA*008:04 sequence in exon 2, encoding a C instead of G corresponding to cDNA nucleotide position 183. This nucleotide substitution is predicted to encode serine instead of arginine at residue 38 of the α1 domain of the MICA molecule.

Comparison of matched unrelated and matched related donor myeloablative hematopoietic cell transplantation for adults with acute myeloid leukemia in first remission.

Hematopoietic cell transplantation (HCT) from a matched related donor (MRD) benefits many adults with acute myeloid leukemia (AML) in first complete remission (CR1). The majority of patients does not have such a donor and will require an alternative donor if HCT is to be undertaken. We retrospectively analyzed 226 adult AML CR1 patients undergoing myeloablative unrelated donor (URD) (10/10 match, n=62; 9/10, n=29) or MRD (n=135) HCT from 1996 to 2007. The 5-year estimates of overall survival, relapse and nonrelapse mortality (NRM) were 57.9, 29.7 and 16.0%, respectively. Failure for each of these outcomes was slightly higher for 10/10 URD than MRD HCT, although statistical significance was not reached for any end point. The adjusted hazard ratios (HRs) were 1.43 (0.89-2.30, P=0.14) for overall mortality, 1.17 (0.66-2.08, P=0.60) for relapse and 1.79 (0.86-3.74, P=0.12) for NRM, respectively, and the adjusted odds ratio for grades 2-4 acute graft-versus-host disease was 1.50 (0.70-3.24, P=0.30). Overall mortality among 9/10 and 10/10 URD recipients was similar (adjusted HR 1.16 (0.52-2.61), P=0.71). These data indicate that URD HCT can provide long-term survival for CR1 AML; outcomes for 10/10 URD HCT, and possibly 9/10 URD HCT, suggest that this modality should be considered in the absence of a suitable MRD.

The World Marrow Donor Association: 20 years of international collaboration for the support of unrelated donor and cord blood hematopoietic cell transplantation.

The transplantation of hematopoietic stem cells from unrelated volunteer donors and cord blood units is made possible through an international collaboration of registries and cord blood banks. The World Marrow Donor Association (WMDA) is a non-profit association based in Leiden, the Netherlands, whose mission is to assure that high-quality stem cell products are available for all patients in need, while maintaining the health and safety of the volunteer donors. This goal is accomplished through the work of six working groups and six board committees, in which issues of global significance to the clinical hematopoietic cell transplantation community are identified and guidelines are established. In this special issue of Bone Marrow Transplantation, the activities of the WMDA and a vision for future directions in the field are presented.

An update to HLA nomenclature, 2010.

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.

Genetic variation in CXCL12 and risk of cervical carcinoma: a population-based case-control study.

CXCL12 provides a chemotactic signal-directing leucocyte migration and regulates metastatic behaviour of tumour cells. We conducted a population-based case-control study to test the hypothesis that common genetic variation in CXCL12 individual single nucleotide polymorphism (SNP) alleles and haplotypes] is associated with the risk of cervical carcinoma. Cases (n = 917) were residents of western Washington State diagnosed with invasive squamous cell cervical carcinoma (SCC), invasive adenocarcinoma or adenosquamous carcinoma, or adenocarcinoma in situ of the cervix. Control participants (n = 849) were identified from the source population by random digit telephone dialling and frequency matched to cases on county and age. Nine CXCL12 tagSNPs chosen from the SeattleSNPs database were genotyped. The minor allele of intronic SNP rs266085 was inversely associated with cervical cancer under a recessive genetic effects model (OR = 0.74, 95% CI: 0.56-0.98). Among the ten common haplotypes inferred from the nine tagSNPs, one haplotype defined by minor alleles at 5'-flanking SNP rs17885289 and rs266085, and common alleles at the other seven SNPs occurred among 7.8% of cases and 10.6% of controls (dominant model OR = 0.72, 95% CI: 0.56-0.93; recessive model OR = 0.35, 95% CI: 0.12-0.97; and log-additive model OR = 0.72, 95% CI: 0.57-0.90). A stepwise procedure identified rs17885289, rs266085 and 3'-untranslated region (UTR) SNP rs266093 as the most parsimonious subset of SNPs necessary to define the haplotype inversely associated with cervical cancer risk in our study. A 3'-UTR SNP, rs1801157, previously found to be related to HIV pathogenesis, was not associated with cervical cancer risk. Further population-based studies are warranted to confirm these associations between genetic variation in CXCL12 and cervical cancer risk.

14thInternational HLA and Immunogenetics Workshop: report on hematopoietic cell transplantation.

Deciphering the role of human leukocyte antigen (HLA), killer immunoglobulin like receptor, and immune response genes in a model as complex as unrelated donor hematopoietic cell transplantation is a challenge. The allelic diversity of these genes is shaped by the race and ethnicity of transplant donors and recipients. Coupled with the genetic polymorphism is the complexity of clinical phenotypes of transplant populations: donor and recipient demographic characteristics and the regimens used by transplant physicians to prepare patients for transplantation and to prevent and treat graft-vs-host disease (GVHD). Furthermore, GVHD is itself a complex disease shaped by both genes and 'environment'. How does one begin to deconstruct the genetic barrier to understand risk factors important to transplant outcome? To begin with, population-based studies, particularly retrospective ones, benefit from adequate sample sizes to measure genetic effects. The more homogeneous the population for variables that influence clinical endpoints, the higher the likelihood that a real genetic effect can be uncovered. Even so, the feasibility of studies can be hampered if genotype and clinical data are not both complete and precise. For studies of HLA, diversity of alleles and antigens contributed by ethnically different transplant populations is an asset, because not only can a broader range of HLA mismatches be studied but they provide the opportunity for side-by-side analyses that may yield clues as to why transplant outcomes differ between populations.

Clinical significance of donor-recipient HLA matching on survival after myeloablative hematopoietic cell transplantation from unrelated donors.

The application of unrelated donor hematopoietic cell transplantation can be expanded with the use of mismatched donors if human leukocyte antigen (HLA) disparity does not lead to increased morbidity and mortality. The rules that govern permissibility of HLA mismatches are not well defined. The International Histocompatibility Working Group in hematopoietic cell transplantation measured the risks associated with locus-specific disparity in 4796 patients transplanted for low, intermediate, or high-risk hematologic diseases. The permissibility of a given HLA mismatch is in part defined by the locus and by disease risk.

Effect of HLA-A2 allele disparity on clinical outcome in hematopoietic cell transplantation from unrelated donors.

Population-based differences in clinical outcome after unrelated donor hematopoietic cell transplantation suggest that the significance of human leukocyte antigen (HLA) mismatching may be related to locus-specific and allele-specific differences that distinguish ethnically diverse transplant donors and recipients. We studied the risks associated with HLA-A locus mismatching in two large transplant populations from the International Histocompatibility Working Group in hematopoietic cell transplantation data set to better understand permissible and nonpermissible HLA-A mismatches.

Clinical importance of HLA-DPB1 in haematopoietic cell transplantation.

There is increasing evidence for a significant effect of human leukocyte antigen (HLA)-DPB1 mismatching on complications following unrelated donor haematopoietic cell transplantation (HCT). In this analysis of 5930 patient/donor pairs, we found that a DPB1 mismatch predicted significantly for an increased risk of acute graft-vs-host disease [hazard ratio (HR): 1.33; P-value = <0.0001], while protecting against disease relapse (HR: 0.82, P-value = 0.01). These data support an immunogenic role for HLA-DPB1 in HCT and the need for pretransplant tissue typing at this locus.

Hematopoietic stem cell transplantation: killer immunoglobulin-like receptor component.

Recognition of recipient human leukocyte antigen (HLA) class I ligand by donor natural killer cell killer immunoglobulin-like receptors (KIR) has been proposed as the basis for donor allograft reactivity against malignancy leading to reduction in posttransplant relapse and higher survival for acute myelogenous leukemia. Analysis of KIR ligand effects in 1770 patients undergoing myeloablative T-replete hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors showed that lack of KIR ligand in patients for inhibitory KIR was associated with lower hazards of relapse in leukemia patients with in HLA-mismatched transplants [hazard ratio (HR): 0.061; 95% confidence interval (CI): 0.43-0.85; P-value = 0.004]. Absence of HLA-C group 2 or HLA-Bw4 KIR ligands were each associated with lower hazards of relapse (HR: 0.47; 95% CI: 0.28-0.79; P-value = 0.004; HR: 0.56; 95% CI: 0.33-0.97; P-value = 0.04, respectively). Based on these analyses, recipient homozygosity for HLA-B or -C epitopes that define KIR ligands is likely to be a predictive factor for leukemia relapse following myeloablative HCT from unrelated donors. KIR genotyping for unrelated donors and recipients will clarify the role of these receptors in transplant outcome.

MHC class I, II, and III microsatellite marker matching and survival in unrelated donor hematopoietic cell transplantation.

Microsatellites (Msats) are effective markers for disease association mapping. The International Histocompatibility Working Group in hematopoietic cell transplantation applied Msats to determine whether potential new transplantation determinants are encoded within the major histocompatibility complex. Retrospective analysis of human leukocyte antigen-identical unrelated donor transplants provided a homogeneous population to measure Msat-associated risks of mortality.

Immune response gene polymorphisms in unrelated donor hematopoietic cell transplantation.

Immune response genes (IRG) play an important role in inflammation and control of infection after allogeneic transplantation. The International Histocompatibility Working Group (IHWG) in hematopoietic cell transplantation took a candidate gene approach to define the risks associated with genetic variation for a panel of well-characterized IRG.

MHC microsatellite diversity and linkage disequilibrium among common HLA-A, HLA-B, DRB1 haplotypes: implications for unrelated donor hematopoietic transplantation and disease association studies.

Twenty-two human major histocompatibility complex (MHC) region microsatellite (Msat) markers were studied for diversity and linkage disequilibrium (LD) with HLA loci in hematopoietic cell transplant recipients and their HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 allele-matched unrelated donors. These Msats showed highly significant LD over much of the MHC region. The Msat diversity of five common Caucasian haplotypes (HLA-A1-B8-DR3, A3-B7-DR15, A2-B44-DR4, A29-B44-DR7, and A2-B7-DR15) was examined using a new measure called 'haplotype specific heterozygosity' (HSH). Each of the five haplotypes had at least one Msat marker with an HSH value of zero indicating that only one Msat allele was observed for the particular HLA haplotype. In addition, the ability of Msats to predict HLA-A-B-DRB1 haplotypes was studied. Over 90% prediction probability of two common haplotypes (HLA-A1-B8-DR3 and HLA-A3-B7-DR15) was achieved with information from three Msats (D6S265/D6S2787/D6S2894 and D6S510/D6S2810/D6S2876, respectively). We demonstrate how the HSH index can be used in the selection of informative Msats for transplantation and disease association studies. Markers with low HSH values can be used to predict specific HLA haplotypes or multilocus genotypes to supplement the screening of HLA-matched donors for transplantation. Markers with high HSH values will be most informative in studies investigating MHC region disease-susceptibility genes where HLA haplotypic effects are known to exist.

BCR-ABL transcripts are early predictors for hematological relapse in chronic myeloid leukemia after hematopoietic cell transplantation with reduced intensity conditioning.

Kinetics of BCR-ABL transcript elimination and its prognostic implications on relapse were analyzed in patients with chronic myeloid leukemia (CML) after reduced intensity hematopoietic cell transplantation (HCT). In all, 19 CML patients were conditioned with 2 Gy total-body irradiation in combination with (n=14) or without (n=3) fludarabine 3 x 30 mg/m(2) (Flu) or 4.5 Gy total lymphoid irradiation (TLI) with Flu and OKT3 3 x 5 mg (n=2) and were treated with cyclosporine (CSP) and mycophenolate mofetil after allogeneic HCT. BCR-ABL transcripts were analyzed by nested RT-PCR and Taqman((R)) RT-PCR on days +28, +56 and +84 after HCT and were evaluated for their association with relapse. Of the 19 patients, 14 achieved sustained remissions of which six had a negative RT-PCR 28 days after HCT. Five patients relapsed +41, +54, +57, +136 and +234 days after HCT. Predictors for relapse were advanced disease stage (P=0.02) and slow reduction of BCR-ABL transcripts at day 28 (P=0.006) and day 56 (P=0.047) post-transplant. We conclude that a complete clearance of BCR-ABL transcripts is achievable within 4 weeks from HCT even after minimal conditioning and that early kinetics of BCR-ABL transcripts significantly correlate with the probability of hematological relapse.

Tissue typing in support of unrelated hematopoietic cell transplantation.

The success of unrelated hematopoietic cell transplantation (HCT) for the treatment of hematologic malignancies has closely paralleled development of robust typing methods for comprehensive and precise donor-recipient matching. The application of molecular methods in clinical research has led to a more complete understanding of the immunogenetic barriers involving host-vs-graft (HVG) and graft-vs-host (GVH) reactions. Along with the development of less toxic transplant regimens, advances in the prevention and treatment of graft-vs-host disease (GVHD) and in the supportive care of the transplant recipient, improved HLA matching of potential unrelated donors has led to clinical results that begin to compare favorably with that of HLA-identical sibling transplants.