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PubMed1999

The HLA dictionary 1999: a summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR, and -DQ antigens.

This report presents serologic equivalents of 90 HLA-A, 190 HLA-B, and 145 HLA-DRB1 alleles. The equivalents cover over 70% of the presently identified HLA-A, -B, and -DRB1 alleles. The dictionary is an update of the one published in 1997 and now also includes equivalents for HLA-C, DRB3, DRB4, DRB5, and DQB1 alleles. The data summarize information obtained by the WHO HLA Nomenclature Committee, the International Cell Exchange (UCLA), the National Marrow Donor Program (NMDP), and by individual laboratories. In addition, a listing is provided of alleles that are expressed as antigens with serologic reaction patterns that differ from the well-established HLA specificities and that often lack official WHO nomenclature. The provided equivalents will be useful in guiding searches for unrelated donors in which patients and/or potential donors are typed by either serology or DNA-based methods. These equivalents will also serve typing and matching procedures for organ transplant programs where HLA typings from donors and from recipients on waiting lists represent mixtures of serologic and molecular typings. Some guidelines are provided for the use of appropriate WHO HLA nomenclature for serologic typings and for generic and allele specific typings obtained with molecular methods. The tables with HLA equivalents and the questionnaire for submission of serology on poorly identified alleles will also be available at the WMDA web page: www.bmdw.org/wmda.

Alleles↗

PubMed1997

Understanding donors' motivations: a study of unrelated bone marrow donors.

Medical advances in bone marrow transplantation techniques and immunosuppressive medications have dramatically increased the number of such transplants performed each year, and consequently, the demand for bone marrow from unrelated donors. Although physiological aspects of bone marrow donation have been thoroughly investigated, very few studies have examined psychosocial factors that may impact individuals' donation decisions and outcomes. To examine one particular set of donor psychosocial issues, this study investigated motives for bone marrow donation among 343 unrelated bone marrow donors who donated through the National Marrow Donor Program. Six distinct types of donor motives were identified from open-ended questionnaire responses. Donors most frequently reported motives reflecting some awareness of both the costs (to themselves) and potential benefits (to themselves and the recipient) of donation. A desire to act in accordance with social or religious precepts, expected positive feelings about donating, empathy for the recipient, and the simple desire to help another person were also commonly cited reasons for donating. Among a series of donor background characteristics, donors' gender was the variable most strongly associated with motive type; women were most likely to cite expected positive feelings, empathy, and the desire to help someone. Central study findings indicated that donor motives predicted donors reactions to donation even after the effects of donor background characteristics (including gender) were controlled. Donors who reported exchange motives (weighing costs and benefits) and donors who reported simple (or idealized) helping motives experienced the donation as less positive in terms of higher predonation ambivalence and negative postdonation psychological reactions than did remaining donors. Donors who reported positive feeling and empathy motives had the most positive donation reactions in terms of lower ambivalence, and feeling like better persons postdonation. These finding add substantially to the body of work concerning medical volunteerism generally, and also have important practical implications for the recruitment and education of potential bone marrow donors.

Adult↗

PubMed1994

Matched unrelated transplants.

The National Marrow Donor Program (NMDP) has a computerized registry of more than 900,000 volunteer bone marrow donors for patients in need of a transplant. The donors available through the NMDP offer an option for the 70% of patients who could benefit from a marrow transplant but who do not have a suitable related donor. The complex process of finding a compatible unrelated donor involves seven steps, and the median length of time to find a donor through the NMDP is approximately 6 months. Each month, approximately 50 marrow transplants are facilitated by the NMDP.

Bone Marrow Transplantation↗

PubMed1999

Four new DP alleles identified in a study of 500 unrelated bone marrow donor-recipient pairs.

HLA-DP genotyping of 500 donor recipient pairs in a retrospective analysis sponsored by the National Marrow Donor Program (NMDP) identified four new DP alleles, two DPB1 and two DPA1. DNA sequencing confirmed that DPB1*8001 and *8101, each found in a single individual, are novel combinations of previously described sequence motifs in the six variable regions of DPB1. DPA1*02014, found in two individuals, is identical to DPA1*02011 except for a novel silent substitution, a G to A transition at the third position of codon 14. DPA1*01032, found in one individual, is identical to DPB1*01031 except for a silent G to A transition at the third position of codon 20. The identification of these novel alleles brings the total number of reported DPB1 alleles to 85 and DPA1 alleles to 15.

Alleles↗

PubMed1999

The HLA dictionary 1999: a summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR and -DQ antigens.

This report presents serologic equivalents of 90 HLA-A, 190 HLA-B and 145 HLA-DRB1 alleles. The equivalents cover over 70% of the presently identified HLA-A, -B and -DRB1 alleles. The dictionary is an update of the one published in 1997 and now also includes equivalents for HLA-C, DRB3, DRB4, DRB5 and DQB1 alleles. The data summarize information obtained by the WHO HLA Nomenclature Committee, the International Cell Exchange (UCLA), the National Marrow Donor Program (NMDP) and by individual laboratories. In addition, a listing is provided of alleles which are expressed as antigens with serologic reaction patterns that differ from the well-established HLA specificities and that often lack official WHO nomenclature. The provided equivalents will be useful in guiding searches for unrelated donors in which patients and/or potential donors are typed by either serology or DNA-based methods. These equivalents will also serve typing and matching procedures for organ transplant programs where HLA typings from donors and from recipients on waiting lists represent mixtures of serologic and molecular typings. Some guidelines are provided for the use of appropriate WHO HLA nomenclature for serological typings and for generic and allele specific typings obtained with molecular methods. The tables with HLA equivalents and the questionnaire for submission of serology on poorly identified alleles will also be available at the WMDA web page: www:bmdw.org/wmda.

Alleles↗

PubMed2000

Large-scale DNA-based typing of HLA-A and HLA-B at low resolution is highly accurate specific and reliable.

DNA-based typing of HLA class I alleles of the HLA-A and HLA-B loci using sequence-specific oligonucleotide primers and/or probes has been used for the large-scale typing of individuals for the National Marrow Donor Program unrelated donor registry. Typing was performed by 16 laboratories at a low level of resolution (e.g. A*01, B*07). The results of blinded quality control analysis for the first 12 months of the project show the typing to be highly accurate, specific and reliable. The total error rate based on 11,545 HLA-A and 11,428 HLA-B assignments was 1.1% for HLA-A and 1.9% for HLA-B. This level of accuracy is particularly remarkable because the quality control samples could not be distinguished from 64,180 donor samples tested at the same time by the laboratories.

Bone Marrow Transplantation↗

PubMed2000

A novel HLA-B40 allele and novel exon 1 sequences of two B40 alleles identified in potential marrow donors.

Sequence-specific oligonucleotide probe hybridization and sequence-specific primer polymerase chain reaction (PCR) typing suggested the presence of variants of HLA-B*40 in three individuals. Two were part of 3,500 potential marrow donors being screened for the National Marrow Donor Program, while the third was a clinical specimen. PCR products encompassing HLA-B locus exons 1 through 3 were prepared and subcloned. In one individual, a native of the Pacific Islands, sequencing revealed a novel HLA-B*40 allele (B*4023). In two other individuals, a previously unknown exon 1 sequence was determined for HLA-B*4016 (ethnicity unknown) and B*4020 (Hispanic). These findings further illustrate the substantial genetic variation present at the HLA-B locus within human populations.

Alleles↗

PubMed2000

Novel HLA-B*15 alleles identified in potential marrow donors.

Several methods for low-resolution class I typing of potential bone marrow donors are available. The National Marrow Donor Program (NMDP) has initiated pilot projects for large-scale DNA-based class I typing to initially characterize donors. Sequence-specific oligonucleotide probe hybridization and sequence-specific primer polymerase chain reaction (PCR) screening of 3,500 NMDP potential donors suggested the presence of variants of known HLA-B*15 variants in 3 donors. PCR products encompassing HLA-B locus exons 1 through 3 were prepared and subcloned. Sequencing revealed 3 alleles differing from known HLA-B*15 alleles by nucleotide substitutions resulting in predicted novel HLA-B antigens. The new alleles occur in distinct ethnic groups. These findings further illustrate the substantial genetic variation present at the HLA-B locus within human populations.

Alleles↗

PubMed2001

Non-conservative substitutions distinguish previously uncharacterized HLA-A molecules.

The extent of class I HLA polymorphism is not yet realized, and to provide a glimpse of the HLA-A polymorphism which remains undetected, we have analyzed approximately 3,700 National Marrow Donor Program (NMDP) Donor/Recipient Pair Retrospective Study Samples with HLA-A DNA sequence-based typing (SBT). Seventeen new HLA-A alleles were detected, with a total of 19 nucleotide substitutions distinguishing these new alleles from their closest HLA-A relatives. Nearly all of the new alleles differ by single nucleotide substitutions; a majority of these substitutions can be explained by gene conversion events but 6 alleles likely originated by point mutation. Fifteen of the 19 nucleotide substitutions translate into amino acid differences in the molecule. Structurally, the inferred amino acid alterations were non-conservative in terms of chemical property, and most substitutions were positioned in 1 or more of the specificity pockets which determine peptide binding. Although these new alleles were identified in a primarily Caucasian sample population, 9 of the 17 new HLA-A alleles were found in samples of non-Caucasoid origin. A new allele detection rate of 1 in approximately 200 individuals in our data set would, therefore, be higher in a non-Caucasoid sample population. In summary, the single nucleotide substitutions that distinguish undetected HLA-A alleles translate into functionally distinct HLA-A molecules. Further studies of the role of HLA-A in transplantation, in disease association, and in evolution must therefore accommodate the discovery of new alleles differing by single nucleotides.

Alleles↗

PubMed2001

The HLA Dictionary 2001: a summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR and -DQ antigens.

This report presents the serologic equivalents of 123 HLA-A, 272 HLA-B and 155 HLA-DRB1 alleles. The equivalents cover over 64% of the presently identified HLA-A, -B and -DRB1 alleles. The dictionary is an update of the one published in 1999 and also includes equivalents for HLA-C, DRB3, DRB4, DRB5 and DQB1 alleles. The data summarize information obtained by the WHO Nomenclature Committee for Factors of the HLA System, the International Cell Exchange (UCLA), the National Marrow Donor Program (NMDP) and individual laboratories. In addition, a listing is provided of alleles which are expressed as antigens with serologic reaction patterns that differ from the well-established HLA specificities. The equivalents provided will be useful in guiding searches for unrelated hematopoietic stem cell donors in which patients and/or potential donors are typed by either serology or DNA-based methods. These equivalents will also serve typing and matching procedures for organ transplant programs where HLA typings from donors and from recipients on waiting lists represent mixtures of serologic and molecular typings. The tables with HLA equivalents and a questionnaire for submission of serologic reaction patterns for poorly identified allelic products will also be available on the WMDA web page: http://www.worldmarrow.org.

HLA Antigens↗

PubMed2001

Three new DP alleles identified in a study of 800 unrelated bone marrow donor-recipient pairs.

HLA-DP genotyping of 800 unrelated donor-recipient pairs in phase 5 of a retrospective analysis of unrelated bone marrow transplantation, sponsored by the National Marrow Donor Program (NMDP), has identified two new DPB1 alleles (DPB1*8701 and DBP1*8801) and one new DPA1 (DPA1*0108) allele. Sequencing confirmed that all three of these new alleles represent novel combinations of previously described sequence motifs, reinforcing the notion that "gene conversion-like" events play an important role in generating HLA allelic diversity. The identification of these new alleles brings the total number of DPA1 alleles to 20 and the total number of DPB1 alleles to 94.

Alleles↗

PubMed2002

HLA Class I typing of volunteers for a bone marrow registry: QC analysis by DNA-based methodology identifies serological typing discrepancies in the assignment of HLA-A and B antigens.

Until recently, the majority of newly recruited volunteer donors were typed for HLA-A and -B by serology onto the National Marrow Donor Program Registry. Quality control of this serological typing performed by contracted laboratories was carried out by retesting approximately 1% of each laboratory's test volume utilizing DNA-based techniques (SSOP). The criteria used for selection included samples presumed to be homozygotes, samples with split antigen specificities and samples with antigens considered to be difficult to define. Out of 1983 samples analyzed, 156 HLA-A (3.9%) and 265 HLA-B (6.7%) locus discrepancies were identified. Review of these discrepancies by both the serological and QC laboratory revealed that the majority of discrepancies were due to errors in serological typing. Serological discrepancies were categorized as follows: blank antigens identified (36.8%) and misassignments (63.2%). Misassignments were defined as either the incorrect assignment of antigens within a group ("wrong split"), or a complete misassignment. Antigens reported as blanks most frequently belonged to the A19 and A28 groups and to the B70, 46 and 40 groups. The most frequent misassignments within groups were the A19 and A10 groups, and the B40 and B15 groups. Other HLA-A misassignments included A2 vs A28 or A2 vs A69, while other HLA-B misassignments included B35 and B70. This QC analysis showed that serological typing of class I antigens for the purposes of NMDP registry typing is prone to a significant error rate. Careful evaluation and selection of contracted laboratories by the NMDP suggests methodological limitations rather than poor performance as the main cause of these observations.

Alleles↗

PubMed2003

Unrelated donor stem cell transplant: donor selection and search process.

The article describes the unrelated donor and cord blood search process through the National Marrow Donor Program (NMDP) for practising hematologist-oncologists and stem cell transplant physicians. The recent changes in the diseases, type of transplants and stem cell sources are discussed. Important data showing the effects of HLA loci and non-HLA factors on the transplant outcome, including new services offered by NMDP were reviewed.

Cord Blood Stem Cell Transplantation↗

PubMed1999

Factors associated with attrition from a national bone marrow registry.

During its 10-year existence, the National Marrow Donor Program (NMDP) has been extremely successful at recruiting potential bone marrow donors to join the volunteer registry. Due in part to successful recruitment and the longevity of the registry, the focus of the NMDP has now shifted to decreasing potential attrition when volunteers are recontacted for additional testing to determine whether they would be the optimal donor for a specific patient. Our own interest in the bone marrow donation process led us to examine four domains of variables - demographic characteristics, volunteer history, recruitment-related characteristics and donation-related concerns - that we hypothesized would be associated with increased likelihood of donor attrition at a key donor decision-point (DR-stage blood typing). Questionnaires were mailed to potential donors after they were contacted at the DR-stage, and had made the decision of whether or not to continue with blood typing. Our final sample included 756 volunteers who decided to continue with typing, and 258 individuals who declined further participation in the registry. In the bivariate analyses, factors in three of the four domains (all except demographic characteristics) were found to be substantially correlated with likelihood of attrition. Logistic regression indicated that nine central variables across the three domains produced the majority of increased attrition likelihood. Finally, a dose-response analysis suggested that as the number of attrition-related factors endorsed by an individual increased, his/her likelihood of dropping out of the registry also increased. Implications for future research and interventions to reduce potential donor attrition are discussed.

Adult↗

PubMed2001

Non-HLA barriers to unrelated donor stem cell transplantation.

A prospective survey involving 544 searches of the US National Marrow Donor Program (NMDP) Registry was conducted to identify reasons why many patients who have apparent HLA-matched donors do not proceed to transplant. Coordinators at NMDP transplant centers, patients and referring physicians were surveyed shortly after the initial search, and follow-up surveys were sent to the coordinators as the search was ongoing. The death of the patient, worsening of the patient's medical condition and length of the search process were the most commonly cited barriers to transplantation. Other times a decision was made not to transplant through the NMDP due to the use of a donor from another source, a preference for chemotherapy or immunotherapy, hesitancy on the part of the transplant physician or patient, or because the patient did not require a transplant. Responses differed between U.S. and international cases. An unrelated donor outside the NMDP was the most common reason cited by international coordinators (46%), whereas the death of the patient was the most common reason among US coordinators (13%). The death of the patient was the second most common reason cited by international coordinators at 9%. Financial problems were listed by 41% of US coordinators as a potential barrier at the time of initial search, but only 5% indicated this as an actual barrier on a follow-up survey. Finances were cited as the most important reason 3% of the time overall, and 6% for African Americans and Asian/Pacific Islanders.

Adolescent↗

PubMed2001

Donating stimulated peripheral blood stem cells vs bone marrow: do donors experience the procedures differently?

As the demand for undifferentiated stem cells for the treatment of leukemia and other cancers has increased, new methods for their collection have been developed. One of these new methods, allogeneic peripheral blood stem cell (PBSC) donation, involves the administration of a granulocyte colony-stimulating factor (G-CSF, filgrastim), and a 1-2 day apheresis collection procedure. Our goal in the current study was to examine donors' psychosocial and physical experiences of PBSC vs marrow donation. Potential participants included 80 donors from the National Marrow Donor Program (NMDP) who donated a second time between 1991 and 1997. All of these donors had previously donated marrow. A final cohort of 70 donors (25 PBSC and 45 marrow) participated in a retrospective questionnaire study of their donation experiences. In general, all second-time donors reported low levels of concern about the physical consequences of donation. However, PBSC donors were more likely to have postponed the decision to donate a second time. Despite their reservations, PBSC donors reported fewer donation-related side-effects than did marrow donors. Finally, PBSC donors reported that marrow donation was more physically difficult, time-consuming, and inconvenient, and that they preferred PBSC to marrow donation.

Adult↗

PubMed2003

Availability of unrelated donors for hematopoietic stem cell transplantation for hemoglobinopathies.

Hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with hemoglobinopathies. However, fewer than 30% of individuals will have an HLA-identical sibling. Improvement in outcomes after HSCT using unrelated donors (URD), and the development of novel nontoxic preparative regimens may make URD HSCT an option for hemoglobinopathy patients who do not have an HLA-identical sibling donor. The National Marrow Donor Program (NMDP) maintains a Registry of 4 million volunteer donors, and facilitates URD HSCT for patients with life-threatening blood diseases. In light of the increased representation of minorities in the NMDP registry, donor searches were run in April 2001 for a cohort of 272 thalassemia patients and 77 sickle cell disease (SCD) patients for whom searches had been submitted between 1989 and 2001 in order to determine the current likelihood of finding a potential donor of hematopoietic stem cells for hemoglobinopathy patients. About 59.7% SCD patients 80.2% thalassemia patients will find at least one potential 6/6 HLA matched donor or umbilical cord blood (UCB) unit. All patients will find at least one donor or UCB that is a potential 5/6 HLA match. In conclusion the majority of hemoglobinopathy patients will find at least one potential HLA matched unrelated bone marrow donor or UCB.

Anemia, Sickle Cell↗

PubMed2004

Hematopoietic stem cell donor registry strategies for assigning search determinants and matching relationships.

Registries and cord blood banks around the world collect and store the HLA types of volunteers in order to identify matched unrelated donors for patients requiring hematopoietic stem cell transplantation. This task is complicated by the many formats in which HLA types are provided by the testing laboratories (types obtained by serology vs by DNA-based methods; high vs intermediate vs low resolution) and by the need to identify which of these diverse types are most likely to match the HLA assignments of a searching patient as closely as possible. Conversion of the assignments to 'search determinants' may be included within the algorithm used to select and prioritize a list of potentially suitable donors, either as an aid to matching or as a tool to optimize the performance of comparisons within large data files. The strategies used by registries to create search determinants are described. A set of search determinants, utilized by the National Marrow Donor Program, is provided as an example and is intended to initiate further discussion aimed at understanding the process used by each registry with the possibility of developing a standard process among registries worldwide.

Algorithms↗