Common, intermediate and well-documented HLA alleles in world populations: CIWD version 3.0.0.

A catalog of common, intermediate and well-documented (CIWD) HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQB1 and -DPB1 alleles has been compiled from over 8 million individuals using data from 20 unrelated hematopoietic stem cell volunteer donor registries. Individuals are divided into seven geographic/ancestral/ethnic groups and data are summarized for each group and for the total population. P (two-field) and G group assignments are divided into one of four frequency categories: common (≥1 in 10 000), intermediate (≥1 in 100 000), well-documented (≥5 occurrences) or not-CIWD. Overall 26% of alleles in IPD-IMGT/HLA version 3.31.0 at P group resolution fall into the three CIWD categories. The two-field catalog includes 18% (n = 545) common, 17% (n = 513) intermediate, and 65% (n = 1997) well-documented alleles. Full-field allele frequency data are provided but are limited in value by the variations in resolution used by the registries. A recommended CIWD list is based on the most frequent category in the total or any of the seven geographic/ancestral/ethnic groups. Data are also provided so users can compile a catalog specific to the population groups that they serve. Comparisons are made to three previous CWD reports representing more limited population groups. This catalog, CIWD version 3.0.0, is a step closer to the collection of global HLA frequencies and to a clearer view of HLA diversity in the human population as a whole.

Extended HLA Haplotypes and Their Impact on DPB1 Matching of Unrelated Hematologic Stem Cell Transplant Donors.

Although HLA-DPB1 has long been considered of lesser importance in the selection of an unrelated donor (URD) hematologic stem cell transplantation, currently in many instances the DPB1 type of the donor is relevant or even critical. At present, however, only a minority of registry donors are DPB1 typed. It is also unclear to what extent the DPB1 alleles are linked to the 5-locus HLA-A-, B-, C-, DRB1, -DQB1 haplotypes. We sought to study whether there is such a linkage by using donors in the Finnish Stem Cell Registry as the study population. The 6-locus HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 haplotype frequencies were estimated from a group of 43,365 Finnish registry donors using the German National Bone Marrow Registry algorithm. Five-locus haplotype (HLA-A, -B, -C, -DRB1, -DQB1) and HLA-DPB1 allele frequencies were calculated as marginal frequencies of the estimated 6-locus haplotype frequencies. The Finnish average frequency of individual DPB1 alleles was compared with their respective frequencies in association with individual 5-locus HLA haplotypes (haplotype-specific frequencies). Finally, the probability of DPB1 matching in 10/10 matched URD transplants was assessed. Haplotype-specific DPB1 frequencies differed significantly from the average DPB1 frequencies in 81 of 100 most frequent Finnish 5-locus HLA haplotypes, including some infrequent DPB1 alleles that were associated almost exclusively with certain individual 5-locus haplotypes. Five-locus haplotypes that are enriched in Finland but rare among other Europeans carried stronger DPB1 associations than haplotypes that are frequent European-wide. Finally, 10/10 matched transplants from domestic registry donors were significantly more likely to also be DPB1 matched than those from foreign donors. The results indicate an extension of linkage disequilibrium in the MHC complex in the Finnish population. With continuing upfront DPB1 typing of registry donors, it will be possible to perform similar extended 6-locus haplotype frequency estimations also in other registries. The associations are likely to be population specific but may be weaker in more heterogeneous populations. In the future the results might be used to predict the probability of DPB1 match or permissive/nonpermissive DPB1 mismatch for non-DPB1 typed donors in registry donor searches.

HLA-selected platelets for platelet refractory patients with HLA antibodies: a single-center experience.

BACKGROUND: Platelet refractoriness due to HLA immunization represents a problem in transfusion management of thrombocytopenic hematology patients. Refractory patients can be managed by HLA-selected platelet transfusions, but the optimal matching strategy is debated and how the degree of HLA mismatch influences transfusion outcome is poorly studied. STUDY DESIGN AND METHODS: We studied 32 hematology patients who received 142 matched platelet units between 2007 and 2016. Four matching strategies were compared: 1) genomic HLA typing at the two digit level, performed using polymerase chain reaction-sequence-specific oligonucleotide probing; 2) serologic "eplet score" calculated using HLAMatchmaker; 3) cross-matching using lymphocyte cytotoxicity; and 4) matching based on donor-specific antibody (DSA) specificity, determined using Luminex. A 1-hour corrected count increment (CCI) of more than 7.5 × 109 /L was considered a successful response. RESULTS: Selection of platelets with either a complete HLA match or an acceptable HLA mismatch based on genomic typing and DSA information, each predicted 86% successful transfusion responses. For HLA-mismatched transfusions, the eplet score correlated with CCI and the fraction of successful transfusions, but less well compared to DSA matching. Cytotoxic crossmatching was least predictive. For transfusions across one to four DSAs, the antibody reaction strength correlated with the 1-hour CCI, but many transfusions were successful despite the presence of DSA. CONCLUSION: A complete HLA-A and -B match or an acceptable mismatch based on DSA should guide identification of donors. Still, transfusions across DSAs are often successful, emphasizing that the presence of DSA is necessary but not sufficient for platelet clearance.

A European HLA Isolate and Its Implications for Hematopoietic Stem Cell Transplant Donor Procurement.

Europeans have often been considered a homogenous group in registry donor match predictions, but it is now evident that HLA haplotype frequencies vary across the European continent. Earlier studies have indicated that Finns in northeastern Europe have unique HLA characteristics, and the increasing availability of high-resolution registry donor data is now making more detailed comparisons possible. In the first phase of the present study, estimated HLA haplotype frequencies in stem cell donor registries of Finland and its neighbors Sweden and Russia were calculated using the algorithm of the German National Bone Marrow Donor Registry (ZKRD) and their frequencies were compared with one another and also with that of Germany. Virtual donor searches for 1492 high-resolution typed Finnish patients in the Finnish, Swedish and German registries were then performed, using individual match predictions for each registry. In the last phase, the impact of specifically Finnish-enriched HLA haplotypes on Finnish patients and the use of Finnish registry donors was assessed by analyzing 647 consecutive hematopoietic stem cell transplantation (HSCT) donor searches and 40 exported Finnish HSCTs. The Finnish HLA landscape was more homogenous than the 3 other studied populations, but also genetically distinct from them. The match predictions found a probable 10/10 match for 71%, 41%, and 31% of the Finnish patients in the German, Finnish, and Swedish registries, respectively. Thirty-four of Finland's 100 most frequent HLA haplotypes were represented with a frequency of <.0003 in Germany, and with an 8- to 3262-fold greater frequency in Finland than in Germany. Patients carrying these Finnish-enriched haplotypes were less likely to receive a matched HSCT but more likely to receive it from a domestic donor. Registry donors carrying them were more likely to donate stem cells, both nationally and internationally. The Finnish HLA isolate has a significant impact on both Finnish patients and registry donors, explaining the high use of national registry donors for Finnish patients. Haplotype frequency estimations are an important tool for small registries as well, to help optimize donor match predictions and the size of individual registries.

Donor Haplotype B of NK KIR Receptor Reduces the Relapse Risk in HLA-Identical Sibling Hematopoietic Stem Cell Transplantation of AML Patients.

Successful allogeneic hematopoietic stem cell transplantation (HSCT) depends not only on good HLA match but also on T-cell mediated graft-versus-leukemia (GvL) effect. Natural killer (NK) cells are able to kill malignant cells by receiving activation signal from the killer-cell immunoglobulin-like receptors (KIR) recognizing HLA molecules on a cancer cell. It has been recently reported that the risk of relapse in allogeneic hematopoietic stem cell transplantation (HSCT) is reduced in acute myeloid leukemia (AML) patients whose donors have several activating KIR genes or KIR B-motifs in unrelated donor setting, obviously due to enhanced GvL effect by NK cells. We studied the effect on relapse rate of donor KIR haplotypes in the HLA-identical adult sibling HSCT, done in a single center, in Helsinki University Central Hospital, Helsinki, Finland. Altogether, 134 patients with 6 different diagnoses were identified. Their donors were KIR genotyped using the Luminex and the SSP techniques. The clinical endpoint, that is, occurrence of relapse, was compared with the presence or absence of single KIR genes. Also, time from transplantation to relapse was analyzed. The patients with AML whose donors have KIR2DL2 or KIR2DS2 had statistically significantly longer relapse-free survival (P = 0.015). Our data support previous reports that donors with KIR B-haplotype defining genes have a lower occurrence of relapse in HSCT of AML patients. Determination of donor KIR haplotypes could be a useful addition for a risk assessment of HSCT especially in AML patients.

Syndecan-1 and tenascin expression in cystic tumors of the pancreas.

CONTEXT: Since benign and malignant mucin-producing tumors of the pancreas may be difficult to distinguish from each other; preoperative methods for differential diagnosis would reduce unnecessary surgery. OBJECTIVE: To compare syndecan-1 and tenascin immunoexpression in benign and malignant cystic pancreatic tumors. DESIGN: We used immunohistochemical staining for syndecan-1 and tenascin antibodies in tumor tissue samples. SETTING: Helsinki University Central Hospital. PATIENTS: Tissue material came from 33 patients undergoing surgery from 1979 to 2005 for cystic pancreatic tumors. RESULTS: A statistically significant difference appeared in syndecan-1 expression between benign (mucinous cystic neoplasms and intraductal papillary mucinous neoplasms) and mucinous carcinomas, but there was no significant difference in tenascin immunoexpression between these tumor groups. CONCLUSION: Our findings suggest that low syndecan-1 expression might serve as a predictive factor for malignancy in cystic tumors of the pancreas.