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Allogeneic Hematopoietic Cell Transplantation (HCT) is a curative therapy for hematologic disorders and often requires human leukocyte antigen (HLA)-matched donors. Donor registries have recruited donors utilizing evolving technologies of HLA genotyping methods. This necessitates in-silico ambiguity resolution and statistical imputation based on haplotype frequencies estimated from donor data stratified by self-identified race and ethnicity (SIRE). However, SIRE has limited genetic validity and presents a challenge for individuals with unknown or mixed SIRE. We present MR-GRIMM "Multi-Race Graph IMputation and Matching" that simultaneously imputes the race/ethnic category and HLA genotype using a SIRE based prior. Additionally, we propose a novel method to impute HLA typing inconsistent with current haplotype frequencies. The performance of MR-GRIMM was validated using a dataset of 170,000 donor-recipient pairs. MR-GRIMM has an average 20 % lower matching error (1-AUC) than single-race imputation. The recall metric (sensitivity) of the race/ethnic category imputation from HLA was measured by comparing the imputed donor race with the donor-provided SIRE. Accuracies of 0.74 and 0.55 were obtained for the prediction of 5 broad and 21 detailed US population groups respectively. The operational implementation of this algorithm in a registry search could help improve match predictions and access to HLA-matched donors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mutation-bearing peptide ligands from mutated nucleophosmin-1 (NPM1) protein have been empirically found to be presented by HLA class I in acute myeloid leukemia (AML). We hypothesized that HLA genotype may impact allogeneic hematopoietic stem cell transplantation (allo-HCT) outcomes in NPM1-mutated AML owing to differences in antigen presentation. We evaluated the effect of the variable of predicted strong binding to mutated NPM1 peptides using HLA class I genotypes from matched donor-recipient pairs on transplant recipients' overall survival (OS) and disease-free survival (DFS) as part of the primary objectives and cumulative incidence of relapse and nonrelapse mortality (NRM) as part of secondary objectives. Baseline and outcome data reported to the Center for International Blood and Marrow Transplant Research from a study cohort of adult patients (n = 1020) with NPM1-mutated de novo AML in first (71%) or second (29%) complete remission undergoing 8/8 matched related (18%) or matched unrelated (82%) allo-HCT were analyzed retrospectively. Class I alleles from donor-recipient pairs were analyzed for predicted strong HLA binding to mutated NPM1 using netMHCpan 4.0. A total of 429 (42%) donor-recipient pairs were classified as having predicted strong-binding HLA alleles (SBHAs) to mutated NPM1. In multivariable analyses adjusting for clinical covariates, the presence of predicted SBHAs was associated with a lower risk of relapse (hazard ratio [HR], .72; 95% confidence interval [CI], .55 to .94; P = .015). OS (HR, .81; 95% CI, .67 to .98; P = .028) and DFS (HR, .84; 95% CI, .69 to 1.01; P = .070) showed a suggestion of better outcomes if predicted SBHAs were present but did not meet the prespecified P value of <.025. NRM did not differ (HR, 1.04; P = .740). These hypothesis-generating data support further exploration of HLA genotype-neoantigen interactions in the allo-HCT context., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Donor-recipient HLA matching at the DPB1 locus improves the outcomes of hematopoietic stem cell transplantation (HCT). Retrospective outcome studies found that in HCTs matched for all 8 alleles of the A, B, C, and DRB1 loci at high resolution (8/8 match), few transplantations were also allele-matched at the DPB1 locus. DPB1 allele matching was once thought to be logistically impractical; however, a DPB1-permissive mismatch model based on T cell epitope (TCE) reactivity expands the proportion of suitable donors. To understand the likelihood of finding a DPB1-permissive donor, we sought to expand population genetic match likelihood models for the US unrelated donor registry, the National Marrow Donor Program (NMDP). After extending HLA haplotype frequency estimates to include the DPB1 locus, our models found that the likelihood of having a DPB1-permissive donor was not much lower than likelihood of 8/8 matching. A maximum of 5 additional donors would need to be typed to find a more optimal DPB1-permissive donor at least 90% of the time. Linkage disequilibrium patterns between the DPB1 locus and other classical HLA loci varied markedly by haplotype and population, indicating that the known recombination hotspot between DQ and DP gene complexes has not had a uniform impact; thus, DPB1-permissive donors are easier to identify within minority populations. DPB1 TCE categories were highly predictable from HLA typing at other loci when imputed with extended haplotype frequency data. Our overall results indicate that registry search strategies that seek a more optimally matched HCT donor encompassing HLA-DPB1 permissibility are likely to be highly productive., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Supporting allogeneic hematopoietic cell transplantation (HCT) is an integral function of the clinical HLA laboratory, which provides HLA testing for recipients and donors. However, the timing, scope, and methods of the HLA tests vary significantly in the field. This summary provides a comprehensive and practical HLA testing approach to maximize the efficiency of the donor search process, minimize donor-specific HLA antibody (DSA) associated risks, enable optimal donor selections, and support HCT multidisciplinary teams. This is not a comprehensive donor selection guide, but pertinent donor selection considerations and publicly available online selection tools are highlighted. In the absence of healthy HLA identical siblings, younger 8/8 (HLA-A, -B, -C, -DRB1) HLA-matched unrelated donors remain the most favorable choice for HCT. Emerging practices in preparative regimens and graft versus host disease (GvHD) prophylaxis as well as building evidence of the importance of other HLA (e.g., HLA-DPB1 allele and functional matching) and non-HLA (e.g., age, CMV, and KIR) donor attributes urge the transplant centers and the HLA laboratories to construct a comprehensive approach for the routine histocompatibility testing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Despite its demonstrated importance in hematopoietic cell transplantation, the HLA-DPB1 locus is only typed in one in five unrelated donors in the United States. Addressing this issue, we developed a DPB1 Prediction Service that leverages seven-locus haplotype frequencies (HLA-A ∼ C ∼ B ∼ DRB3/4/5 ∼ DRB1 ∼ DQB1 ∼ DPB1) to extend the imputation of six-locus HLA typing (HLA-A ∼ C ∼ B ∼ DRB3/4/5 ∼ DRB1 ∼ DQB1) to the HLA-DPB1 locus, including the novel prediction of HLA-DPB1 TCE groups to calculate donor-recipient TCE permissive match probabilities. Simulations of current-day patient searches reveal the service can fill in missing gaps for another four in five donors that appears on lists. To validate its performance, samples of 206,328 registered donors and 5,218 donor-recipient pairs with known high-resolution HLA-DPB1 typing were used for predicted-versus-observed comparisons. These comparisons demonstrated that the predictions were correct for 11.9-19.7% of HLA-DPB1 genotypes, 64.9-70.0% of TCE groups, and 61.0% of permissive match categories. Although HLA-DPB1 match predictions must be confirmed by additional typing, knowledge of TCE match probabilities facilitates rapid and improved identification of best donor options, especially for populations of color. Thus, we developed the TCE Prediction Tool user interface for a pilot program with several transplant centers to preview the accuracy and utility of this prediction framework, which provides valuable upfront optimization of donor selection., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: Ultrahigh resolution (UHR) HLA matching is reported to result in better outcomes following unrelated donor hematopoietic cell transplantation, improving survival and reducing post-transplant complications. However, most studies included relatively small numbers of patients. Here we report the findings from a large, multicenter validation study., Methods: UHR HLA typing was available on 5,140 conventionally 10 out of 10 HLA-matched patients with malignant disease transplanted between 2008 and 2017., Results: After UHR HLA typing, 82% of pairs remained 10 out of 10 UHR-matched; 12.3% of patients were 12 out of 12 UHR HLA-matched. Compared with 12 out of 12 UHR-matched patients, probabilities of grade 2-4 acute graft-versus-host disease (aGVHD) were significantly increased with UHR mismatches (overall P = .0019) and in those patients who were HLA-DPB1 T-cell epitope permissively mismatched or nonpermissively mismatched (overall P = .0011). In the T-cell-depleted subset, the degree of UHR HLA mismatch was only associated with increased transplant-related mortality (TRM) (overall P = .0068). In the T-cell-replete subset, UHR HLA matching was associated with a lower probability of aGVHD (overall P = .0020); 12 out of 12 UHR matching was associated with reduced TRM risk when compared with HLA-DPB1 T-cell epitope permissively mismatched patients, whereas nonpermissive mismatching resulted in a greater risk (overall P = .0003)., Conclusion: This study did not confirm that UHR 12 out of 12 HLA matching increases the probability of overall survival but does demonstrate that aGVHD risk, and in certain settings TRM, is lowest in UHR HLA-matched pairs and thus warrants consideration when multiple 10 out of 10 HLA-matched donors of equivalent age are available., Competing Interests: Stephanie J. LeeHonoraria: Wolters KluwerConsulting or Advisory Role: Incyte, Pfizer, EMD Serono, Kadmon, MSD Oncology, Sanofi, Genzyme, Regeneron, 4SCResearch Funding: Kadmon, Takeda, Amgen, Bristol-Myers Squibb, EMD Serono, MSD, Novartis, Incyte, Syndax, Pfizer, AstraZenecaPatents, Royalties, Other Intellectual Property: Patent pending for high-affinity T-cell receptors that target the Merkel polyomavirus Jeffrey AulettaConsulting or Advisory Role: MORE Health, AlloVir, AscellaHealth Vijaya R. BhattConsulting or Advisory Role: Abbvie, Incyte, Agios, Genentech, Rigel, Partnership for Health Analytic Research, LLC, Omeros, TakedaResearch Funding: Incyte, Tolero Pharmaceuticals, National Marrow Donor Program, Abbvie, Pfizer, Jazz PharmaceuticalsOther Relationship: Oncoceutics, Novartis, Pfizer Loren GragertOther Relationship: National Marrow Donor Program/Be The Match, United Network For Organ Sharing Yoshihiro InamotoHonoraria: Kyowa Kirin Co, Ltd, Astellas Pharma, Sumitomo Dainippon, Novartis, Chugai Pharma, Bristol-Myers Squibb, MSD K.K.Consulting or Advisory Role: Novartis, Janssen, Meiji Seika Kaisha Gerald P. MorrisResearch Funding: Ferring Inc, AmgenTravel, Accommodations, Expenses: Thermo Fisher Scientific Sophie PaczesnyPatents, Royalties, Other Intellectual Property: Dr Paczesny has a patent on “Methods of detection of graft-versus-host disease” licensed to Viracor-IBT Laboratories Ran ReshefConsulting or Advisory Role: Atara Biotherapeutics, Novartis, Bristol-Myers Squibb, Gilead Sciences, TScan TherapeuticsResearch Funding: Atara Biotherapeutics, Incyte, Pharmacyclics, Shire, Immatics, Takeda, Gilead Sciences, Precision Biosciences, Astellas Pharma, Bristol-Myers Squibb Bronwen E. ShawHonoraria: TherakosConsulting or Advisory Role: Orcabio Peter ShawConsulting or Advisory Role: NovartisOther Relationship: Link PharmaNo other potential conflicts of interest were reported.

Minor histocompatibility antigens (mHAs), recipient-derived peptide epitopes presented on the cell surface, are known to mediate graft-versus-host disease (GVHD); however, there are no current methods to associate mHA features with GVHD risk. This deficiency is due in part to the lack of technological means to accurately predict, let alone confirm, the tremendous number of potential mHAs in each individual transplant. Previous studies have shown that different HLA molecules present varying fractions of candidate peptide epitopes; however, the genetic "distance" between HLA-matched donors and recipients is relatively constrained. From these 2 observations, it is possible that the HLA type for a donor-recipient pair (DRP) would provide a surrogate measurement of the number of predicted mHAs, which could be related to GVHD risk. Because different HLA molecules present variable numbers of peptide antigens, a predicted cumulative peptide-binding efficiency can be calculated for individual DRP based on the pair's HLA type. The purpose of this study was to test whether cumulative peptide-binding efficiency is associated with the risk of acute GVHD (aGVHD) or relapse. In this retrospective Center for International Blood and Marrow Transplant Research study, a total of 3242 HLA-matched DRPs were analyzed for predicted cumulative peptide-binding efficiency using their HLA types and were divided into tertiles based on their scores. Univariable and multivariable analyses was performed to test for associations between cumulative peptide-binding efficiency for DRPs, divided into the HLA-matched related donor (MRD) and HLA-matched unrelated donor (MUD) cohorts, and the primary outcomes of aGVHD and relapse. Secondary outcomes investigated included overall survival, disease-free survival, and transplantation-related mortality. Using a computationally generated peptidome as a test dataset, the tested series of HLA class I displayed peptide-binding frequencies ranging from 0.1% to 3.8% of the full peptidome, and HLA class II molecules had peptide-binding frequencies of 12% to 77% across the HLA-DRB1 allotypes. By increasing binding efficiency tertile, the cumulative incidence of aGVHD at 6 months for MUD patients was 41%, 41%, and 45% for HLA class I (P = .336) and 44%, 41%, and 42% for HLA class II (P = .452). The cumulative incidences of relapse at 3 years for MUD transplant recipients were 36%, 38%, and 38% for HLA class I (P = .533) and 37%, 37%, and 38% for HLA class II (P = .896). The findings were similar for MRD transplant recipients. Multivariable analysis did not identify any impact of peptide-binding efficiency on aGVHD or relapse in MUD or MRD transplant recipients. Whereas GVHD is mediated by minor antigen mismatches in the context of HLA-matched allo-HCT, peptide-binding efficiency, which was used as a surrogate measurement for predicted number of binding antigens, did not provide additional clinical information for GVHD risk assessment. The negative result may be due to the limitations of this surrogate marker, or it is possible that GVHD is driven by a subset of immunogenic mHAs. Further research should be directed at direct mHA epitope and immunogenicity prediction., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

The search for a suitable human leukocyte antigen (HLA)-matched unrelated adult stem cell donor (URD) or umbilical cord blood unit (UCB) is a complex process. The National Marrow Donor Program (NMDP) developed a search algorithm known as HapLogic, which is currently provided within the NMDP Traxis application. The HapLogic algorithm has been in use since 2006 and has advanced URD/UCB HLA-matching technology. The algorithm has been shown to have high predictive accuracy, which can streamline URD/UCB selection and drive efficiencies in the search process to the benefit of the stem cell transplantation community. Here, we describe the fundamental components of the NMDP matching algorithm, output, validation, and future directions., (Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Unrelated stem cell registries have been collecting HLA typing of volunteer bone marrow donors for over 25years. Donor selection for hematopoietic stem cell transplantation is based primarily on matching the alleles of donors and patients at five polymorphic HLA loci. As HLA typing technologies have continually advanced since the beginnings of stem cell transplantation, registries have accrued typings of varied HLA typing ambiguity. We present a new typing resolution score (TRS), based on the likelihood of self-match, that allows the systematic comparison of HLA typings across different methods, data sets and populations. We apply the TRS to chart improvement in HLA typing within the Be The Match Registry of the United States from the initiation of DNA-based HLA typing to the current state of high-resolution typing using next-generation sequencing technologies. In addition, we present a publicly available online tool for evaluation of any given HLA typing. This TRS objectively evaluates HLA typing methods and can help define standards for acceptable recruitment HLA typing., (Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Mismatch of human leukocyte antigens (HLA) adversely impacts the outcome of patients after allogeneic hematopoietic stem-cell transplantation (alloHSCT). This translates into the clinical requirement to timely identify suitable HLA-matched donors which in turn curtails the chances of recipients, especially those from a racial minority, to successfully undergo alloHSCT. We thus sought to broaden the existing pool of registered unrelated donors based on analysis that eliminating the expression of the HLA-A increases the chance for finding a donor matched at HLA-B, -C, and -DRB1 regardless of a patient's race. Elimination of HLA-A expression in HSC was achieved using artificial zinc finger nucleases designed to target HLA-A alleles. Significantly, these engineered HSCs maintain their ability to engraft and reconstitute hematopoiesis in immunocompromised mice. This introduced loss of HLA-A expression decreases the need to recruit large number of donors to match with potential recipients and has particular importance for patients whose HLA repertoire is under-represented in the current donor pool. Furthermore, the genetic engineering of stem cells provides a translational approach to HLA-match a limited number of third-party donors with a wide number of recipients.

Background: Hematopoietic stem-cell transplantation (HSCT) is a potentially lifesaving therapy for several blood cancers and other diseases. For patients without a suitable related HLA-matched donor, unrelated-donor registries of adult volunteers and banked umbilical cord-blood units, such as the Be the Match Registry operated by the National Marrow Donor Program (NMDP), provide potential sources of donors. Our goal in the present study was to measure the likelihood of finding a suitable donor in the U.S. registry., Methods: Using human HLA data from the NMDP donor and cord-blood-unit registry, we built population-based genetic models for 21 U.S. racial and ethnic groups to predict the likelihood of identifying a suitable donor (either an adult donor or a cord-blood unit) for patients in each group. The models incorporated the degree of HLA matching, adult-donor availability (i.e., ability to donate), and cord-blood-unit cell dose., Results: Our models indicated that most candidates for HSCT will have a suitable (HLA-matched or minimally mismatched) adult donor. However, many patients will not have an optimal adult donor--that is, a donor who is matched at high resolution at HLA-A, HLA-B, HLA-C, and HLA-DRB1. The likelihood of finding an optimal donor varies among racial and ethnic groups, with the highest probability among whites of European descent, at 75%, and the lowest probability among blacks of South or Central American descent, at 16%. Likelihoods for other groups are intermediate. Few patients will have an optimal cord-blood unit--that is, one matched at the antigen level at HLA-A and HLA-B and matched at high resolution at HLA-DRB1. However, cord-blood units mismatched at one or two HLA loci are available for almost all patients younger than 20 years of age and for more than 80% of patients 20 years of age or older, regardless of racial and ethnic background., Conclusions: Most patients likely to benefit from HSCT will have a donor. Public investment in donor recruitment and cord-blood banks has expanded access to HSCT. (Funded by the Office of Naval Research, Department of the Navy, and the Health Resources and Services Administration, Department of Health and Human Services.).

Measures of allele and haplotype diversity, which are fundamental properties in population genetics, often follow heavy tailed distributions. These measures are of particular interest in the field of hematopoietic stem cell transplant (HSCT). Donor/Recipient suitability for HSCT is determined by Human Leukocyte Antigen (HLA) similarity. Match predictions rely upon a precise description of HLA diversity, yet classical estimates are inaccurate given the heavy-tailed nature of the distribution. This directly affects HSCT matching and diversity measures in broader fields such as species richness. We, therefore, have developed a power-law based estimator to measure allele and haplotype diversity that accommodates heavy tails using the concepts of regular variation and occupancy distributions. Application of our estimator to 6.59 million donors in the Be The Match Registry revealed that haplotypes follow a heavy tail distribution across all ethnicities: for example, 44.65% of the European American haplotypes are represented by only 1 individual. Indeed, our discovery rate of all U.S. European American haplotypes is estimated at 23.45% based upon sampling 3.97% of the population, leaving a large number of unobserved haplotypes. Population coverage, however, is much higher at 99.4% given that 90% of European Americans carry one of the 4.5% most frequent haplotypes. Alleles were found to be less diverse suggesting the current registry represents most alleles in the population. Thus, for HSCT registries, haplotype discovery will remain high with continued recruitment to a very deep level of sampling, but population coverage will not. Finally, we compared the convergence of our power-law versus classical diversity estimators such as Capture recapture, Chao, ACE and Jackknife methods. When fit to the haplotype data, our estimator displayed favorable properties in terms of convergence (with respect to sampling depth) and accuracy (with respect to diversity estimates). This suggests that power-law based estimators offer a valid alternative to classical diversity estimators and may have broad applicability in the field of population genetics. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) displays remarkable ethnic predisposition for whites, with relative sparing of African-American and Asian populations. In addition, CLL displays among the highest familial predispositions of all hematologic malignancies, yet the genetic basis for these differences is not clearly defined. The highly polymorphic HLA genes of the major histocompatibility complex play a central role in immune surveillance and confer risk for autoimmune and infectious diseases and several different cancers, the role for which in the development of CLL has not been extensively investigated. The National Marrow Donor Program/Be The Match has collected HLA typing from CLL patients in need of allogeneic hematopoietic stem cell transplant and has recruited millions of volunteers to potentially donate hematopoietic stem cells. HLA genotypes for 3491 US white, 397 African-American, and 90 Hispanic CLL patients were compared with 50 000 controls per population from the donor registry. We identified several HLA alleles associated with CLL susceptibility in each population, reconfirming predisposing roles of HLA-A*02:01 and HLA-DRB4*01:01 in whites. Associations for haplotype DRB4*01:01~DRB1*07:01~DQB1*03:03 were replicated across all 3 populations. These findings provide a comprehensive assessment of the role of HLA in the development of severe CLL. [ABSTRACT FROM AUTHOR]

In hematopoietic stem cell transplantation, donor selection is based primarily on matching donor and patient HLA genes. These genes are highly polymorphic and their typing can result in exact allele assignment at each gene (the resolution at which patients and donors are matched), but it can also result in a set of ambiguous assignments, depending on the typing methodology used. To facilitate rapid identification of matched donors, registries employ statistical algorithms to infer HLA alleles from ambiguous genotypes. Linkage disequilibrium information encapsulated in haplotype frequencies is used to facilitate prediction of the most likely haplotype assignment. An HLA typing with less ambiguity produces fewer highprobability haplotypes and a more reliable prediction. We estimated ambiguity for several HLA typing methods across four continental populations using an information theory-based measure, Shannon's entropy. We used allele and haplotype frequencies to calculate entropy for different sets of 1,000 subjects with simulated HLA typing. Using allele frequencies we calculated an average entropy in Caucasians of 1.65 for serology, 1.06 for allele family level, 0.49 for a 2002-era SSO kit, and 0.076 for single- pass SBT. When using haplotype frequencies in entropy calculations, we found average entropies of 0.72 for serology, 0.73 for allele family level, 0.05 for SSO, and 0.002 for single-pass SBT. Application of haplotype frequencies further reduces HLA typing ambiguity. We also estimated expected confirmatory typing mismatch rates for simulated subjects. In a hypothetical registry with all donors typed using the same method, the entropy values based on haplotype frequencies correspond to confirmatory typing mismatch rates of 1.31% for SSO versus only 0.08% for SBT. Intermediate-resolution single-pass SBT contains the least ambiguity of the methods we evaluated and therefore the most certainty in allele prediction. The presented measure objectively evaluates HLA typing methods and can help define acceptable HLA typing for donor recruitment. [ABSTRACT FROM AUTHOR]

Non-permissive HLA-DPB1 mismatches in hematopoietic stem cell transplantations (HSCT) have been defined in terms of T-Cell epitope (TCE) reactivity groups (Zino et al.) and DPB1 expression variants (Petersdorf et al). The non-permissive HLA-DPB1 mismatches identified in both models are associated with a statistically significant increase in the risk of graft versus host disease in HSCT. We aimed to measure the ability to predict TCE and expression permissibility for all major race groups by imputing donor DPB1 genotypes using high-resolution A∼C∼B∼DRB1∼DQB1∼DPB1 haplotype frequencies. We used 512,201 donors typed at high resolution (HR) at A∼C∼B∼DRB1∼DQB1∼DPB1 for evaluating the imputation of DPB1 permissibility. We analyzed 18 populations that had at least 4000 donors typed at HR for all six loci. The most HR donors were observed in the European population (301,401) and the least HR in the Vietnamese population (4326). We used the algorithm outlined in Zino et al. for determining the DPB1 TCE permissibility and Petersdorf et al. for determining the DPB1 expression risk. From each population we randomly selected 2500 HR subjects and then simulated 6250,000 donor-recipient pairs. We removed the donor’s DPB1 genotype for each pair and imputed it back using A∼C∼B∼DRB1∼DQB1∼DPB1 haplotype frequencies. The randomly selected HR subjects were removed from the calculation of the haplotype frequencies. Based on the DPB1 allele likelihoods, we calculated probabilities for each pair being TCE permissive or non-permissive and DPB1 expression permissive or non-permissive. We compared the predicted TCE and expression permissibility for each pair to their true TCE and expression permissibility using the receiver operator characteristic (ROC). The ROC area under the curve (AUC) was greater than 0.90 for every population except Vietnamese (0.87). The three highest AUC were observed in the Filipino (0.96), Middle Eastern (0.95) and the Caribbean (0.95) populations. The average AUC observed was 0.92 with a standard deviation of 0.02 between populations. Imputation of DPB1 permissibility can be performed with strong predictive power for every major population when using A∼C∼B∼DRB1∼DQB1∼DPB1 haplotype frequencies. Donor search results for HSCT could be enhanced with the addition of DPB1 permissibility predictions. [ABSTRACT FROM AUTHOR]

Abstract: Hematopoietic cell transplantation (HCT) using CCR5-Δ32/Δ32 stem cells from an adult donor has resulted in the only known cure of human immunodeficiency virus (HIV) infection. However, it is not feasible to repeat this procedure except rarely because of the low incidence of the CCR5-Δ32 allele, the availability of only a small number of potential donors for most patients, and the need for a very close human leukocyte antigen (HLA) match between adult donors and recipients. In contrast, cord blood (CB) transplantations require significantly less stringent HLA matching. Therefore, our hypothesis is that cure of HIV infections by HCT can be accomplished much more readily using umbilical CB stem cells obtained from a modestly sized inventory of cryopreserved CCR5-Δ32/Δ32 CB units. To test this hypothesis, we developed a screening program for CB units and are developing an inventory of CCR5-Δ32/Δ32 cryopreserved units available for HCT. Three hundred such units are projected to provide for white pediatric patients a 73.6% probability of finding an adequately HLA matched unit with a cell dose of ≥2.5 × 107 total nucleated cells (TNCs)/kg and a 27.9% probability for white adults. With a cell dose of ≥1 × 107 TNCs/kg, the corresponding projected probabilities are 85.6% and 82.1%. The projected probabilities are lower for ethnic minorities. Impetus for using CB HCT was provided by a transplantation of an adult with acute myelogenous leukemia who was not HIV infected. The HCT was performed with a CCR5-Δ32/Δ32 CB unit, and posttransplantation in vitro studies indicated that the patient''s peripheral blood mononuclear cells were resistant to HIV infection. [Copyright &y& Elsevier]

Aim: Recent data show that DP matching plays an important role in hematopoietic cell transplantation. Our previous work demonstrated that in European Americans haplotypic associations for the DP heterodimer are determined by near complete linkage disequilibrium between amino acid motifs on DPA1 (pos 31) and DPB1 (pos 85–87). We aimed to generate motif and allele-level haplotype frequencies (HF) for four race groups to extend these insights to minorities. Methods: We calculated DPA1∼DPB1 HF at allele and motif level from 16,802 Be the Match Registry® members typed by DNA methods, resolving phase, allelic and motif ambiguity using expectation maximization. Motif frequencies were calculated for position 31 on DPA1 and positions 85–87 on DPB1, which play a critical role in the P1 pocket of the peptide binding region. Normalized linkage disequilibrium (LD) was calculated on each haplotype (D′) and globally (Wn) for each population. Results: The top three allele-level haplotypes in all populations account for over 66% of the HF, with DPA1∗01:03 DPB1∗04:01 most common in the Caucasian (CAU), Asian Pacific Islander (API) and Hispanic (HIS) populations and DPA1∗02:02 DPB1∗01:01 in the African American (AFA) population. Wn for DPA1∼DPB1 allele associations for CAU, HIS, API, and AFA populations was .55, .45, .49, and .52 respectively. At the motif level there were only four possible haplotypes. M GPM and Q EAV were the two most common in every population. M GPM was the most common in CAU, HIS and API with frequencies 69%, 68% and 56% respectively, with D′= 0.97 for CAU (complete LD). The most common haplotype for AFA was Q EAV, at 48% and D′=.99. Conclusions: Low global LD was observed at the allele level for all populations. However, at the motif level haplotypes were in near complete LD suggesting that for the DPA1 DPB1 heterodimer the unit of selection for all populations is the combined amino acid motif rather than the allele, as previously observed in European Americans. [ABSTRACT FROM AUTHOR]