C K Hurley

Georgetown University, Washington, Washington, D.C., United States

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Publications (275)738.74 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We examined current outcomes of unrelated donor allogeneic hematopoietic cell transplantation (HCT) to determine the clinical implications of donor-recipient HLA matching. Adult and pediatric patients who had undergone first myeloablative unrelated bone marrow or peripheral blood HCT for AML, ALL, CML, or MDS between 1999 and 2011 were included. All had high resolution typing for HLA-A, -B, -C, -DRB1. Of the total (n=8,003), cases were 8/8 (n=5,449), 7/8 (n=2,071), or 6/8 (n=483) matched. HLA mismatch (6-7/8) conferred significantly increased risk for grade II-IV and III-IV acute graft vs. host disease (GVHD), chronic GVHD, transplant-related mortality (TRM), and overall mortality compared to HLA matched cases (8/8). Type (allele/antigen) and locus (HLA-A, -B, -C, -DRB1) of mismatch were not associated with overall mortality. Among 8/8 matched cases, -DPB1 and -DQB1 mismatch resulted in increased acute GVHD, and -DPB1 mismatch had decreased relapse. Non-permissive -DPB1 allele mismatch was associated with higher TRM compared to permissive -DPB1 mismatch or -DPB1 match, and increased overall mortality compared to permissive -DPB1 mismatch in 8/8 (and 10/10) matched cases. Full matching at HLA-A, -B, -C, -DRB1 is required for optimal unrelated donor HCT survival, and avoidance of non-permissive -DPB1 mismatches in otherwise HLA-matched pairs is indicated.
    Blood 08/2014; · 9.78 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2014; 20(2):S25–S26. · 3.94 Impact Factor
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    ABSTRACT: Natural killer cell stimulatory receptor gene, KIR2DS5, is polymorphic. While KIR2DS5∗002 is most frequently observed, other alleles have also been found. The proteins encoded by these alleles (KIR2DS5∗002 - ∗009) are expressed at varying levels on the surface of NKL and Jurkat transfectants. Gel electrophoresis of all allelic products showed two isoforms which differ in the extent of maturation of N-linked glycosylation. These isoforms differed in intensity and molecular weight among the allelic products. Site-directed mutagenesis was used to identify polymorphic variation at residues 123 and 157 as key in altering glycosylation and levels of surface expression.
    Human immunology 11/2013; · 2.55 Impact Factor
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    ABSTRACT: For more than two decades, international cooperation and information technology have been playing key roles in the identification of suitable unrelated donors and cord blood units for hematopoietic SCT. To ensure consistent coding and interpretation of HLA data among the linked computer systems, the World Marrow Donor Association has standardized the extensions of the World Health Organization (WHO) Nomenclature for factors of the HLA system applied in practice. The first version of this report published in 2007 has become the reference for the technical validation of HLA information on donors and patients in the context of search and matching and is used by registries of volunteer unrelated hematopoietic stem cell donors and umbilical cord blood banks throughout the world. The present update became necessary after the major revision of the WHO HLA nomenclature in April 2010. It now covers issues arising when alleles are withdrawn or renamed because of the continuous updating of the WHO HLA nomenclature. In addition, formal validation and interpretation rules for the so-called 'multiple allele codes' have been added.Bone Marrow Transplantation advance online publication, 1 July 2013; doi:10.1038/bmt.2013.93.
    Bone marrow transplantation 07/2013; · 3.00 Impact Factor
  • Tiernan J Mulrooney, Phillip E Posch, Carolyn Katovich Hurley
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    ABSTRACT: KIR aid in the regulation of NK cell activity. In this study, the effect of the interaction between the KIR2DS and their adapter, DAP12, was investigated beyond the previously defined signaling function. Flow cytometry analysis showed enhanced KIR2DS surface expression on NKL cells when cotransfected with DAP12. Conversely, KIR2DS4 surface expression on primary cells was decreased when the cells were treated with DAP12-specific siRNA. Treatment of the KIR2DS and DAP12-transfected cells with CHX or BFA repressed KIR2DS surface expression, revealing a role for DAP12 in trafficking newly synthesized KIR to the cell surface. Immunoprecipitation of DAP12 revealed an interaction of DAP12 with an immature isoform of KIR2DS, indicating that the interaction likely initiates within the ER. An internalization assay demonstrated a significant impact of DAP12 on KIR2DS surface stability. Confocal microscopy showed that internalized KIR2DS molecules are recruited to lysosomal compartments independent of DAP12 expression. Our results suggest that in vivo conditions that adversely affect DAP12 expression will indirectly reduce surface expression and stability of KIR2DS. These effects could significantly impact ligand recognition and strength of signaling through KIR2DS molecules.
    Journal of leukocyte biology 05/2013; · 4.99 Impact Factor
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    ABSTRACT: Although extensive homology exists between their extracellular domains, NK cell inhibitory receptors killer Ig-like receptor (KIR) 2DL2*001 and KIR2DL3*001 have previously been shown to differ substantially in their HLA-C binding avidity. To explore the largely uncharacterized impact of allelic diversity, the most common KIR2DL2/3 allelic products in European American and African American populations were evaluated for surface expression and binding affinity to their HLA-C group 1 and 2 ligands. Although no significant differences in the degree of cell membrane localization were detected in a transfected human NKL cell line by flow cytometry, surface plasmon resonance and KIR binding to a panel of HLA allotypes demonstrated that KIR2DL3*005 differed significantly from other KIR2DL3 allelic products in its ability to bind HLA-C. The increased affinity and avidity of KIR2DL3*005 for its ligand was also demonstrated to have a larger impact on the inhibition of IFN-γ production by the human KHYG-1 NK cell line compared with KIR2DL3*001, a low-affinity allelic product. Site-directed mutagenesis established that the combination of arginine at residue 11 and glutamic acid at residue 35 in KIR2DL3*005 were critical to the observed phenotype. Although these residues are distal to the KIR/HLA-C interface, molecular modeling suggests that alteration in the interdomain hinge angle of KIR2DL3*005 toward that found in KIR2DL2*001, another strong receptor of the KIR2DL2/3 family, may be the cause of this increased affinity. The regain of inhibitory capacity by KIR2DL3*005 suggests that the rapidly evolving KIR locus may be responding to relatively recent selective pressures placed upon certain human populations.
    The Journal of Immunology 05/2013; · 5.52 Impact Factor
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    ABSTRACT: The impact of HLA homozygosity at mismatched (MM) loci on the outcome of 2,687 myeloablative unrelated donor hematopoietic cell transplantations performed for malignant disease was evaluated among four groups: 7/8 bidirectional MM transplants (donor and recipient heterozygous MM, n=1393), 7/8 host vs. graft (HVG) vector MM (recipient homozygous, n=112), 7/8 graft vs. host (GVH) vector MM (donor homozygous, n=119), and 8/8 matches (n=1063). Multivariate analyses found 7/8 GVH (p=0.001) and bidirectional MM groups (p<0.0001) had significantly worse transplant-related mortality, overall and disease-free survival than the 8/8 match group, a difference not observed with the 7/8 HVG MM group (p>0.01). The three 7/8 groups differed only for grades 3-4 acute GVHD where HVG MM had less GVHD than the 7/8 bidirectional MM (HR 0.52, p=0.0016) and GVH MM (HR 0.43, p=0.0009) but not the 8/8 group (HR 0.83, p=0.39). There were no differences between the 7/8 groups for relapse, chronic GVHD, neutrophil engraftment or graft failure. Unidirectional GVH vector mismatches have the same risk as 7/8 bidirectional mismatches. Recipients with a 7/8 HVG MM have a reduced risk of acute GVHD without an increased risk of disease relapse or graft failure compared to a 7/8 bi-directional MM at a heterozygous locus.
    Blood 05/2013; · 9.78 Impact Factor
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    ABSTRACT: We have updated the catalogue of common and well-documented (CWD) human leukocyte antigen (HLA) alleles to reflect current understanding of the prevalence of specific allele sequences. The original CWD catalogue designated 721 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, and -DPB1 loci in IMGT (IMmunoGeneTics)/HLA Database release 2.15.0 as being CWD. The updated CWD catalogue designates 1122 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1 and -DPB1 loci as being CWD, and represents 14.3% of the HLA alleles in IMGT/HLA Database release 3.9.0. In particular, we identified 415 of these alleles as being 'common' (having known frequencies) and 707 as being 'well-documented' on the basis of ~140,000 sequence-based typing observations and available HLA haplotype data. Using these allele prevalence data, we have also assigned CWD status to specific G and P designations. We identified 147/151 G groups and 290/415 P groups as being CWD. The CWD catalogue will be updated on a regular basis moving forward, and will incorporate changes to the IMGT/HLA Database as well as empirical data from the histocompatibility and immunogenetics community. This version 2.0.0 of the CWD catalogue is available online at cwd.immunogenomics.org, and will be integrated into the Allele Frequencies Net Database, the IMGT/HLA Database and National Marrow Donor Program's bioinformatics web pages.
    Tissue Antigens 04/2013; 81(4):194-203. · 2.93 Impact Factor
  • B Tu, N Cha, R Yang, J Ng, C K Hurley
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    ABSTRACT: In order to reduce the time required to identify a match for unrelated donor hematopoietic stem cell transplantation, a one-step DNA sequencing strategy was employed at the time of recruitment. The impact of this strategy on human leukocyte antigen (HLA) typing resolution and the effect of current registry requirements on resolution and coding of assignments were evaluated. Sanger-based DNA sequencing was used to obtain diploid exons 2 and 3 HLA-A, -B and -C assignments of 2747 unrelated African American and 1822 European American volunteers at recruitment. The results demonstrate the high resolution of the approach and challenge several aspects of the current registry typing strategy. Of the 46% of African American and 74% of European American individuals whose HLA typing resulted in alternative genotypes, the majority (≥93%) was predicted to have only a single 'common' genotype among the alternatives. The common practice of adding secondary assays to resolve alternative genotype assignments that include more than two antigen groups was also evaluated. While the percentage of assignments with greater than two antigen groups reached as high as 21% (HLA-A in European Americans), only 1.8% of individuals at most carried two common genotypes encompassing three antigen groups. The assignment of (National Marrow Donor Program) NMDP-designated allele codes to the one-pass results reduced the resolution substantially and introduced genotypes that were not included in the laboratory's assignments. We suggest the alternative strategy of using the exons 2-3 diploid nucleotide sequence as the assignment submitted to the registry with the added benefit of immortalizing the assignment in time regardless of the introduction of novel alleles. To keep pace with current donor selection criteria and with the increasing number of new alleles, it is time to rethink our recruitment typing strategies.
    Tissue Antigens 03/2013; 81(3):150-60. · 2.93 Impact Factor
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    ABSTRACT: DNA sequencing is a powerful technique for identifying allelic variation within the human leukocyte antigen (HLA) genes. Sequencing is usually focused on the most polymorphic exons of the class I (HLA-A, -B, -C) and class II (HLA-DR, -DQ, and -DP) genes. These exons encode the antigen recognition site, the region of the HLA molecule that binds peptides and interacts with the T cell receptor for antigen and natural killer cell immunoglobulin-like receptors (KIR). Sanger sequencing of amplified DNA from each HLA gene from a preparation containing one or two alleles yields a sequence that is used to identify the alleles by comparison with a reference database.
    Methods in molecular biology (Clifton, N.J.) 01/2013; 1034:161-95. · 1.29 Impact Factor
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    ABSTRACT: The goal of the immunogenomic data analysis working group (IDAWG) is to facilitate the consistent analysis of HLA and KIR data, and the sharing of those data among the immunogenomic and larger genomic communities. However, the data management approaches currently applied by immunogenomic researchers are not widely discussed or reported in the literature, and the effect of different approaches on data analyses is not known. With ASHI's support, the IDAWG developed a 45 question survey on HLA and KIR data generation, data management and data analysis practices. Survey questions detailed the loci genotyped, typing systems used, nomenclature versions reported, computer operating systems and software used to manage and transmit data, the approaches applied to resolve HLA ambiguity and the methods used for basic population-level analyses. Respondents were invited to demonstrate their HLA ambiguity resolution approaches in simulated data sets. By May 2012, 156 respondents from 35 nations had completed the survey. These survey respondents represent a broad sampling of the Immunogenomic community; 52% were European, 30% North American, 10% Asian, 4% South American and 4% from the Pacific. The project will continue in conjunction with the 17th Workshop, with the aim of developing community data sharing standards, ambiguity resolution documentation formats, single-task data Management tools and novel data analysis methods and applications. While additional project details and plans for the 17th IHIW will be forthcoming, we welcome the input and participation in these projects from the histocompatibility and immunogenetics community.
    International Journal of Immunogenetics 12/2012; · 1.36 Impact Factor
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    ABSTRACT: HLA-A, -B, -C, -DRB1, -DQB1 assignments were obtained for 374 pairs of African American mothers and their umbilical cord blood units (CBU) by DNA sequencing. An algorithm developed by the National Marrow Donor Program was used to assign 1122 haplotypes by segregation. Seventy percent of the haplotypes carried assignments at all five loci. In the remainder, alleles at various loci, most often DQB1 in 48% of the haplotypes with a missing assignment, could not be assigned due to sharing of both alleles by mother and CBU. There were 652 haplotypes carrying a unique combination of alleles at the five loci; the majority (74%) were singletons. Novel B∼C and DRB1∼DQB1 associations were observed. The results show the genetic diversity in this population and provide validation for a publically available tool for pedigree analysis. Our observations underscore the need for procurement of increased numbers of units in the national cord blood inventory in order to identify matching donors for all patients requiring hematopoietic stem cell transplantation.
    Tissue Antigens 11/2012; · 2.93 Impact Factor
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    ABSTRACT: The importance of human leukocyte antigen (HLA) matching in unrelated donor transplantation for nonmalignant diseases (NMD) has yet to be defined. We analyzed data from 663 unrelated marrow and peripheral blood stem cell transplants performed from 1995 to 2007 for treatment of NMD. Transplantation from a donor mismatched at the HLA-A, -B, -C, or -DRB1, but not -DQB1 or -DPB1, loci was associated with higher mortality in multivariate analyses (P = .002). The hazard ratio for mortality for single (7/8) and double mismatched (6/8) transplants was 1.29 (0.97-1.72; P = .079) and 1.82 (1.30-2.55; P = .0004), respectively, compared with 8/8 matched transplants. HLA mismatches were not associated with acute or chronic GVHD, but were strongly associated with graft failure. After adjustment for other factors, the odds ratio for graft failure for 7/8 and 6/8 (allele and/or antigen) matched pairs compared with 8/8 matched transplants was 2.81 (1.74-4.54; P < .0001) and 2.22 (1.26-3.97; P = .006), respectively. Patients with NMD should receive transplants from allele matched (8/8) donors if possible. Unlike the case with malignancies, HLA mismatching in NMD is associated with graft failure rather than GVHD.
    Blood 07/2012; 120(14):2918-24. · 9.78 Impact Factor
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    ABSTRACT: Selection of a suitable graft for allogeneic hematopoietic stem cell transplantation involves consideration of both donor and recipient characteristics. Of primary importance is sufficient donor-recipient HLA matching to ensure engraftment and acceptable rates of GVHD. In this Perspective, the National Marrow Donor Program and the Center for International Blood and Marrow Transplant Research provide guidelines, based on large studies correlating graft characteristics with clinical transplantation outcomes, on appropriate typing strategies and matching criteria for unrelated adult donor and cord blood graft selection.
    Blood 05/2012; 120(2):259-65. · 9.78 Impact Factor
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    ABSTRACT: DNA sequencing is a powerful technique for identifying allelic variation within the natural killer cell immunoglobulin-like receptor genes. Because of the relatively large size of the KIR genes, each locus is amplified in two or more overlapping segments. Sanger sequencing of each gene from a preparation containing one or two alleles yields a sequence that is used to identify the alleles by comparison with a reference database.
    Methods in molecular biology (Clifton, N.J.) 01/2012; 882:431-68. · 1.29 Impact Factor
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    ABSTRACT: The optimal donor of hematopoietic progenitor cells shares alleles of the major histocompatibility genes with the recipient. This chapter describes the strategies aimed at identifying such a matched donor from registries of volunteers or from umbilical cord blood banks.
    Methods in molecular biology (Clifton, N.J.) 01/2012; 882:531-47. · 1.29 Impact Factor
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    ABSTRACT: The immune responses of natural killer cells are regulated, in part, by killer cell immunoglobulin-like receptors (KIR). The 16 closely-related genes in the KIR gene system have been diversified by gene duplication and unequal crossing over, thereby generating haplotypes with variation in gene copy number. Allelic variation also contributes to diversity within the complex. In this study, we estimated allele-level haplotype frequencies and pairwise linkage disequilibrium statistics for 14 KIR loci. The typing utilized multiple methodologies by four laboratories to provide at least 2x coverage for each allele. The computational methods generated maximum-likelihood estimates of allele-level haplotypes. Our results indicate the most extensive allele diversity was observed for the KIR framework genes and for the genes localized to the telomeric region of the KIR A haplotype. Particular alleles of the stimulatory loci appear to be nearly fixed on specific, common haplotypes while many of the less frequent alleles of the inhibitory loci appeared on multiple haplotypes, some with common haplotype structures. Haplotype structures cA01 and/or tA01 predominate in this cohort, as has been observed in most populations worldwide. Linkage disequilibrium is high within the centromeric and telomeric haplotype regions but not between them and is particularly strong between centromeric gene pairs KIR2DL5∼KIR2DS3S5 and KIR2DS3S5∼KIR2DL1, and telomeric KIR3DL1∼KIR2DS4. Although 93% of the individuals have unique pairs of full-length allelic haplotypes, large genomic blocks sharing specific sets of alleles are seen in the most frequent haplotypes. These high-resolution, high-quality haplotypes extend our basic knowledge of the KIR gene system and may be used to support clinical studies beyond single gene analysis.
    PLoS ONE 01/2012; 7(11):e47491. · 3.53 Impact Factor
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    A M Lazaro, J Henry, J Ng, C K Hurley, P E Posch
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    ABSTRACT: Seventy-two novel human leukocyte antigen (HLA) class I and class II alleles are described from volunteers for the 'Be The Match Registry®': 17 HLA-A alleles, 12 HLA-C alleles, 31 HLA-B alleles and 12 HLA-DRB1 alleles. Forty-six (≈ 64%) of the 72 novel alleles are single-nucleotide substitution variants when compared with their most homologous allele. Five of these single-nucleotide variants are silent substitutions and one creates a non-expressed allele (B*44:108N). The remaining novel alleles differ from their most similar allele by two to five nucleotide substitutions. One of the novel HLA-C alleles (C*07:150Q) is of questionable expression due to an insertion of 21 nucleotides starting at codon 143 that adds seven amino acids to exon 3. An inter-locus gene conversion may have created the novel allele HLA-A*23:31 that shares its codon differences with HLA-B*07:28. Some of the new alleles encode novel codons and unique amino acid changes at polymorphic positions in the HLA-A (codons 116 and 150), HLA-C (codon 114), HLA-B (codons 11, 21, 35, 42, 48, 73, 98 and 170) and HLA-DRB1 (codon 29) loci.
    Tissue Antigens 01/2012; 79(1):50-7. · 2.93 Impact Factor
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    ABSTRACT: Histocompatibility testing for stem cell and solid organ transplantation has become increasingly complex as newly discovered HLA alleles are described. HLA typing assignments reported by laboratories are used by physicians and donor registries for matching donors and recipients. To communicate effectively, a common language for histocompatibility terms should be established. In early 2010, representatives from Clinical, Registry, and Histocompatibility organizations joined together as the Harmonization of Histocompatibility Typing Terms Working Group to define a consensual language for laboratories, physicians, and registries to communicate histocompatibility typing information. The Working Group defined terms for HLA typing resolution, HLA matching, and a format for reporting HLA assignments. In addition, definitions of verification typing and extended typing were addressed. The original draft of the Definitions of Histocompatibility Typing Terms was disseminated to colleagues from each organization to gain feedback and create a collaborative document. Commentary gathered during this 90-day review period were discussed and implemented for preparation of this report. Histocompatibility testing continues to evolve; thus, the definitions agreed on today probably will require refinement and perhaps additional terminology in the future.
    Blood 12/2011; 118(23):e180-3. · 9.78 Impact Factor
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    ABSTRACT: Currently, there is no well-accepted rating system for reliably predicting which HLA-mismatched (MM) unrelated donor should be selected for a patient without an HLA allele-matched donor. We evaluated the ability of an MM ranking system, HistoCheck, to predict the risk associated with HLA class I disparity in a population of 744 single allele or antigen HLA-A, -B, or -C MM myeloablative unrelated donor hematopoietic stem cell transplantation recipients with acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome, facilitated through the National Marrow Donor Program between 1988 and 2003. Multivariate models were used to adjust for other significant clinical risk factors. HLA MMs were scored using the HistoCheck Web-based tool, and the patients were divided into 4 quartiles: dissimilarity score (DSS) 1.04-2.84 (allele MM), DSS >2.84-13.75 (allele and antigen MM), DSS >13.75-19.39 (antigen MM), and DSS >19.39-36.62 (antigen MM). Using the lowest scoring quartile as the reference, the DSS groups were evaluated for associations with relapse, treatment-related mortality, acute and chronic graft-versus-host disease, leukemia-free survival, and overall survival in the entire cohort and also in subset analyses by disease and disease stage. No significant associations were found between DSS and any outcomes in the overall cohort using the quartile categories or treating DSS as a continuous variable. Higher DSS scores were associated with decreased engraftment in early-stage disease (P = .0003), but not in other disease stages. In summary, DSS does not correlate with transplantation outcomes, and the HistoCheck scoring system does not provide an effective technique for ranking HLA class I MM. The dataset used in this study is available to evaluate new algorithms proposed for donor selection.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2011; 18(5):739-46. · 3.15 Impact Factor

Publication Stats

5k Citations
738.74 Total Impact Points

Institutions

  • 1988–2014
    • Georgetown University
      • • Department of Pediatrics
      • • Department of Oncology
      • • Department of Microbiology and Immunology
      • • Department of Neurology
      • • Lombardi Cancer Center
      Washington, Washington, D.C., United States
  • 2012
    • Medical College of Wisconsin
      • Center for International Blood & Marrow Transplant Research
      Milwaukee, WI, United States
  • 1995–2012
    • Washington DC VA Medical Center
      Washington, Washington, D.C., United States
  • 2003–2011
    • National Marrow Donor Program
      Minneapolis, Minnesota, United States
  • 2010
    • Anthony Nolan Research Institute
      Londinium, England, United Kingdom
  • 2008–2010
    • Children's Hospital Oakland Research Institute
      Oakland, California, United States
    • Galliera Hospital
      Genova, Liguria, Italy
    • Jaeb Center for Health Research
      Tampa, Florida, United States
    • University of Washington Seattle
      • Department of Microbiology
      Seattle, WA, United States
    • Red Cross
      • HLA Laboroatory
      Washington, Washington, D.C., United States
    • Emory University
      • Department of Pathology and Laboratory Medicine
      Atlanta, GA, United States
  • 2009
    • University of California, Berkeley
      Berkeley, California, United States
    • Australian Red Cross
      Melbourne, Victoria, Australia
    • University of California, San Francisco
      San Francisco, California, United States
  • 2007
    • Fred Hutchinson Cancer Research Center
      • Division of Clinical Research
      Seattle, WA, United States
  • 2006
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
  • 2001
    • University of Minnesota Medical Center, Fairview
      Minneapolis, Minnesota, United States
  • 2000
    • Chulalongkorn University
      • Department of Microbiology
      Bangkok, Bangkok, Thailand
  • 1998
    • Hallym University
      • College of Medicine
      Seoul, Seoul, South Korea
  • 1989
    • Georgetown Hospital System
      Georgetown, South Carolina, United States
    • American University Washington D.C.
      Washington, Washington, D.C., United States
  • 1987
    • Howard University Hospital
      Washington, Washington, D.C., United States