Bio

Bio


Marcelo Fernández-Viña, Ph.D., D (ABHI) is a Professor for the Department of Pathology at Stanford University Medical School and serves as Director of the Histocompatibility, Immunogenetics and Disease Profiling Laboratory at this institution. He has been working in the fields of Histocompatibility and Immunogenetics since 1982. He earned a degree in Biochemistry from the School of Basic Sciences in Rosario, Argentina, and his Ph.D. in Internal Medicine from the University of Buenos Aires Medical School in Argentina. Previously he held a position as a Professor in the Department of Laboratory Medicine at the University of Texas M.D. Anderson Cancer Center in Houston. He has more than 180 peer reviewed publications, many of them focusing on HLA variation in multiple world populations, identifying susceptibility and resistance factors for diseases and in the impact of HLA mismatches in allogeneic transplantation; and 59 book chapters. He served as expert Consultant for Donor Searches for NMDP and as President Elect, President and Past President of the American Society for Histocompatibility and Immunogenetics. He served as a member of the Board of Directors and the Executive Committee for the United Network for Organ Sharing. He served as Co-Chair of the Immunobiology Committee of the CIBMTR; He also served as a member of the HHS Advisory Council on Blood Stem Cell Transplantation (ACBSCT).He serves as HLA Expert Consultant for the NMDP for the HRSA contract and is a member of the Histocompatibility Advisory Group for NMDP. He is Councilor of the International Histocompatibility Workshop and a member of the WHO Nomenclature Committee for Factors of the HLA System and was Chairman of the (17th) International HLA & Immunogenetics Workshop, and current President of the International HLA & Immunogenetics Workshop. He is Section Editor of Human Immunology and an Advisory Board Member of the International Journal of Immunogenetics and Bone Marrow Transplantation.

Academic Appointments


Teaching

2019-20 Courses


Publications

All Publications


  • Selection of Unrelated Donors and Cord Blood Units for Hematopoietic Cell Transplantation: Guidelines from NMDP/CIBMTR. Blood Dehn, J., Spellman, S., Hurley, C. K., Shaw, B. E., Barker, J. N., Burns, L. J., Confer, D. L., Eapen, M., Fernandez-Vina, M. A., Hartzman, R., Maiers, M., Marino, S. R., Mueller, C., Perales, M., Rajalingam, R., Pidala, J. 2019

    Abstract

    Allogeneic hematopoietic cell transplantation involves consideration of both donor and recipient characteristics to guide the selection of a suitable graft. Sufficient high resolution donor-recipient human leukocyte antigen (HLA) match is of primary importance in transplantation with adult unrelated donors, using conventional graft-versus-host disease prophylaxis. In cord blood transplantation, optimal unit selection requires consideration of unit quality, cell dose and HLA-match. In this summary, the National Marrow Donor Program (NMDP) and the Center for International Blood and Marrow Transplant Research (CIBMTR), jointly with the NMDP Histocompatibility Advisory Group, provide evidence-based guidelines for optimal selection of unrelated donors and cord blood units.

    View details for DOI 10.1182/blood.2019001212

    View details for PubMedID 31292117

  • HLA alleles and haplotypes observed in 263 US families. Human immunology Osoegawa, K., Mallempati, K. C., Gangavarapu, S., Oki, A., Gendzekhadze, K., Marino, S. R., Brown, N. K., Bettinotti, M. P., Weimer, E. T., Montero-Martin, G., Creary, L. E., Vayntrub, T. A., Chang, C., Askar, M., Mack, S. J., Fernandez-Vina, M. A. 2019

    Abstract

    The 17th International HLA and Immunogenetics Workshop (IHIW) conducted a project entitled "The Study of Haplotypes in Families by NGS HLA". We investigated the HLA haplotypes of 1017 subjects in 263 nuclear families sourced from five US clinical immunogenetics laboratories, primarily as part of the evaluation of related donor candidates for hematopoietic stem cell and solid organ transplantation. The parents in these families belonged to five broad groups - African (72 parents), Asian (115), European (210), Hispanic (118) and "Other" (11). High-resolution HLA genotypes were generated for each subject using next-generation sequencing (NGS) HLA typing systems. We identified the HLA haplotypes in each family using HaplObserve, software that builds haplotypes in families by reviewing HLA allele segregation from parents to children. We calculated haplotype frequencies within each broad group, by treating the parents in each family as unrelated individuals. We also calculated standard measures of global linkage disequilibrium (LD) and conditional asymmetric LD for each ethnic group, and used untruncated and two-field allele names to investigate LD patterns. Finally we demonstrated the utility of consensus DNA sequences in identifying novel variants, confirming them using HLA allele segregation at the DNA sequence level.

    View details for DOI 10.1016/j.humimm.2019.05.018

    View details for PubMedID 31256909

  • The European Society for Blood and Marrow Transplantation (EBMT) Consensus Guidelines for the Detection and Treatment of Donor-specific Anti-HLA Antibodies (DSA) in Haploidentical Hematopoietic Cell Transplantation (vol 53, pg 521, 2018) BONE MARROW TRANSPLANTATION Ciurea, S. O., Cao, K., Fernandez-Vina, M., Kongtim, P., Al Malki, M., Fuchs, E., Luznik, L., Huang, X., Ciceri, F., Locatelli, F., Aversa, F., Castagna, L., Bacigalupo, A., Martelli, M., Blaise, D., Handgretinger, R., Roy, D., O'Donnell, P., Bashey, A., Lazarus, H. M., Ballen, K., Savani, B. N., Mohty, M., Nagler, A. 2019; 54 (5): 784
  • Deconstruction of HLA-DRB1*04:01:01 and HLA-DRB1*15:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis MULTIPLE SCLEROSIS JOURNAL Creary, L. E., Mallempati, K. C., Gangavarapu, S., Caillier, S. J., Oksenberg, J. R., Fernandez-Vina, M. A. 2019; 25 (6): 772?82
  • A specific amino acid motif of HLA-DRB1 mediates risk and interacts with smoking history in Parkinson's disease PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Hollenbach, J. A., Norman, P. J., Creary, L. E., Damotte, V., Montero-Martin, G., Caillier, S., Anderson, K. M., Misra, M. K., Nemat-Gorgani, N., Osoegawa, K., Santaniello, A., Renschen, A., Marin, W. M., Dandekar, R., Parham, P., Tanner, C. M., Hauser, S. L., Fernandez-Vina, M., Oksenberg, J. R. 2019; 116 (15): 7419?24
  • A specific amino acid motif of HLA-DRB1 mediates risk and interacts with smoking history in Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America Hollenbach, J. A., Norman, P. J., Creary, L. E., Damotte, V., Montero-Martin, G., Caillier, S., Anderson, K. M., Misra, M. K., Nemat-Gorgani, N., Osoegawa, K., Santaniello, A., Renschen, A., Marin, W. M., Dandekar, R., Parham, P., Tanner, C. M., Hauser, S. L., Fernandez-Vina, M., Oksenberg, J. R. 2019

    Abstract

    Parkinson's disease (PD) is a neurodegenerative disease in which genetic risk has been mapped to HLA, but precise allelic associations have been difficult to infer due to limitations in genotyping methodology. Mapping PD risk at highest possible resolution, we performed sequencing of 11 HLA genes in 1,597 PD cases and 1,606 controls. We found that susceptibility to PD can be explained by a specific combination of amino acids at positions 70-74 on the HLA-DRB1 molecule. Previously identified as the primary risk factor in rheumatoid arthritis and referred to as the "shared epitope" (SE), the residues Q/R-K/R-R-A-A at positions 70-74 in combination with valine at position 11 (11-V) is highly protective in PD, while risk is attributable to the identical epitope in the absence of 11-V. Notably, these effects are modified by history of cigarette smoking, with a strong protective effect mediated by a positive history of smoking in combination with the SE and 11-V (P = 10-4; odds ratio, 0.51; 95% confidence interval, 0.36-0.72) and risk attributable to never smoking in combination with the SE without 11-V (P = 0.01; odds ratio, 1.51; 95% confidence interval, 1.08-2.12). The association of specific combinations of amino acids that participate in critical peptide-binding pockets of the HLA class II molecule implicates antigen presentation in PD pathogenesis and provides further support for genetic control of neuroinflammation in disease. The interaction of HLA-DRB1 with smoking history in disease predisposition, along with predicted patterns of peptide binding to HLA, provide a molecular model that explains the unique epidemiology of smoking in PD.

    View details for PubMedID 30910980

  • Next-generation HLA typing of 382 International Histocompatibility Working Group reference B-Lymphoblastoid cell lines: report from the 17th International HLA and Immunogenetics Workshop. Human immunology Creary, L. E., Guerra, S. G., Chong, W., Brown, C. J., Turner, T. R., Robinson, J., Bultitude, W. P., Mayor, N. P., Marsh, S. G., Saito, K., Lam, K., Duke, J. L., Mosbruger, T. L., Ferriola, D., Monos, D., Willis, A., Askar, M., Fischer, G., Loong Saw, C., Ragoussis, I., Petrek, M., Serra-Pages, C., Juan Otero, M., Stavropoulos-Giokas, C., Dinou, A., Ameen, R., Al Shemmari, S., Spierings, E., Gendzekhadze, K., Morris, G. P., Zhang, Q., Kashi, Z., Hsu, S., Gangavarapu, S., Mallempati, K. C., Yamamoto, F., Osoegawa, K., Vayntrub, T., Chang, C., Hansen, J. A., Fernandez-Vina, M. A. 2019

    Abstract

    Extended molecular characterization of HLA genes in the IHWG reference B-lymphoblastoid cell lines (B-LCLs) was one of the major goals for the 17th International HLA and Immunogenetics Workshop (IHIW). Although reference B-LCLs have been examined extensively in previous workshops complete high-resolution typing was not completed for all the classical class I and class II HLA genes. To address this, we conducted a single-blind study where select panels of B-LCL genomic DNA samples were distributed to multiple laboratories for HLA genotyping by next-generation sequencing methods. Identical cell panels comprised of 24 and 346 samples were distributed and typed by at least four laboratories in order to derive accurate consensus HLA genotypes. Overall concordance rates calculated at both 2- and 4-field allele-level resolutions ranged from 90.4% to 100%. Concordance for the class I genes ranged from 91.7 to 100%, whereas concordance for class II genes was variable; the lowest observed at HLA-DRB3 (84.2%). At the maximum allele-resolution 78 B-LCLs were defined as homozygous for all 11 loci. We identified 11 novel exon polymorphisms in the entire cell panel. A comparison of the B-LCLs NGS HLA genotypes with the HLA genotypes catalogued in the IPD-IMGT/HLA Database Cell Repository, revealed an overall allele match at 68.4%. Typing discrepancies between the two datasets were mostly due to the lower-resolution historical typing methods resulting in incomplete HLA genotypes for some samples listed in the IPD-IMGT/HLA Database Cell Repository. Our approach of multiple-laboratory NGS HLA typing of the B-LCLs has provided accurate genotyping data. The data generated by the tremendous collaborative efforts of the 17th IHIW participants is useful for updating the current cell and sequence databases and will be a valuable resource for future studies.

    View details for PubMedID 30844424

  • Letter to the Editor regarding "Recipients receiving better HLA-matched hematopoietic cell transplantation grafts, uncovered by a novel HLA typing method, have superior survival: A retrospective study": 2019 May 2 Letter to the Editor Biology of Blood and Marrow Transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Hurley, C. K., Spellman, S., Dehn, J., Barker, J. N., Devine, S., Fernandez-Vina, M., Gautreaux, M., Logan, B., Maiers, M., Mueller, C., Perales, M. A., Yu, N., Pidala, J. 2019

    View details for DOI 10.1016/j.bbmt.2019.05.026

    View details for PubMedID 31145991

  • Correction: The European Society for Blood and Marrow Transplantation (EBMT) Consensus Guidelines for the Detection and Treatment of Donor-specific Anti-HLA Antibodies (DSA) in Haploidentical Hematopoietic Cell Transplantation. Bone marrow transplantation Ciurea, S. O., Cao, K., Fernandez-Vina, M., Kongtim, P., Malki, M. A., Fuchs, E., Luznik, L., Huang, X., Ciceri, F., Locatelli, F., Aversa, F., Castagna, L., Bacigalupo, A., Martelli, M., Blaise, D., Handgretinger, R., Roy, D., O'Donnell, P., Bashey, A., Lazarus, H. M., Ballen, K., Savani, B. N., Mohty, M., Nagler, A. 2018

    Abstract

    The original version of this Article contained a typographical error in the spelling of the author Marcelo Fernandez-Vina, which was incorrectly given as Marcelo Fernadez-Vina. This has now been corrected in the PDF and HTML versions of the Article.

    View details for PubMedID 30232413

  • Donor-specific anti-HLA antibodies in unrelated hematopoietic cell transplantation for non-malignant disorders. Bone marrow transplantation Woolfrey, A., Wang, T., Lee, S. J., Haagenson, M. D., Chen, G., Fleischhauer, K., Horan, J., Hsu, K., Verneris, M., Spellman, S. R., Fernandez-Vina, M. 2018

    View details for DOI 10.1038/s41409-018-0334-y

    View details for PubMedID 30232414

  • The European Society for Blood and Marrow Transplantation (EBMT) Consensus Guidelines for the Detection and Treatment of Donor-specific Anti-HLA Antibodies (DSA) in Haploidentical Hematopoietic Cell Transplantation BONE MARROW TRANSPLANTATION Ciurea, S. O., Cao, K., Fernadez-Vina, M., Kongtim, P., Al Malki, M., Fuchs, E., Luznik, L., Huang, X., Ciceri, F., Locatelli, F., Aversa, F., Castagna, L., Bacigalupo, A., Martelli, M., Blaise, D., Handgretinger, R., Roy, D., O'Donnell, P., Bashey, A., Lazarus, H. M., Ballen, K., Savani, B. N., Mohty, M., Nagler, A. 2018; 53 (5): 521?34

    Abstract

    Haploidentical donors are now increasingly considered for transplantation in the absence of HLA-matched donors or when an urgent transplant is needed. Donor-specific anti-HLA antibodies (DSA) have been recently recognized as an important barrier against successful engraftment of donor cells, which can affect transplant survival. DSA appear more prevalent in this type of transplant due to higher likelihood of alloimmunization of multiparous females against offspring's HLA antigens, and the degree of mismatch. Here we summarize the evidence for the role of DSA in the development of primary graft failure in haploidentical transplantation and provide consensus recommendations from the European Society for Blood and Marrow Transplant Group on testing, monitoring, and treatment of patients with DSA receiving haploidentical hematopoietic progenitor cell transplantation.

    View details for PubMedID 29335625

  • Diversity in exon 5 of HLA-C*04:01:01G is significant in anthropological studies (vol 77, pg 426, 2016) HUMAN IMMUNOLOGY Dunn, P. J., Lamb, G., Selwyn, C., Compton, J., Yang, E., Maiers, M., Fernandez-Vina, M. 2016; 77 (10): 1004

    View details for PubMedID 27345146

  • Are changes in HLA Ags responsible for leukemia relapse after HLA-matched allogeneic hematopoietic SCT? Bone marrow transplantation Hamdi, A., Cao, K., Poon, L. M., Aung, F., Kornblau, S., Fernandez Vina, M. A., Champlin, R. E., Ciurea, S. O. 2015; 50 (3): 411-413

    Abstract

    Loss of heterozygosity (LOH) has been shown to be associated with leukemia relapse after haploidentical transplantation. Whether such changes are an important cause of relapse after HLA-matched transplantation remains unclear. We retrospectively HLA-typed leukemic blasts for 71 patients with AML/myelodysplastic syndrome obtained from stored samples, and the results were compared with those obtained at diagnosis and/or before the transplant. No LOH or any other changes in HLA Ag were found in any of the samples tested post transplant as compared with pretransplant specimens. One patient had LOH in HLA class I Ag (HLA-A,-B and -C); however, these changes were present in the pretransplant sample indicating that they occurred before the transplant. We concluded that, in contrast with haploidentical transplantation, HLA loss does not have a major role as a mechanism of relapse after allogeneic transplantation with a closely HLA-matched donor.

    View details for DOI 10.1038/bmt.2014.285

    View details for PubMedID 25621795

  • HLA-DPB1 and HLA Class I Confer Risk of and Protection from Narcolepsy. American journal of human genetics Ollila, H. M., Ravel, J., Han, F., Faraco, J., Lin, L., Zheng, X., Plazzi, G., Dauvilliers, Y., Pizza, F., Hong, S., Jennum, P., Knudsen, S., Kornum, B. R., Dong, X. S., Yan, H., Hong, H., Coquillard, C., Mahlios, J., Jolanki, O., Einen, M., Lavault, S., Högl, B., Frauscher, B., Crowe, C., Partinen, M., Huang, Y. S., Bourgin, P., Vaarala, O., Désautels, A., Montplaisir, J., Mack, S. J., Mindrinos, M., Fernandez-Vina, M., Mignot, E. 2015; 96 (1): 136-146

    Abstract

    Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1(?)01:02-DQB1(?)06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1(?)01:03-DPB1(?)04:02 (DP0402; odds ratio [OR] = 0.51 [0.38-0.67], p = 1.01 × 10(-6)) and HLA-DPA1(?)01:03-DPB1(?)04:01 (DP0401; OR = 0.61 [0.47-0.80], p = 2.07 × 10(-4)) and predisposing effects of HLA-DPB1(?)05:01 in Asians (OR = 1.76 [1.34-2.31], p = 4.71 × 10(-05)). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38-0.55] p = 8.99 × 10(-17)) and DP0501 (OR = 1.38 [1.18-1.61], p = 7.11 × 10(-5)). HLA-class-II-independent associations with HLA-A(?)11:01 (OR = 1.32 [1.13-1.54], p = 4.92 × 10(-4)), HLA-B(?)35:03 (OR = 1.96 [1.41-2.70], p = 5.14 × 10(-5)), and HLA-B(?)51:01 (OR = 1.49 [1.25-1.78], p = 1.09 × 10(-5)) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza.

    View details for DOI 10.1016/j.ajhg.2014.12.010

    View details for PubMedID 25574827

    View details for PubMedCentralID PMC4289679

  • Recommendations for Donor Human Leukocyte Antigen Assessment and Matching for Allogeneic Stem Cell Transplantation: Consensus Opinion of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biology of blood and marrow transplantation Howard, C. A., Fernandez-Vina, M. A., Appelbaum, F. R., Confer, D. L., Devine, S. M., Horowitz, M. M., Mendizabal, A., Laport, G. G., Pasquini, M. C., Spellman, S. R. 2015; 21 (1): 4-7

    Abstract

    The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) conducts large, multi-institutional clinical trials with the goal of improving the outcomes of hematopoietic cell transplantation (HCT) for patients with life-threatening disorders. Well-designed HCT trials benefit from standardized criteria for defining diagnoses, treatment plans, and graft source selection. In this perspective, we summarize evidence supporting criteria for the selection of related and unrelated adult volunteer progenitor cell donors or umbilical cord blood units. These standardized criteria for graft source selection have been adopted by the BMT CTN to enhance the interpretation of clinical findings within and among future clinical protocols.

    View details for DOI 10.1016/j.bbmt.2014.09.017

    View details for PubMedID 25278457

    View details for PubMedCentralID PMC4272893

  • Complement-Binding Donor-Specific Anti-HLA Antibodies and Risk of Primary Graft Failure in Hematopoietic Stem Cell Transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Ciurea, S. O., Thall, P. F., Milton, D. R., Barnes, T. H., Kongtim, P., Carmazzi, Y., López, A. A., Yap, D. Y., Popat, U., Rondon, G., Lichtiger, B., Aung, F., Afshar-Kharghan, V., Ma, Q., Fernández-Viña, M., Champlin, R. E., Cao, K. 2015; 21 (8): 1392?98

    Abstract

    Detection of donor-specific anti-HLA antibodies (DSA) has been associated with graft rejection in all forms of transplantation. The mechanism by which DSA increase the risk of graft failure remains unclear. We hypothesized that complement-binding DSA are associated with engraftment failure in hematopoietic stem cell transplantation (HSCT) and analyzed 122 haploidentical transplant recipients tested prospectively for DSA. Retrospective analysis to detect C1q binding DSA (C1q+DSA) was performed on 22 allosensitized recipients. Twenty-two of 122 patients (18%) had DSA, 19 of which were women (86%). Seven patients with DSA (32%) rejected the graft. Median DSA level at transplant for patients who failed to engraft was 10,055 mean fluorescence intensity (MFI) versus 2065 MFI for those who engrafted (P = .007). Nine patients with DSA were C1q positive in the initial samples with median DSA levels of 15,279 MFI (range, 1554 to 28,615), compared with 7 C1q-negative patients with median DSA levels of 2471 MFI (range, 665 to 12,254) (P = .016). Of 9 patients who were C1q positive in the initial samples, 5 patients remained C1q positive at time of transplant (all with high DSA levels [median, 15,279; range, 6487 to 22,944]) and experienced engraftment failure, whereas 4 patients became C1q negative pretransplant and all engrafted the donor cells (P = .008). In conclusion, patients with high DSA levels (>5000 MFI) and complement-binding DSA antibodies (C1q positive) appear to be at much higher risk of primary graft failure. The presence of C1q+DSA should be assessed in allosensitized patients before HSCT. Reduction of C1q+DSA levels might prevent engraftment failure in HSCT.

    View details for PubMedID 25985919

  • HLA-DQ Allele Competition in Narcolepsy: A Comment on Tafti et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe SLEEP Ollila, H. M., Fernandez-Vina, M., Mignot, E. 2015; 38 (1): 147-151

    Abstract

    Although HLA-DQB1*06:02 is the strongest predisposing genetic factor for narcolepsy, the effect of this gene must be considered alongside that of its polymorphic partner, DQA1. In this paper, we extend an analysis of the effect of HLA-DQB1 on narcolepsy risk published recently by Tafti et al.Imputing allelic variation at the level of HLA-DQA1, we show that this locus also has a considerable effect on disease susceptibility. Our data are also compatible with previous findings in multi-ethnic group data sets showing that allele competition effects within the DQ1 group determine the amount of DQ0602 (the DQA1*01:02/DQB1*06:02 heterodimer), and consequently, the risk of developing narcolepsy. We also found an independent predisposing effect of DQB1*03:01 via a currently unknown mechanism.Both DQA1 and DQB1 influence narcolepsy risk.

    View details for DOI 10.5665/sleep.4342

    View details for Web of Science ID 000347169300017

    View details for PubMedID 25325462

    View details for PubMedCentralID PMC4262948

  • HLA allotype expressivity in transplantation BLOOD Fernandez-Vina, M. 2014; 124 (26): 3839?40

    View details for PubMedID 25525081

  • HLA DQB1*06:02 Negative Narcolepsy with Hypocretin/Orexin Deficiency SLEEP Han, F., Lin, L., Schormair, B., Pizza, F., Plazzi, G., Ollila, H. M., Nevsimalova, S., Jennum, P., Knudsen, S., Winkelmann, J., Coquillard, C., Babrzadeh, F., Strom, T. M., Wang, C., Mindrinos, M., Vina, M. F., Mignot, E. 2014; 37 (10): 1601-1608

    Abstract

    To identify rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02.China (Peking University People's Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy (University of Bologna), Korea (Catholic University), and USA (Stanford University).CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with and 144 without cataplexy) from 6 sites. Numbers of cases with and without DQB1*06:02 and low CSF hypocretin-1 were compiled. HLA class I (A, B, C), class II (DRBs, DQA1, DQB1, DPA1, and DPB1), and whole exome sequencing were conducted in 9 DQB1*06:02 negative cases with low CSF hypocretin-1. Sanger sequencing of selected exons in DNMT1, HCRT, and MOG was performed to exclude mutations in known narcolepsy-associated genes.Classic narcolepsy markers DQB1*06:02 and low CSF hypocretin-1 were found in 87.4% of cases with cataplexy, and in 20.0% without cataplexy. Nine cases (all with cataplexy) were DQB1*06:02 negative with low CSF hypocretin-1, constituting 1.7% [0.8%-3.4%] of all cases with cataplexy and 1.8% [0.8%-3.4%] of cases with low CSF hypocretin independent of cataplexy across sites. Five HLA negative subjects had severe cataplexy, often occurring without clear triggers. Subjects had diverse ethnic backgrounds and HLA alleles at all loci, suggesting no single secondary HLA association. The rare subtype DPB1*0901, and homologous DPB1*10:01 subtype, were present in 5 subjects, suggesting a secondary association with HLA-DP. Preprohypocretin sequencing revealed no mutations beyond one previously reported in a very early onset case. No new MOG or DNMT1 mutations were found, nor were suspicious or private variants in novel genes identified through exome sequencing.Hypocretin, MOG, or DNMT1 mutations are exceptional findings in DQB1*06:02 negative cases with hypocretin deficiency. A secondary HLA-DP association may be present in these cases. These represent particularly difficult diagnostic challenges.

    View details for DOI 10.5665/sleep.4066

    View details for Web of Science ID 000343147400006

    View details for PubMedCentralID PMC4173917

  • HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency. Sleep Han, F., Lin, L., Schormair, B., Pizza, F., Plazzi, G., Ollila, H. M., Nevsimalova, S., Jennum, P., Knudsen, S., Winkelmann, J., Coquillard, C., Babrzadeh, F., Strom, T. M., Wang, C., Mindrinos, M., Fernandez Vina, M., Mignot, E. 2014; 37 (10): 1601-1608

    Abstract

    To identify rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02.China (Peking University People's Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy (University of Bologna), Korea (Catholic University), and USA (Stanford University).CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with and 144 without cataplexy) from 6 sites. Numbers of cases with and without DQB1*06:02 and low CSF hypocretin-1 were compiled. HLA class I (A, B, C), class II (DRBs, DQA1, DQB1, DPA1, and DPB1), and whole exome sequencing were conducted in 9 DQB1*06:02 negative cases with low CSF hypocretin-1. Sanger sequencing of selected exons in DNMT1, HCRT, and MOG was performed to exclude mutations in known narcolepsy-associated genes.Classic narcolepsy markers DQB1*06:02 and low CSF hypocretin-1 were found in 87.4% of cases with cataplexy, and in 20.0% without cataplexy. Nine cases (all with cataplexy) were DQB1*06:02 negative with low CSF hypocretin-1, constituting 1.7% [0.8%-3.4%] of all cases with cataplexy and 1.8% [0.8%-3.4%] of cases with low CSF hypocretin independent of cataplexy across sites. Five HLA negative subjects had severe cataplexy, often occurring without clear triggers. Subjects had diverse ethnic backgrounds and HLA alleles at all loci, suggesting no single secondary HLA association. The rare subtype DPB1*0901, and homologous DPB1*10:01 subtype, were present in 5 subjects, suggesting a secondary association with HLA-DP. Preprohypocretin sequencing revealed no mutations beyond one previously reported in a very early onset case. No new MOG or DNMT1 mutations were found, nor were suspicious or private variants in novel genes identified through exome sequencing.Hypocretin, MOG, or DNMT1 mutations are exceptional findings in DQB1*06:02 negative cases with hypocretin deficiency. A secondary HLA-DP association may be present in these cases. These represent particularly difficult diagnostic challenges.

    View details for DOI 10.5665/sleep.4066

    View details for PubMedID 25197808

  • Validation of statistical imputation of allele-level multilocus phased genotypes from ambiguous HLA assignments TISSUE ANTIGENS Madbouly, A., Gragert, L., Freeman, J., Leahy, N., Gourraud, P., Hollenbach, J. A., Kamoun, M., Fernandez-Vina, M., Maiers, M. 2014; 84 (3): 285-292

    Abstract

    Genetic matching for loci in the human leukocyte antigen (HLA) region between a donor and a patient in hematopoietic stem cell transplantation (HSCT) is critical to outcome; however, methods for HLA genotyping of donors in unrelated stem cell registries often yield results with allelic and phase ambiguity and/or do not query all clinically relevant loci. We present and evaluate a statistical method for in silico imputation of HLA alleles and haplotypes in large ambiguous population data from the Be The Match(®) Registry. Our method builds on haplotype frequencies estimated from registry populations and exploits patterns of linkage disequilibrium (LD) across HLA haplotypes to infer high resolution HLA assignments. We performed validation on simulated and real population data from the Registry with non-trivial ambiguity content. While real population datasets caused some predictions to deviate from expectation, validations still showed high percent recall for imputed results with average recall >76% when imputing HLA alleles from registry data. We simulated ambiguity generated by several HLA genotyping methods to evaluate the imputation performance on several levels of typing resolution. On average, imputation percent recall of allele-level HLA haplotypes was >95% for allele-level typing, >92% for intermediate resolution typing and >58% for serology (low-resolution) typing. Thus, allele-level HLA assignments can be imputed through the application of a set of statistical and population genetics inferences and with knowledge of haplotype frequencies and self-identified race and ethnicities.

    View details for DOI 10.1111/tan.12390

    View details for Web of Science ID 000341252500005

    View details for PubMedID 25040134

  • Risk associations between HLA-DPB1 T-cell epitope matching and outcome of unrelated hematopoietic cell transplantation are independent of HLA-DPA1. Bone marrow transplantation Fleischhauer, K., Fernandez-Viña, M. A., Wang, T., Haagenson, M., Battiwalla, M., Baxter-Lowe, L. A., Ciceri, F., Dehn, J., Gajewski, J., Hale, G. A., Heemskerk, M. B., Marino, S. R., McCarthy, P. L., Miklos, D., Oudshoorn, M., Pollack, M. S., Reddy, V., Senitzer, D., Shaw, B. E., Waller, E. K., Lee, S. J., Spellman, S. R. 2014; 49 (9): 1176-1183

    Abstract

    HLA-DP antigens are beta-alpha heterodimers encoded by polymorphic HLA-DPB1 and -DPA1 alleles, respectively, in strong linkage disequilibrium (LD) with each other. Non-permissive unrelated donor (UD)-recipient HLA-DPB1 mismatches across three different T-cell epitope (TCE) groups are associated with increased mortality after hematopoietic SCT (HCT), but the role of HLA-DPA1 is unclear. We studied 1281 onco-hematologic patients after 10/10 HLA-matched UD-HCT facilitated by the National Marrow Donor Program. Non-permissive mismatches defined solely by HLA-DPB1 TCE groups were associated with significantly higher risks of TRM compared to permissive mismatches (hazard ratio (HR) 1.30, confidence interval (CI) 1.06-1.53; P=0.009) or allele matches. Moreover, non-permissive HLA-DPB1 TCE group mismatches in the graft versus host (GvH) direction significantly decreased the risk of relapse compared to permissive mismatches (HR 0.55, CI 0.37-0.80; P=0.002) or allele matches. Splitting each group into HLA-DPA1*02:01 positive or negative, in frequent LD with HLA-DPB1 alleles from two of the three TCE groups, or into HLA-DPA1 matched or mismatched, did not significantly alter the observed risk associations. Our findings suggest that the effects of clinically non-permissive HLA-DPB1 TCE group mismatches are independent of HLA-DPA1, and that selection of donors with non-permissive DPB1 TCE mismatches in GvH direction might provide some protection from disease recurrence.

    View details for DOI 10.1038/bmt.2014.122

    View details for PubMedID 24955785

  • Cytotoxic T-lymphocyte antigen-4 single nucleotide polymorphisms are not associated with outcomes after unrelated donor transplantation: a center for international blood and marrow transplant research analysis. Biology of blood and marrow transplantation Sengsayadeth, S., Wang, T., Lee, S. J., Haagenson, M. D., Spellman, S., Fernandez Viña, M. A., Muller, C. R., Verneris, M. R., Savani, B. N., Jagasia, M. 2014; 20 (6): 900-903

    Abstract

    Cytotoxic T-lymphocyte antigen-4 (CTLA-4) plays an essential role in T cell homeostasis by restraining immune responses. AG and GG genotypes of donor CTLA-4 SNP rs4553808 in patients after unrelated donor hematopoietic stem cell transplantations (HSCT) have been shown to be an independent predictor of inferior relapse-free survival (RFS) and overall survival (OS) compared with those with the AA genotype, in single-center studies. We tested the hypothesis that SNP rs4553808 is associated with RFS, OS, nonrelapse mortality (NRM) and the cumulative incidence of acute graft-versus-host disease (GVHD) and chronic GVHD in adults with acute myeloid leukemia and advanced myelodysplastic syndrome undergoing a first 8/8 or 7/8 HLA-matched unrelated donor HSCT. Multivariable analysis adjusting for relevant donor and recipient characteristics showed no significant association between SNP rs4553808 and OS, RFS, NRM, and incidence of acute and chronic GVHD. An exploratory analysis of other CTLA-4 SNPs, as well as studying the interaction with antithymocyte globulin, also demonstrated no significant associations. Our results indicate that CTLA-4 SNPs are not associated with HSCT outcomes.

    View details for DOI 10.1016/j.bbmt.2014.03.005

    View details for PubMedID 24631737

  • Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation. Blood Fernandez-Viña, M. A., Wang, T., Lee, S. J., Haagenson, M., Aljurf, M., Askar, M., Battiwalla, M., Baxter-Lowe, L., Gajewski, J., Jakubowski, A. A., Marino, S., Oudshoorn, M., Marsh, S. G., Petersdorf, E. W., Schultz, K., Turner, E. V., Waller, E. K., Woolfrey, A., Umejiego, J., Spellman, S. R., Setterholm, M. 2014; 123 (8): 1270-1278

    Abstract

    In subjects mismatched in the HLA alleles C*03:03/C*03:04 no allogeneic cytotoxic T-lymphocyte responses are detected in vitro. Hematopoietic stem cell transplantation (HSCT) with unrelated donors (UDs) showed no association between the HLA-C allele mismatches (CAMMs) and adverse outcomes; antigen mismatches at this and mismatches other HLA loci are deleterious. The absence of effect of the CAMM may have resulted from the predominance of the mismatch C*03:03/C*03:04. Patients with hematologic malignancies receiving UD HSCT matched in 8/8 and 7/8 HLA alleles were examined. Transplants mismatched in HLA-C antigens or mismatched in HLA-A, -B, or -DRB1 presented significant differences (P < .0001) in mortality (hazard ratio [HR] = 1.37, 1.30), disease-free survival (HR = 1.33, 1.27), treatment-related mortality (HR = 1.54, 1.54), and grade 3-4 acute graft-versus-host disease (HR = 1.49, 1.77) compared with the 8/8 group; transplants mismatched in other CAMMs had similar outcomes with HR ranging from 1.34 to 172 for these endpoints. The C*03:03/C*03:04 mismatched and the 8/8 matched groups had identical outcomes (HR ranging from 0.96-1.05). The previous finding that CAMMs do not associate with adverse outcomes is explained by the predominance (69%) of the mismatch C*03:03/03:04 in this group that is better tolerated than other HLA mismatches.

    View details for DOI 10.1182/blood-2013-10-532671

    View details for PubMedID 24408320

    View details for PubMedCentralID PMC3931192

  • Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy BLOOD Eapen, M., Klein, J. P., Ruggeri, A., Spellman, S., Lee, S. J., Anasetti, C., Arcese, W., Barker, J. N., Baxter-Lowe, L. A., Brown, M., Fernandez-Vina, M. A., Freeman, J., He, W., Iori, A. P., Horowitz, M. M., Locatelli, F., Marino, S., Maiers, M., Michel, G., Sanz, G. F., Gluckman, E., Rocha, V. 2014; 123 (1): 133-140

    Abstract

    We studied the effect of allele-level matching at human leukocyte antigen (HLA)-A, -B, -C, and -DRB1 in 1568 single umbilical cord blood (UCB) transplantations for hematologic malignancy. The primary end point was nonrelapse mortality (NRM). Only 7% of units were allele matched at HLA-A, -B, -C, and -DRB1; 15% were mismatched at 1, 26% at 2, 30% at 3, 16% at 4, and 5% at 5 alleles. In a subset, allele-level HLA match was assigned using imputation; concordance between HLA-match assignment and outcome correlation was confirmed between the actual and imputed HLA-match groups. Compared with HLA-matched units, neutrophil recovery was lower with mismatches at 3, 4, or 5, but not 1 or 2 alleles. NRM was higher with units mismatched at 1, 2, 3, 4, or 5 alleles compared with HLA-matched units. The observed effects are independent of cell dose and patient age. These data support allele-level HLA matching in the selection of single UCB units.

    View details for DOI 10.1182/blood-2013-05-506253

    View details for Web of Science ID 000329742300024

    View details for PubMedID 24141369

    View details for PubMedCentralID PMC3879902

  • Dual Cases of Type 1 Narcolepsy with Schizophrenia and Other Psychotic Disorders JOURNAL OF CLINICAL SLEEP MEDICINE Canellas, F., Lin, L., Rosa Julia, M., Clemente, A., Vives-Bauza, C., Ollila, H. M., Hong, S. C., Arboleya, S. M., Einen, M. A., Faraco, J., Fernandez-Vina, M., Mignot, E. 2014; 10 (9): 1011-1018

    Abstract

    Cases of narcolepsy in association with psychotic features have been reported but never fully characterized. These patients present diagnostic and treatment challenges and may shed new light on immune associations in schizophrenia.Our case series was gathered at two narcolepsy specialty centers over a 9-year period. A questionnaire was created to improve diagnosis of schizophrenia or another psychotic disorder in patients with narcolepsy. Pathophysiological investigations included full HLA Class I and II typing, testing for known systemic and intracellular/synaptic neuronal antibodies, recently described neuronal surface antibodies, and immunocytochemistry on brain sections to detect new antigens.Ten cases were identified, one with schizoaffective disorder, one with delusional disorder, two with schizophreniform disorder, and 6 with schizophrenia. In all cases, narcolepsy manifested first in childhood or adolescence, followed by psychotic symptoms after a variable interval. These patients had auditory hallucinations, which was the most differentiating clinical feature in comparison to narcolepsy patients without psychosis. Narcolepsy therapy may have played a role in triggering psychotic symptoms but these did not reverse with changes in narcolepsy medications. Response to antipsychotic treatment was variable. Pathophysiological studies did not reveal any known autoantibodies or unusual brain immunostaining pattern. No strong HLA association outside of HLA DQB1*06:02 was found, although increased DRB3*03 and DPA1*02:01 was notable.Narcolepsy can occur in association with schizophrenia, with significant diagnostic and therapeutic challenges. Dual cases maybe under diagnosed, as onset is unusually early, often in childhood. Narcolepsy and psychosis may share an autoimmune pathology; thus, further investigations in larger samples are warranted.

    View details for DOI 10.5664/jcsm.4040

    View details for Web of Science ID 000341999700012

    View details for PubMedID 25142772

    View details for PubMedCentralID PMC4153110

  • Amino acid substitution at peptide-binding pockets of HLA class I molecules increases risk of severe acute GVHD and mortality BLOOD Pidala, J., Wang, T., Haagenson, M., Spellman, S. R., Askar, M., Battiwalla, M., Baxter-Lowe, L. A., Bitan, M., Fernandez-Vina, M., Gandhi, M., Jakubowski, A. A., Maiers, M., Marino, S. R., Marsh, S. G., Oudshoorn, M., Palmer, J., Prasad, V. K., Reddy, V., Ringden, O., Saber, W., Santarone, S., Schultz, K. R., Setterholm, M., Trachtenberg, E., Turner, E. V., Woolfrey, A. E., Lee, S. J., Anasetti, C. 2013; 122 (22): 3651-3658

    Abstract

    HLA disparity has a negative impact on the outcomes of hematopoietic cell transplantation (HCT). We studied the independent impact of amino acid substitution (AAS) at peptide-binding positions 9, 99, 116, and 156, and killer immunoglobulin-like receptor binding position 77 of HLA-A, B, or C, on the risks for grade 3-4 acute graft-versus-host disease (GVHD), chronic GVHD, treatment-related mortality (TRM), relapse, and overall survival. In multivariate analysis, a mismatch at HLA-C position 116 was associated with increased risk for severe acute GVHD (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.15-1.82, P = .0016). Mismatch at HLA-C position 99 was associated with increased transplant-related mortality (HR = 1.37, 95% CI = 1.1-1.69, P = .0038). Mismatch at HLA-B position 9 was associated with increased chronic GVHD (HR = 2.28, 95% CI = 1.36-3.82, P = .0018). No AAS were significantly associated with outcome at HLA-A. Specific AAS pair combinations with a frequency >30 were tested for association with HCT outcomes. Cysteine to tyrosine substitution at position 99 of HLA-C was associated with increased TRM (HR = 1.78, 95% = CI 1.27-2.51, P = .0009). These results demonstrate that donor-recipient mismatch for certain peptide-binding residues of the HLA class I molecule is associated with increased risk for acute and chronic GVHD and death.

    View details for DOI 10.1182/blood-2013-05-501510

    View details for Web of Science ID 000329726200021

    View details for PubMedID 23982174

    View details for PubMedCentralID PMC3837514

  • HLA Class I and Class II Conserved Extended Haplotypes and Their Fragments or Blocks in Mexicans: Implications for the Study of Genetic Diversity in Admixed Populations PLOS ONE Zuniga, J., Yu, N., Barquera, R., Alosco, S., Ohashi, M., Lebedeva, T., Acuna-Alonzo, V., Yunis, M., Granados-Montiel, J., Cruz-Lagunas, A., Vargas-Alarcon, G., Rodriguez-Reyna, T. S., Fernandez-Vina, M., Granados, J., Yunis, E. J. 2013; 8 (9)

    Abstract

    Major histocompatibility complex (MHC) genes are highly polymorphic and informative in disease association, transplantation, and population genetics studies with particular importance in the understanding of human population diversity and evolution. The aim of this study was to describe the HLA diversity in Mexican admixed individuals. We studied the polymorphism of MHC class I (HLA-A, -B, -C), and class II (HLA-DRB1, -DQB1) genes using high-resolution sequence based typing (SBT) method and we structured the blocks and conserved extended haplotypes (CEHs) in 234 non-related admixed Mexican individuals (468 haplotypes) by a maximum likelihood method. We found that HLA blocks and CEHs are primarily from Amerindian and Caucasian origin, with smaller participation of African and recent Asian ancestry, demonstrating a great diversity of HLA blocks and CEHs in Mexicans from the central area of Mexico. We also analyzed the degree of admixture in this group using short tandem repeats (STRs) and HLA-B that correlated with the frequency of most probable ancestral HLA-C/-B and -DRB1/-DQB1 blocks and CEHs. Our results contribute to the analysis of the diversity and ancestral contribution of HLA class I and HLA class II alleles and haplotypes of Mexican admixed individuals from Mexico City. This work will help as a reference to improve future studies in Mexicans regarding allotransplantation, immune responses and disease associations.

    View details for DOI 10.1371/journal.pone.0074442

    View details for Web of Science ID 000326520200031

    View details for PubMedID 24086347

    View details for PubMedCentralID PMC3781075

  • Multiple mismatches at the low expression HLA loci DP, DQ, and DRB3/4/5 associate with adverse outcomes in hematopoietic stem cell transplantation. Blood Fernández-Viña, M. A., Klein, J. P., Haagenson, M., Spellman, S. R., Anasetti, C., Noreen, H., Baxter-Lowe, L. A., Cano, P., Flomenberg, N., Confer, D. L., Horowitz, M. M., Oudshoorn, M., Petersdorf, E. W., Setterholm, M., Champlin, R., Lee, S. J., de Lima, M. 2013; 121 (22): 4603-4610

    Abstract

    A single mismatch in highly expressed HLA-A, -B, -C, and -DRB1 loci (HEL) is associated with worse outcomes in hematopoietic stem cell transplantation, while less is known about the cumulative impact of mismatches in the lesser expressed HLA loci DRB3/4/5, DQ, and DP (LEL). We studied whether accumulation of LEL mismatches is associated with deleterious effects in 3853 unrelated donor transplants stratified according to number of matches in the HEL. In the 8/8 matched HEL group, LEL mismatches were not associated with any adverse outcome. Mismatches at HLA-DRB1 were associated with occurrence of multiple LEL mismatches. In the 7/8 HEL group, patients with 3 or more LEL mismatches scored in the graft-versus-host vector had a significantly higher risk of mortality (1.45 and 1.43) and transplant-related mortality (1.68 and 1.54) than the subgroups with 0 or 1 LEL mismatches. No single LEL locus had a more pronounced effect on clinical outcome. Three or more LEL mismatches are associated with lower survival after 7/8 HEL matched transplantation. Prospective evaluation of matching for HLA-DRB3/4/5, -DQ, and -DP loci is warranted to reduce posttransplant risks in donor-recipient pairs matched for 7/8 HEL.

    View details for DOI 10.1182/blood-2013-02-481945

    View details for PubMedID 23596045

    View details for PubMedCentralID PMC3668493

  • Birth Order and Transplantation Outcome in HLA-Identical Sibling Stem Cell Transplantation: An Analysis on Behalf of the Center for International Blood and Marrow Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Dobbelstein, C., Ahn, K. W., Haagenson, M., Hale, G. A., Van Rood, J. J., Miklos, D., Waller, E. K., Spellman, S. R., Fernandez-Vina, M., Ganser, A., Aljurf, M., Bornhaeuser, M., Gupta, V., Marino, S. R., Pollack, M. S., Reddy, V., Eder, M., Lee, S. J. 2013; 19 (5): 741-745

    Abstract

    Allogeneic stem cell transplantation (SCT) is the most effective treatment option for many hematologic malignancies, but graft-versus-host disease (GVHD) remains a major cause of treatment failure. Along with well-established risk factors for transplantation outcomes, recent single-center studies have identified a birth order effect in HLA-identical sibling SCT, with lower rates of acute and chronic GVHD and improved overall survival when the donor is younger than the recipient. One hypothesized mechanism for this effect is microchimerism due to fetomaternal and transmaternal sibling cell trafficking during pregnancy as the donor is exposed to recipient antigens in utero. The aim of the present study was to validate previously reported single-center data in a large, multicenter cohort provided by the Center for International Blood and Marrow Transplantation. All adult and pediatric patients (n = 11,365) with a hematologic malignancy who underwent allogeneic SCT with a graft from an HLA-identical sibling donor between 1990 and 2007 were included. When donors were younger than recipients, there was a significantly lower rate of acute GVHD grade II-IV and chronic GVHD in children, as well as a lower rate of chronic GVHD in adolescents. However, the hypothesized overall positive effect of lower relapse and better survival when donors are younger than recipients was not observed. Our data suggest that if otherwise equally matched, a graft from a younger sibling may be superior to a graft from an older sibling for children and adolescents undergoing SCT.

    View details for DOI 10.1016/j.bbmt.2013.01.020

    View details for Web of Science ID 000318132500010

    View details for PubMedID 23380341

  • Common and well-documented HLA alleles: 2012 update to the CWD catalogue TISSUE ANTIGENS Mack, S. J., Cano, P., Hollenbach, J. A., He, J., Hurley, C. K., Middleton, D., Moraes, M. E., Pereira, S. E., Kempenich, J. H., Reed, E. F., Setterholm, M., Smith, A. G., Tilanus, M. G., Torres, M., Varney, M. D., Voorter, C. E., Fischer, G. F., Fleischhauer, K., Goodridge, D., Klitz, W., Little, A., Maiers, M., Marsh, S. G., Mueller, C. R., Noreen, H., Rozemuller, E. H., Sanchez-Mazas, A., Senitzer, D., Trachtenberg, E., Fernandez-Vina, M. 2013; 81 (4): 194-203

    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.

    View details for DOI 10.1111/tan.12093

    View details for Web of Science ID 000316628100002

    View details for PubMedID 23510415

    View details for PubMedCentralID PMC3634360

  • 16th IHIW: Global distribution of extended HLA haplotypes INTERNATIONAL JOURNAL OF IMMUNOGENETICS Askar, M., Daghstani, J., Thomas, D., Leahy, N., Dunn, P., Claas, F., Doran, S., Saji, H., Kanangat, S., Karoichane, M., Tambur, A., Monos, D., El-Khalifa, M., Turner, V., Kamoun, M., Mustafa, M., Ramon, D., Gandhi, M., Vernaza, A., Gorodezky, C., Wagenknecht, D., Gautreaux, M., Hajeer, A., Kashi, Z., Fernandez-Vina, M. 2013; 40 (1): 31-38

    Abstract

    This report describes the project to identify the global distribution of extended HLA haplotypes, a component of 16th International HLA and Immunogenetics Workshop (IHIW), and summarizes the initial analyses of data collected. The project aims to investigate extended HLA haplotypes, compare their distribution among different populations, assess their frequency in hematopoietic stem cell unrelated donor registries and initiate an international family studies database and DNA repository to be made publicly available. HLA haplotypes compiled in immunogenetics laboratories during the evaluation of transplant candidates and related potential donors were analysed. Haplotypes were determined using the pedigree analysis tool publicly available from the National Marrow Donor Program (NMDP) website. Nineteen laboratories from 10 countries (11 laboratories from North America, five from Asia, two from Latin America and one from Australia) contributed data on a total of 1719 families comprised of 7474 individuals. We identified 10393 HLA haplotypes, of which 1682 haplotypes included high-resolution typing at HLA-A, B, C, DRB1 and DQB1 loci. We also present haplotypes containing MICA and other HLA loci and haplotypes containing rare alleles seen in these families. The project will be extended through the 17th IHIW, and investigators interested in joining the project may communicate with the first author.

    View details for DOI 10.1111/iji.12029

    View details for Web of Science ID 000313488000006

    View details for PubMedID 23302097

  • 16th IHIW: Extending the number of resources and bioinformatics analysis for the investigation of HLA rare alleles INTERNATIONAL JOURNAL OF IMMUNOGENETICS Gonzalez-Galarza, F. F., Mack, S. J., Hollenbach, J., Fernandez-Vina, M., Setterholm, M., Kempenich, J., Marsh, S. G., Jones, A. R., Middleton, D. 2013; 40 (1): 60-65

    Abstract

    Continuing a project presented at the 15th International HLA and Immunogenetics Workshop (IHIWS) on the rarity of HLA alleles, we sought to expand the number of data sources and bioinformatics tools available in the Allele Frequencies Net Database website (AFND, www.allelefrequencies.net). In this 16th IHIWS Rare Alleles project, HLA alleles described in the latest IMGT/HLA Database (release 3.8.0) were queried against different sources including data from registries (stem cell) and from 74 different laboratories around the world. We demonstrated that approximately 40% of the alleles officially named in the IMGT/HLA Database have been reported only once across all different sources. To facilitate the large-scale analysis of rare alleles, we have produced an online tool called the Rare Allele Detector that simplifies the detection of alleles that are considered to be 'very rare', 'rare' or 'frequent'. Tools and associated data can be accessed via the www.allelefrequencies.net website.

    View details for DOI 10.1111/iji.12030

    View details for Web of Science ID 000313488000010

    View details for PubMedID 23198982

  • New approaches in alternative donor transplantation. Biology of blood and marrow transplantation Fernandez Vina, M., Heslop, H. E., Barker, J. N. 2013; 19 (1): S91-6

    View details for DOI 10.1016/j.bbmt.2012.10.027

    View details for PubMedID 23110984

  • New Approaches in Alternative Donor Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Vina, M. F., Heslop, H. E., Barker, J. N. 2013; 19 (1): S91-S96
  • Improved Early Outcomes Using a T Cell Replete Graft Compared with T Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Ciurea, S. O., Mulanovich, V., Saliba, R. M., Bayraktar, U. D., Jiang, Y., Bassett, R., Wang, S. A., Konopleva, M., Fernandez-Vina, M., Montes, N., Bosque, D., Chen, J., Rondon, G., Alatrash, G., Alousi, A., Bashir, Q., Korbling, M., Qazilbash, M., Parmar, S., Shpall, E., Nieto, Y., Hosing, C., Kebriaei, P., Khouri, I., Popat, U., de Lima, M., Champlin, R. E. 2012; 18 (12): 1835-1844

    Abstract

    Haploidentical stem cell transplantation (SCT) has been generally performed using a T cell depleted (TCD) graft; however, a high rate of nonrelapse mortality (NRM) has been reported, particularly in adult patients. We hypothesized that using a T cell replete (TCR) graft followed by effective posttransplantation immunosuppressive therapy would reduce NRM and improve outcomes. We analyzed 65 consecutive adult patients with hematologic malignancies who received TCR (N = 32) or TCD (N = 33) haploidentical transplants. All patients received a preparative regimen consisting of melphalan, fludarabine, and thiotepa. The TCR group received posttransplantation treatment with cyclophosphamide (Cy), tacrolimus (Tac), and mycophenolate mofetil (MMF). Patients with TCD received antithymocyte globulin followed by infusion of CD34+ selected cells with no posttransplantation immunosuppression. The majority of patients in each group had active disease at the time of transplantation. Outcomes are reported for the TCR and TCD recipients, respectively. Engraftment was achieved in 94% versus 81% (P = NS). NRM at 1 year was 16% versus 42% (P = .02). Actuarial overall survival (OS) and progression-free survival (PFS) rates at 1 year posttransplantation were 64% versus 30% (P = .02) and 50% versus 21% (P = .02). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 20% versus 11% (P = .20), and chronic GVHD (cGVHD) 7% versus 18% (P = .03). Improved reconstitution of T cell subsets and a lower rate of infection were observed in the TCR group. These results indicate that a TCR graft followed by effective control of GVHD posttransplantation may lower NRM and improve survival after haploidentical SCT.

    View details for DOI 10.1016/j.bbmt.2012.07.003

    View details for Web of Science ID 000311593900010

    View details for PubMedID 22796535

  • HLA factors in transplantation for nonmalignant hematologic disorders BLOOD Fernandez-Vina, M. A. 2012; 120 (14): 2781-2782

    Abstract

    In this issue of Blood, a study by Horan and colleagues shows that differences in the HLA alleles of patients and unrelated donors in hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases result in increased risk for adverse treatment outcome.(1) This is the largest dataset examined so far for the evaluation of HLA mismatches in HSCT for nonmalignant diseases. It includes predominantly pediatric patients diagnosed with 39 diseases. Many patients received nonmyeloablative conditioning; a significant proportion of the infused grafts were depleted of T-lymphocytes; 6 diseases account for 77% of the cases.

    View details for DOI 10.1182/blood-2012-08-446567

    View details for Web of Science ID 000311616900007

    View details for PubMedID 23043027

  • A combined DPA1 similar to DPB1 amino acid epitope is the primary unit of selection on the HLA-DP heterodimer IMMUNOGENETICS Hollenbach, J. A., Madbouly, A., Gragert, L., Vierra-Green, C., Flesch, S., Spellman, S., Begovich, A., Noreen, H., Trachtenberg, E., Williams, T., Yu, N., Shaw, B., Fleischhauer, K., Fernandez-Vina, M., Maiers, M. 2012; 64 (8): 559-569

    Abstract

    Here, we present results for DPA1 and DPB1 four-digit allele-level typing in a large (n = 5,944) sample of unrelated European American stem cell donors previously characterized for other class I and class II loci. Examination of genetic data for both chains of the DP heterodimer in the largest cohort to date, at the amino acid epitope, allele, genotype, and haplotype level, allows new insights into the functional units of selection and association for the DP heterodimer. The data in this study suggest that for the DPA1-DPB1 heterodimer, the unit of selection is the combined amino acid epitope contributed by both the DPA1 and DPB1 genes, rather than the allele, and that patterns of LD are driven primarily by dimer stability and conformation of the P1 pocket. This may help explain the differential pattern of allele frequency distribution observed for this locus relative to the other class II loci. These findings further support the notion that allele-level associations in disease and transplantation may not be the most important unit of analysis, and that they should be considered instead in the molecular context.

    View details for DOI 10.1007/s00251-012-0615-3

    View details for Web of Science ID 000306341300001

    View details for PubMedID 22526601

    View details for PubMedCentralID PMC3395342

  • High-throughput, high-fidelity HLA genotyping with deep sequencing PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wang, C., Krishnakumar, S., Wilhelmy, J., Babrzadeh, F., Stepanyan, L., Su, L. F., Levinson, D., Fernandez-Vina, M. A., Davis, R. W., Davis, M. M., Mindrinos, M. 2012; 109 (22): 8676-8681

    Abstract

    Human leukocyte antigen (HLA) genes are the most polymorphic in the human genome. They play a pivotal role in the immune response and have been implicated in numerous human pathologies, especially autoimmunity and infectious diseases. Despite their importance, however, they are rarely characterized comprehensively because of the prohibitive cost of standard technologies and the technical challenges of accurately discriminating between these highly related genes and their many allelles. Here we demonstrate a high-resolution, and cost-effective methodology to type HLA genes by sequencing, which combines the advantage of long-range amplification, the power of high-throughput sequencing platforms, and a unique genotyping algorithm. We calibrated our method for HLA-A, -B, -C, and -DRB1 genes with both reference cell lines and clinical samples and identified several previously undescribed alleles with mismatches, insertions, and deletions. We have further demonstrated the utility of this method in a clinical setting by typing five clinical samples in an Illumina MiSeq instrument with a 5-d turnaround. Overall, this technology has the capacity to deliver low-cost, high-throughput, and accurate HLA typing by multiplexing thousands of samples in a single sequencing run, which will enable comprehensive disease-association studies with large cohorts. Furthermore, this approach can also be extended to include other polymorphic genes.

    View details for DOI 10.1073/pnas.1206614109

    View details for PubMedID 22589303

  • Tracking human migrations by the analysis of the distribution of HLA alleles, lineages and haplotypes in closed and open populations PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Vina, M., Hollenbach, J. A., Lyke, K. E., Sztein, M. B., Maiers, M., Klitz, W., Cano, P., Mack, S., Single, R., Brautbar, C., Israel, S., Raimondi, E., Khoriaty, E., Inati, A., Andreani, M., Testi, M., Moraes, M., Thomson, G., Stastny, P., Cao, K. 2012; 367 (1590): 820?29

    Abstract

    The human leucocyte antigen (HLA) system shows extensive variation in the number and function of loci and the number of alleles present at any one locus. Allele distribution has been analysed in many populations through the course of several decades, and the implementation of molecular typing has significantly increased the level of diversity revealing that many serotypes have multiple functional variants. While the degree of diversity in many populations is equivalent and may result from functional polymorphism(s) in peptide presentation, homogeneous and heterogeneous populations present contrasting numbers of alleles and lineages at the loci with high-density expression products. In spite of these differences, the homozygosity levels are comparable in almost all of them. The balanced distribution of HLA alleles is consistent with overdominant selection. The genetic distances between outbred populations correlate with their geographical locations; the formal genetic distance measurements are larger than expected between inbred populations in the same region. The latter present many unique alleles grouped in a few lineages consistent with limited founder polymorphism in which any novel allele may have been positively selected to enlarge the communal peptide-binding repertoire of a given population. On the other hand, it has been observed that some alleles are found in multiple populations with distinctive haplotypic associations suggesting that convergent evolution events may have taken place as well. It appears that the HLA system has been under strong selection, probably owing to its fundamental role in varying immune responses. Therefore, allelic diversity in HLA should be analysed in conjunction with other genetic markers to accurately track the migrations of modern humans.

    View details for PubMedID 22312049

  • Frequency of HLA-DP-specific antibodies and a possible new cross-reacting group HUMAN IMMUNOLOGY Callender, C. J., Fernandez-Vina, M., Leffell, M. S., Zachary, A. A. 2012; 73 (2): 175-179

    Abstract

    Clinical studies have demonstrated that HLA-DP-specific antibodies can be detrimental to a transplanted kidney. The number of patients affected is proportional to the frequency of DP antibodies. We determined the frequency of HLA-DP-specific antibodies en toto and in the absence of cross-reactive DR antibodies. Of 650 waitlisted renal patients, 271 (42%) were reactive with HLA-DP antigens in solid-phase immunoassays. Of these 271 sera, 58 (21%) were negative for reactivity with cross-reactive DR antigens, and 16 (5.9%) had no class II antibody other than DP. Eliminating sera containing DR cross-reactive antibodies reduced the frequency but not the overall strength of DP antibodies. Although most DP antibodies were not expected to yield a positive cytotoxicity crossmatch, 2 DP-specific antibodies yielded cytotoxic crossmatch tests with titers of >512. The occurrence of HLA-DP-specific antibody differed significantly between previously transplanted (62%) and nontransplanted (38%) patients, but no difference was observed among patients categorized by race or sex. One serum demonstrated strong cross-reactivity between DP and DRB1*01:03 in the absence of DR1 or DR11 reactivity. Sequence alignments were performed and a possible new cross-reactivity between DRB1*01:03 and DP2, DP9, DP10, DP13, DP16, and DP17 was defined. Two additional sera confirmed this cross-reactivity.

    View details for DOI 10.1016/j.humimm.2011.11.006

    View details for Web of Science ID 000300123200006

    View details for PubMedID 22138757

  • Humoral HLA sensitization matters in CBT outcome BLOOD Fernandez-Vina, M. A., de Lima, M., Ciurea, S. O. 2011; 118 (25): 6482-6484

    Abstract

    In this issue of Blood, Cutler and colleagues present evidence that donor-specific anti-HLA antibodies are associated with graft failure in double umbilical cord blood transplantation (CBT).1 Engraftment of donor cells is the first important step in successful transplantation and, until recently, the causes of engraftment failure remained elusive.

    View details for Web of Science ID 000298157600008

    View details for PubMedID 22174308

  • The Outcomes of Family Haploidentical Hematopoietic Stem Cell Transplantation in Hematologic Malignancies Are Not Associated with Patient Age BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Dong, L., Wu, T., Gao, Z., Zhang, M., Kan, F., Spellman, S. R., Tan, X., Zhao, Y., Wang, J., Lu, D., Miklos, D., Petersdorf, E., Fernandez-Vina, M., Lee, S. J. 2011; 17 (8): 1205-1213

    Abstract

    Haploidentical hematopoietic cell transplantation (HCT) has been used to treat hematologic malignancies, but it is unknown whether the procedure is more effective in adults or children. To address this question, we analyzed patients aged 1 to 65 years old receiving myeloablative conditioning regimens followed by family 2 to 3 antigen HLA-mismatched HCT and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR; n = 137) or performed in Dao-Pei Hospital in China, China (n = 181). The Dao-Pei cohort had more acute and chronic graft-versus-host disease (GVHD), less relapse, lower transplant-related mortality (TRM), and better leukemia-free survival (LFS) than the CIBMTR cohort. Overall survival (OS) and outcomes were similar between adults and children. In the CIBMTR cohort receiving ex vivo T cell depletion (TCD), adults had higher TRM (relative risk [RR] 2.71, 95% confidence interval [CI] 1.29-5.69, P = .008) and lower OS (RR 1.75, 95% CI 1.08-2.84, P = .023) than children. In the CIBMTR subset that did not receive ex vivo TCD, relapse was lower in adults compared to children (RR 0.24, 95% CI 0.07-0.80, P = .020), but TRM, LFS, and OS were similar. We conclude that outcomes in adults and children are similar overall, although children have better survival than adults if ex vivo TCD is used.

    View details for DOI 10.1016/j.bbmt.2010.12.703

    View details for Web of Science ID 000293429600013

    View details for PubMedID 21193055

    View details for PubMedCentralID PMC3113644

  • Immunogenetics as a tool in anthropological studies IMMUNOLOGY Sanchez-Mazas, A., Fernandez-Vina, M., Middleton, D., Hollenbach, J. A., Buhler, S., Di, D., Rajalingam, R., Dugoujon, J., Mack, S. J., Thorsby, E. 2011; 133 (2): 143-164

    Abstract

    The genes coding for the main molecules involved in the human immune system--immunoglobulins, human leucocyte antigen (HLA) molecules and killer-cell immunoglobulin-like receptors (KIR)--exhibit a very high level of polymorphism that reveals remarkable frequency variation in human populations. 'Genetic marker' (GM) allotypes located in the constant domains of IgG antibodies have been studied for over 40 years through serological typing, leading to the identification of a variety of GM haplotypes whose frequencies vary sharply from one geographic region to another. An impressive diversity of HLA alleles, which results in amino acid substitutions located in the antigen-binding region of HLA molecules, also varies greatly among populations. The KIR differ between individuals according to both gene content and allelic variation, and also display considerable population diversity. Whereas the molecular evolution of these polymorphisms has most likely been subject to natural selection, principally driven by host-pathogen interactions, their patterns of genetic variation worldwide show significant signals of human geographic expansion, demographic history and cultural diversification. As current developments in population genetic analysis and computer simulation improve our ability to discriminate among different--either stochastic or deterministic--forces acting on the genetic evolution of human populations, the study of these systems shows great promise for investigating both the peopling history of modern humans in the time since their common origin and human adaptation to past environmental (e.g. pathogenic) changes. Therefore, in addition to mitochondrial DNA, Y-chromosome, microsatellites, single nucleotide polymorphisms and other markers, immunogenetic polymorphisms represent essential and complementary tools for anthropological studies.

    View details for DOI 10.1111/j.1365-2567.2011.03438.x

    View details for Web of Science ID 000289832100001

    View details for PubMedID 21480890

    View details for PubMedCentralID PMC3088978

  • An update to HLA Nomenclature, 2010 BONE MARROW TRANSPLANTATION Marsh, S. G., Albert, E. D., Bodmer, W. F., Bontrop, R. E., DuPont, B., Erlich, H. A., Fernandez-Vina, M., Geraghty, D. E., Holdsworth, R., Hurley, C. K., Lau, M., Lee, K. W., Mach, B., Maiers, M., Mayr, W. R., Mueller, C. R., Parham, P., Petersdorf, E. W., Sasazuki, T., STROMINGER, J. L., Svejgaard, A., Terasaki, P. I., Tiercy, J. M., Trowsdale, J. 2010; 45 (5): 846-848

    Abstract

    The WHO Nomenclature Committee for Factors of the HLA System met during the 15th International Histocompatibility and Immunogenetics Workshop in Buzios, Brazil in September 2008. This update is an extract of the main report that documents the additions and revisions to the nomenclature of human leukocyte antigen (HLA) specificities following the principles established in previous reports.

    View details for DOI 10.1038/bmt.2010.79

    View details for Web of Science ID 000277596700008

    View details for PubMedID 20348972

  • Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups AMERICAN JOURNAL OF HUMAN GENETICS Mignot, E., Lin, L., Rogers, W., Honda, Y., Qiu, X. H., Lin, X. Y., Okun, M., Hohjoh, H., Miki, T., Hsu, S. H., Leffell, M. S., GRUMET, F. C., Fernandez-Vina, M., Honda, M., Risch, N. 2001; 68 (3): 686-699

    Abstract

    Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles-DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy.

    View details for Web of Science ID 000166994200013

    View details for PubMedID 11179016

  • A NOVEL FLOW CYTOMETRY CROSSMATCH FOR DETECTING TRUE DP-DSA INTERACTING TO THE NATIVE DP MOLECULES ON CELL SURFACE < DP-FXM > Wang, L., Fernandez-Vina, M., Chen, G. ELSEVIER SCIENCE INC. 2019: 126?27
  • GENERATION AND CHARACTERIZATION OF HUMANIZED ANTI-HLA-A2 ANTIBODY Rodriguez-Paris, J. M., Wang, L., Lin, L., Fernandez-Vina, M., Chen, G. ELSEVIER SCIENCE INC. 2019: 109
  • HLA-DP PROTEIN EXPRESSION LEVEL AND ITS IMPACT ON FLOW CYTOMETRY CROSSMATCH (FXM) Wang, L., Chen, G., Fernandez-Vina, M. ELSEVIER SCIENCE INC. 2019: 9?10
  • Urgent Time to Allogeneic Hematopoietic Cell Transplantation: A National Survey of Transplant Physicians and Unrelated Donor Search Coordinators Facilitated by the Histocompatibility Advisory Group to the National Marrow Donor Program. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Pidala, J., Mupfudze, T. G., Payton, T., Barker, J., Perales, M., Shaw, B. E., Fernandez-Vina, M., Burns, L. J., Dehn, J. 2019

    Abstract

    PURPOSE: To characterize donor search and selection practices, the National Marrow Donor Program (NMDP) Histocompatibility Advisory Group developed a survey of allogeneic hematopoietic cell transplant (HCT) physicians and search coordinators. Objectives were to describe search practices, understand practices surrounding urgent time to HCT, and characterize strategies used when identifying a matched unrelated donor (MUD) is unlikely.METHODS: Participants included United States physician members of the American Society for Transplantation and Cellular Therapy (ASTCT) and donor search coordinators within the NMDP network. The web-based survey was conducted February to May 2018.RESULTS: A total of 317/858 physicians (37%) and 225/327 coordinators (69%) responded, of which 263 and 194 respectively were eligible and were included in the analysis. Most centers, 142 (95%) were represented; 108 (72%) had at least one physician and 128 (85%) had at least one coordinator respondent. Most (68% physicians, 61% coordinators) indicated donor selection decisions were made by individual physicians. Urgent time to HCT was most commonly (90 and 87%, of physicians and coordinators, respectively) defined as HCT within 4-6 weeks of search initiation. Higher HCT urgency was associated with a higher disease risk index. For urgent cases with low probability of an 8/8 MUD, 75 and 80% of physicians and coordinators endorsed short (1-2 weeks) unrelated donor search before proceeding to an alternative donor source. NMDP-provided solutions to expedite donor identification were strongly endorsed.CONCLUSIONS: This survey clarified current donor selection practices in the United States and defined urgent time to HCT. These data provide insight to NMDP on potential solutions to support the path to transplant, such as highlighting futile searches and providing alternative donor options at the time of search initiation.

    View details for DOI 10.1016/j.bbmt.2019.08.002

    View details for PubMedID 31419569

  • 17th IHIW component "Immunogenetics of Ageing" - New NGS data. Human immunology Ivanova, M., Creary, L. E., Al Hadra, B., Lukanov, T., Mazzocco, M., Sacchi, N., Ameen, R., Al-Shemmari, S., Moise, A., Ursu, L. D., Constantinescu, I., Vayntrub, T., Fernandez-Vina, M. A., Shivarov, V., Naumova, E. 2019

    Abstract

    The 'Immunogenetics of Aging' project is a component introduced in the 14th International HLA and Immunogenetics Workshop (IHIW) and developed further within subsequent workshops. The aim was to determine the relevance of immunogenetic markers, focusing on HLA, cytokine genes, and some innate immunity genes, for successful aging and an increased capacity to reach the extreme limits of life-span. Within the 17th IHIW we applied Next Generation Sequencing methods to refine further HLA associations at allele level in longevity, and to extend our knowledge to additional loci such as HLA-DQA1, HLA-DPB1 and HLA-DPA1. Analysis of relatively small number of healthy elderly and young controls from four populations showed that some HLA class I and class II alleles were significantly positively associated with healthy aging. Additionally we observed statistically significant differences in HLA allele distribution when the analysis was performed separately in elderly females and males compared to sex-matched young controls. Haplotypes, probably associated with better control of viral and malignant diseases were increased in the elderly sample. These preliminary NGS data could confirm our hypotheses that survival and longevity might be associated with selection of HLA alleles and haplotypes conferring disease resistance or susceptibility. Therefore HLA alleles and haplotypes could be informative immunogenetic markers for successful ageing.

    View details for DOI 10.1016/j.humimm.2019.07.287

    View details for PubMedID 31331679

  • Next-generation HLA typing of 382 International Histocompatibility Working Group reference B-lymphoblastoid cell lines: Report from the 17th International HLA and Immunogenetics Workshop Creary, L. E., Guerra, S. G., Chong, W., Brown, C. J., Turner, T. R., Robinson, J., Bultitude, W. P., Mayor, N. P., Marsh, S. E., Saito, K., Lam, K., Duke, J. L., Mosbruger, T. L., Ferriola, D., Monos, D., Willis, A., Askar, M., Fischer, G., Saw, C., Ragoussis, J., Petrek, M., Serra-Pages, C., Juan, M., Stavropoulos-Giokas, C., Dinou, A., Ameen, R., Al Shemmari, S., Spierings, E., Gendzekhadze, K., Morris, G. P., Zhang, Q., Kashi, Z., Hsu, S., Gangavarapu, S., Mallempati, K. C., Yamamoto, F., Osoegawa, K., Vayntrub, T., Chang, C., Hansen, J. A., Fernandez-Vina, M. A. ELSEVIER SCIENCE INC. 2019: 449?60
  • High-resolution characterization of allelic and haplotypic HLA frequency distribution in a Spanish population using high-throughput next-generation sequencing Montero-Martin, G., Mallempati, K. C., Gangavarapu, S., Sanchez-Gordo, F., Herrero-Mata, M. J., Balas, A., Vicario, J. L., Sanchez-Garcia, F., Gonzalez-Escribano, M. F., Muro, M., Moya-Quiles, M. R., Gonzalez-Fernandez, R., Ocejo-Vinyals, J. G., Marin, L., Creary, L. E., Osoegawa, K., Vayntrub, T., Caro-Oleas, J. L., Vilches, C., Planelles, D., Fernandez-Vina, M. A. ELSEVIER SCIENCE INC. 2019: 429?36
  • Complete nucleotide sequence characterization of DRB5 alleles reveals a homogeneous allele group that is distinct from other DRB genes Barsakis, K., Babrzadeh, F., Chi, A., Mallempati, K., Pickle, W., Mindrinos, M., Fernandez-Vina, M. A. ELSEVIER SCIENCE INC. 2019: 437?48
  • Role of killer cell immunoglobulin-like receptor (KIR)-ligand interactions to prevent relapse in patients (pts) receiving matched unrelated stem cell transplant (SCT) for acute myeloid leukemia (AML). Rafei, H., Fernandez-Vina, M., Carmazzi, Y., Moore, B., Willis, D., Basar, R., Banerjee, P., Daher, M., Hosing, C., Kebriaei, P., Khouri, I. F., Mehta, R., Nieto, Y., Qazilbash, M. H., Shpall, E. J., Champlin, R. E., Marin, D., Rezvani, K., Cao, K. AMER SOC CLINICAL ONCOLOGY. 2019
  • Complete nucleotide sequence characterization of DRB5 alleles reveals a homogeneous allele group that is distinct from other DRB genes. Human immunology Barsakis, K., Babrzadeh, F., Chi, A., Mallempati, K., Pickle, W., Mindrinos, M., Fernandez-Vina, M. A. 2019

    Abstract

    Next Generation Sequencing allows for testing and typing of entire genes of the HLA region. A better and comprehensive sequence assessment can be achieved by the inclusion of full gene sequences of all the common alleles at a given locus. The common alleles of DRB5 are under-characterized with the full exon-intron sequence of two alleles available. In the present study the DRB5 genes from 18 subjects alleles were cloned and sequenced; haplotype analysis showed that 17 of them had a single copy of DRB5 and one consanguineous subject was homozygous at all HLA loci. Methodological approaches including robust and efficient long-range PCR amplification, molecular cloning, nucleotide sequencing and de novo sequence assembly were combined to characterize DRB5 alleles. DRB5 sequences covering from 5'UTR to the end of intron 5 were obtained for DRB5*01:01, 01:02 and 02:02; partial coverage including a segment spanning exon 2 to exon 6 was obtained for DRB5*01:03, 01:08N and 02:03. Phylogenetic analysis of the generated sequences showed that the DRB5 alleles group together and have distinctive differences with other DRB loci. Novel intron variants of DRB5*01:01:01, 01:02 and 02:02 were identified. The newly characterized DRB5 intron variants of each DRB5 allele were found in subjects harboring distinct associations with alleles of DRB1, B and/or ethnicity. The new information provided by this study provides reference sequences for HLA typing methodologies. Extending sequence coverage may lead to identify the disease susceptibility factors of DRB5 containing haplotypes while the unexpected intron variations may shed light on understanding of the evolution of the DRB region.

    View details for PubMedID 30954494

  • High-resolution characterization of allelic and haplotypic HLA frequency distribution in a Spanish population using high-throughput next-generation sequencing. Human immunology Montero-Martin, G., Mallempati, K. C., Gangavarapu, S., Sanchez-Gordo, F., Herrero-Mata, M. J., Balas, A., Vicario, J. L., Sanchez-Garcia, F., Gonzalez-Escribano, M. F., Muro, M., Moya-Quiles, M. R., Gonzalez-Fernandez, R., Ocejo-Vinyals, J. G., Marin, L., Creary, L. E., Osoegawa, K., Vayntrub, T., Caro-Oleas, J. L., Vilches, C., Planelles, D., Fernandez-Vina, M. A. 2019

    Abstract

    Next-generation sequencing (NGS) at the HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1 and -DRB3/4/5 loci was performed on 282 healthy unrelated individuals from different major regions of Spain. High-resolution HLA genotypes defined by full sequencing of class I loci and extended coverage of class II loci were obtained to determine allele frequencies and also to estimate extended haplotype frequencies. HLA alleles were typed at the highest resolution level (4-field level, 4FL); with exception of a minor deviation in HLA-DPA1, no statistically significant deviations from expected Hardy Weinberg Equilibrium (HWE) proportions were observed for all other HLA loci. This study provides new 4FL-allele and -haplotype frequencies estimated for the first time in the Spanish population. Furthermore, our results describe extended haplotypes (including the less frequently typed HLA-DPA1 and HLA-DQA1 loci) and show distinctive haplotype associations found at 4FL-allele definition in this Spanish population study. The distinctive allelic and haplotypic diversity found at the 4FL reveals the high level of heterozygosity and specific haplotypic associations displayed that were not apparent at 2-field level (2FL). Overall, these results may contribute as a useful reference source for future population studies, for HLA-disease association studies as a healthy control group dataset and for improving donor recruitment strategies of bone marrow registries. HLA genotyping data of this Spanish population cohort was also included in the 17th International Histocompatibility and Immunogenetics Workshop (IHIW) as part of the study of HLA diversity in unrelated worldwide populations using NGS.

    View details for PubMedID 30763600

  • Quality Control Project of NGS HLA Genotyping for the 17th International HLA and Immunogenetics Workshop. Human immunology Osoegawa, K., Vayntrub, T. A., Wenda, S., De Santis, D., Barsakis, K., Ivanova, M., Hsu, S., Barone, J., Holdsworth, R., Diviney, M., Askar, M., Willis, A., Railton, D., Laflin, S., Gendzekhadze, K., Oki, A., Sacchi, N., Mazzocco, M., Andreani, M., Ameen, R., Stavropoulos-Giokas, C., Dinou, A., Torres, M., Dos Santos Francisco, R., Serra-Pages, C., Goodridge, D., Balladares, S., Bettinotti, M. P., Iglehart, B., Kashi, Z., Martin, R., Saw, C. L., Ragoussis, I., Downing, J., Navarrete, C., Chong, W., Saito, K., Petrek, M., Tokic, S., Padros, K., Beatriz Rodriguez, M., Zakharova, V., Shragina, O., Marino, S. R., Brown, N. K., Shiina, T., Suzuki, S., Spierings, E., Zhang, Q., Yin, Y., Morris, G. P., Hernandez, A., Ruiz, P., Khor, S., Tokunaga, K., Geretz, A., Thomas, R., Yamamoto, F., Mallempati, K. C., Gangavarapu, S., Kanga, U., Tyagi, S., Marsh, S. G., Bultitude, W. P., Liu, X., Cao, D., Penning, M., Hurley, C. K., Cesbron, A., Mueller, C., Mytilineos, J., Weimer, E., Bengtsson, M., Fischer, G., Hansen, J. A., Chang, C., Mack, S. J., Creary, L. E., Fernandez-Vina, M. A. 2019

    Abstract

    The 17th International HLA and Immunogenetics Workshop (IHIW) organizers conducted a Pilot Study (PS) in which 13 laboratories (15 groups) participated to assess the performance of the various sequencing library preparation protocols, NGS platforms and software in use prior to the workshop. The organizers sent 50 cell lines to each of the 15 groups, scored the 15 independently generated sets of NGS HLA genotyping data, and generated "consensus" HLA genotypes for each of the 50 cell lines. Proficiency Testing (PT) was subsequently organized using four sets of 24 cell lines, selected from 48 of 50 PS cell lines, to validate the quality of NGS HLA typing data from the 34 participating IHIW laboratories. Completion of the PT program with a minimum score of 95% concordance at the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 loci satisfied the requirements to submit NGS HLA typing data for the 17th IHIW projects. Together, these PS and PT efforts constituted the 17th IHIW Quality Control project. Overall PT concordance rates for HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRB1, HLA-DRB3, HLA-DRB4 and HLA-DRB5 were 98.1%, 97.0% and 98.1%, 99.0%, 98.6%, 98.8%, 97.6%, 96.0%, 99.1%, 90.0% and 91.7%, respectively. Across all loci, the majority of the discordance was due to allele dropout. The high cost of NGS HLA genotyping per experiment likely prevented the retyping of initially failed HLA loci. Despite the high HLA genotype concordance rates of the software, there remains room for improvement in the assembly of more accurate consensus DNA sequences by NGS HLA genotyping software.

    View details for PubMedID 30738112

  • Tools for Building, Analyzing and Evaluating HLA Haplotypes from Families. Human immunology Osoegawa, K., Mack, S. J., Prestegaard, M., Fernandez-Vina, M. A. 2019

    Abstract

    The highly polymorphic classical human leukocyte antigen (HLA) genes display strong linkage disequilibrium (LD) that results in conserved multi-locus haplotypes. For unrelated individuals in defined populations, HLA haplotype frequencies can be estimated using the expectation-maximization (EM) method. Haplotypes can also be constructed using HLA allele segregation from nuclear families. It is straightforward to identify many HLA genotyping inconsistencies by visually reviewing HLA allele segregation in family members. It is also possible to identify potential crossover events when two or more children are available in a nuclear family. This process of visual inspection can be unwieldy, and we developed the "HaplObserve" program to standardize the process and automatically build haplotypes using family-based HLA allele segregation. HaplObserve facilitates systematically building haplotypes, and reporting potential crossover events. HLA Haplotype Validator (HLAHapV) is a program originally developed to impute chromosomal phase from genotype data using reference haplotype data. We updated and adapted HLAHapV to systematically compare observed and estimated haplotypes. We also used HLAHapV to identify haplotypes when uninformative HLA genotypes are present in families. Finally, we developed "pould", an R package that calculates haplotype frequencies, and estimates standard measures of global (locus-level) LD from both observed and estimated haplotypes.

    View details for PubMedID 30735756

  • Next-generation sequencing reveals new information about HLA allele and haplotype diversity in a large European American population. Human immunology Creary, L. E., Gangavarapu, S., Mallempati, K. C., Montero-Martín, G., Caillier, S. J., Santaniello, A., Hollenbach, J. A., Oksenberg, J. R., Fernández-Viña, M. A. 2019

    Abstract

    The human leukocyte antigen (HLA) genes are extremely polymorphic and are useful molecular markers to make inferences about human population history. However, the accuracy of the estimation of genetic diversity at HLA loci very much depends on the technology used to characterize HLA alleles; high-resolution genotyping of long-range HLA gene products improves the assessment of HLA population diversity as well as other population parameters compared to lower resolution typing methods. In this study we examined allelic and haplotype HLA diversity in a large healthy European American population sourced from the UCSF-DNA bank. A high-resolution next-generation sequencing method was applied to define non-ambiguous 3- and 4-field alleles at the HLA-A, HLA-C, HLA-B, HLA-DRB1, HLA-DRB3/4/5, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1 loci in samples provided by 2248 unrelated individuals. A number of population parameters were examined including balancing selection and various measurements of linkage disequilibrium were calculated. There were no detectable deviations from Hardy-Weinberg proportions at HLA-A, HLA-DRB1, HLA-DQA1 and HLA-DQB1. For the remaining loci moderate and significant deviations were detected at HLA-C, HLA-B, HLA-DRB3/4/5, HLA-DPA1 and HLA-DPB1 loci mostly from population substructures. Unique 4-field associations were observed among alleles at 2 loci and haplotypes extending large intervals that were not apparent in results obtained using testing methodologies with limited sequence coverage and phasing. The high diversity at HLA-DPA1 results from detection of intron variants of otherwise well conserved protein sequences. It may be speculated that divergence in exon sequences may be negatively selected. Our data provides a valuable reference source for future population studies that may allow for precise fine mapping of coding and non-coding sequences determining disease susceptibility and allo-immunogenicity.

    View details for DOI 10.1016/j.humimm.2019.07.275

    View details for PubMedID 31345698

  • HLA HHaplotypes In 250 Families: The Baylor Laboratory Results And A Aerspective On A Core NGS Testing Model For The 17th International HLA And Immunogenetics Workshop. Human immunology Askar, M., Madbouly, A., Zhrebker, L., Willis, A., Kennedy, S., Padros, K., Rodriguez, M. B., Bach, C., Spriewald, B., Ameen, R., Shemmari, S. A., Tarassi, K., Tsirogianni, A., Hamdy, N., Mossallam, G., Hönger, G., Spinnler, R., Fischer, G., Fae, I., Charlton, R., Dunk, A., Vayntrub, T. A., Halagan, M., Osoegawa, K., Fernández-Viña, M. 2019

    Abstract

    Since their inception, the International HLA & Immunogenetics Workshops (IHIW) served as a collaborative platform for exchange of specimens, reference materials, experiences and best practices. In this report we present a subset of the results of human leukocyte antigen (HLA) haplotypes in families tested by next generation sequencing (NGS) under the 17th IHIW. We characterized 961 haplotypes in 921 subjects belonging to 250 families from 8 countries (Argentina, Austria, Egypt, Jamaica, Germany, Greece, Kuwait, and Switzerland). These samples were tested in a single core laboratory in a high throughput fashion using 6 different reagents/software platforms. Families tested included patients evaluated clinically as transplant recipients (kidney and hematopoietic cell transplant) and their respective family members. We identified 486 HLA alleles at the following loci HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQA1, -DQB1, -DPA1, -DPB1 (77, 115, 68, 69, 10, 6, 4, 44, 31, 20 and 42 alleles, respectively). We also identified nine novel alleles with polymorphisms in coding regions. This approach of testing samples from multiple laboratories across the world in different stages of technology implementation in a single core laboratory may be useful for future international workshops. Although data presented may not be reflective of allele and haplotype frequencies in the countries to which the families belong, they represent an extensive collection of 3rd and 4th field resolution level 11-locus haplotype associations of 486 alleles identified in families from 8 countries.

    View details for DOI 10.1016/j.humimm.2019.07.298

    View details for PubMedID 31558329

  • Assessment by Extended-Coverage Next-Generation Sequencing Typing of DPA1 and DPB1 Mismatches in Siblings Matching at HLA-A, -B, -C, -DRB1, and -DQ Loci. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Mariano, L., Zhang, B. M., Osoegawa, K., Lowsky, R., Fernandez-Vina, M. 2019

    Abstract

    Allogeneic hematopoietic stem cell transplant from an HLA matched sibling donor is usually the preferable choice. The use of next-generation sequencing (NGS) for HLA typing in clinical practice provides broader coverage and higher resolution of HLA genes. We evaluated the frequency of DPB1 crossing-over events among patients and potential related donors typed with NGS. From July 2016 to January 2018, 593 patients and 2385 siblings were typed. We evaluated sibling matching status in 546 patients, and 44.8% of these patients had siblings that matched at HLA-A, -B, -C, -DRB1, and -DQB1 loci. In 306 patient-HLA matched sibling pairs, we found 6 pairs (1.96%) with 1 DPB1 mismatch, and 5 of these pairs included an additional mismatch in DPA1. No additional mismatches were observed at the low expression loci. Using the T cell epitope algorithm, 4 of these DP mismatches were classified as permissive, 1 as nonpermissive in the host-versus-graft direction, and 1 as nonpermissive in the graft-versus-host direction. The frequency of DPB1 and DPA1 mismatches is low, and their impact in related donor transplants is not well established. Although DP typing in related transplants goes beyond guidelines, it is especially relevant for sensitized patients. NGS-based HLA typing provides full gene coverage, and its use in clinical practice can enable better donor selection.

    View details for DOI 10.1016/j.bbmt.2019.07.033

    View details for PubMedID 31381995

  • TRANSETHNIC ANALYSIS OF HIGH-RESOLUTION HLA ALLELES AND COMPLEMENT 4 STRUCTURAL POLYMORPHISMS IN SCHIZOPHRENIA Ollila, H., Li, M., Mindrinos, M., Wang, C., Fernandez-Vina, M., Kuehn, R., Krishnakumar, S., Wilhelmy, J., Tsuang, M. T., Glatt, S. J., Mignot, E., Levinson, D. F. ELSEVIER SCIENCE BV. 2019: S937
  • Full-length next-generation sequencing of HLA class I and II genes in a cohort from Thailand HUMAN IMMUNOLOGY Geretz, A., Ehrenberg, P. K., Bouckenooghe, A., Vina, M., Michael, N. L., Chansinghakule, D., Limkittikul, K., Thomas, R. 2018; 79 (11): 773?80

    Abstract

    The human leukocyte antigen (HLA) genes are highly variable and are known to play an important role in disease outcomes, including infectious diseases. Prior knowledge of HLA polymorphisms in a population usually forms the basis for an effective case-control study design. As a prelude to future disease association analyses, we report HLA class I and II diversity in 334 unrelated donors from a Dengue vaccine efficacy trial conducted in Thailand. Long-range PCR amplification of six HLA loci was performed on DNA extracted from saliva samples. HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1 were genotyped using a next-generation sequencing method presented at the 17th International HLA and Immunogenetics Workshop. In total, we identified 201 HLA alleles, including 35 HLA-A, 57 HLA-B, 28 HLA-C, 24 HLA-DPB1, 21 HLA-DQB1 and 36 HLA-DRB1 alleles. Very common HLA alleles with frequencies greater than 10 percent were A?11:01:01, A?33:03:01, A?24:02:01, B?46:01:01, C?07:02:01, C?01:02:01, C?08:01:01, DPB1?05:01:01, DPB1?13:01:01, DPB1?04:01:01, DPB1?02:01:02, DQB1?03:01:01, DQB1?05:02:01, DQB1?03:03:02, DRB1?12:02:01, DRB1?09:01:02, and DRB1?15:02:01. A novel HLA allele, B?15:450, had a non-synonymous substitution and occurred in more than one donor. Population-based full-length NGS HLA typing is more conclusive and provides a sound foundation for exploring disease association in a given population.

    View details for PubMedID 30243890

  • Report from the Killer-cell Immunoglobulin-like Receptors (KIR) component of the 17th International HLA and Immunogenetics Workshop. Human immunology Misra, M. K., Augusto, D. G., Martin, G. M., Nemat-Gorgani, N., Sauter, J., Hofmann, J. A., Traherne, J. A., Gonzalez-Quezada, B., Gorodezky, C., Bultitude, W. P., Marin, W., Vierra-Green, C., Anderson, K. M., Balas, A., Caro-Oleas, J. L., Cisneros, E., Colucci, F., Dandekar, R., Elfishawi, S. M., Fernandez-Vina, M. A., Fouda, M., Gonzalez-Fernandez, R., GroSSe, A., Herrero-Mata, M. J., Hollenbach, S. Q., Marsh, S. G., Mentzer, A., Middleton, D., Moffett, A., Moreno-Hidalgo, M. A., Mossallam, G. I., Nakimuli, A., Oksenberg, J. R., Oppenheimer, S. J., Parham, P., Petzl-Erler, M., Planelles, D., Sanchez-Garcia, F., Sanchez-Gordo, F., Schmidt, A. H., Trowsdale, J., Vargas, L. B., Vicario, J. L., Vilches, C., Norman, P. J., Hollenbach, J. A. 2018

    Abstract

    The goals of the KIR component of the 17th International HLA and Immunogenetics Workshop (IHIW) were to encourage and educate researchers to begin analyzing KIR at allelic resolution, and to survey the nature and extent of KIR allelic diversity across human populations. To represent worldwide diversity, we analyzed 1269 individuals from ten populations, focusing on the most polymorphic KIR genes, which express receptors having three immunoglobulin (Ig)-like domains (KIR3DL1/S1, KIR3DL2 and KIR3DL3). We identified 13 novel alleles of KIR3DL1/S1, 13 of KIR3DL2 and 18 of KIR3DL3. Previously identified alleles, corresponding to 33 alleles of KIR3DL1/S1, 38 of KIR3DL2, and 43 of KIR3DL3, represented over 90% of the observed allele frequencies for these genes. In total we observed 37 KIR3DL1/S1 allotypes, 40 for KIR3DL2 and 44 for KIR3DL3. As KIR allotype diversity can affect NK cell function, this demonstrates potential for high functional diversity worldwide. Allelic variation further diversifies KIR haplotypes. We determined KIR3DL3??KIR3DL1/S1??KIR3DL2 haplotypes from five of the studied populations, and observed multiple population-specific haplotypes in each. This included 234 distinct haplotypes in European Americans, 191 in Ugandans, 35 in Papuans, 95 in Egyptians and 86 in Spanish populations. For another 35 populations, encompassing 642,105 individuals we focused on KIR3DL2 and identified another 375 novel alleles, with approximately half of them observed in more than one individual. The KIR allelic level data gathered from this project represents the most comprehensive summary of global KIR allelic diversity to date, and continued analysis will improve understanding of KIR allelic polymorphism in global populations. Further, the wealth of new data gathered in the course of this workshop component highlights the value of collaborative, community-based efforts in immunogenetics research, exemplified by the IHIW.

    View details for PubMedID 30321631

  • THE COMMON UNCOMMON EXTENDED HLA HAPLOTYPE: DO TWO WEAK ASSOCIATIONS MAKE IT STRONG? Askar, M. Z., Williams, J. D., Madbouly, A. S., Kang, S., Kennedy, S., Willis, A., Knudsen, T., Robinson, J., Creary, L. E., Fernandez-Vina, M. A. ELSEVIER SCIENCE INC. 2018: 116
  • EXTENDED HLA HAPLOTYPES IN A GREEK POPULATION BY NGS TECHNOLOGY Tarassi, K., Willis, A., Williams, J. D., Knudsen, T., Robinson, J., Kennedy, S., Kitsiou, V., Osoegawa, K., Kouniaki, D., Athanassiades, T., Fernandez-Vina, M., Tsirogianni, A., Askar, M. Z. ELSEVIER SCIENCE INC. 2018: 117
  • HLA ALLELE AND HAPLOTYPE FREQUENCIES CHARACTERIZED USING NEXT-GENERATION SEQUENCING METHODS IN UNRELATED WORLD-WIDE POPULATIONS: SUMMARY FROM THE 17TH INTERNATIONAL HLA AND IMMUNOGENETICS WORKSHOP Creary, L. E., Chang, C., Martin, G., Mallempati, K. C., Gangavarapu, S., Osoegawa, K., Vayntrub, T. A., Fernandez-Vina, M. A. ELSEVIER SCIENCE INC. 2018: 30
  • NGS CHARACTERIZATION OF EXTENDED HLA HAPLOTYPES IN JAMAICAN FAMILIES FROM THE CARIBBEAN BONE MARROW REGISTRY: A STUDY OF THE 17TH INTERNATIONAL HLA & IMMUNOGENETICS WORKSHOP Askar, M. Z., Charlton, R. K., Dunk, A., Willis, A., Williams, J. D., Knudsen, T., Robinson, J., Kennedy, S., Nelson, W., Geraghty, D., Osoegawa, K., Fernandez-Vina, M. ELSEVIER SCIENCE INC. 2018: 115
  • THE HLA GENETIC STRUCTURE OF AN ARGENTINIAN REGISTRY POPULATION REFLECT A DIVERGENT DEMOGRAPHIC HISTORY Creary, L. E., Galarza, P., Chang, C., Shields, B., Maha, G. C., Rodriguez Cardozo, M., Osoegawa, K., Vayntrub, T. A., Fernandez-Vina, M. A. ELSEVIER SCIENCE INC. 2018: 122
  • Allelic resolution NGS HLA typing of Class I and Class II loci and haplotypes in Cape Town, South Africa. Human immunology Thorstenson, Y. R., Creary, L. E., Huang, H., Rozot, V., Nguyen, T. T., Babrzadeh, F., Kancharla, S., Fukushima, M., Kuehn, R., Wang, C., Li, M., Krishnakumar, S., Mindrinos, M., Fernandez Vina, M. A., Scriba, T. J., Davis, M. M. 2018

    Abstract

    The development of next-generation sequencing (NGS) methods for HLA genotyping has already had an impact on the scope and precision of HLA research. In this study, allelic resolution HLA typing was obtained for 402 individuals from Cape Town, South Africa. The data were produced by high-throughput NGS sequencing as part of a study of T-cell responses to Mycobacterium tuberculosis in collaboration with the University of Cape Town and Stanford University. All samples were genotyped for 11 HLA loci, namely HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1, -DRB3, -DRB4, and -DRB5. NGS HLA typing of samples from Cape Town inhabitants revealed a unique cohort, including unusual haplotypes, and 22 novel alleles not previously reported in the IPD-IMGT/HLA Database. Eight novel alleles were in Class I loci and 14 were in Class II. There were 62 different alleles of HLA-A, 72 of HLA-B, and 47 of HLA-C. Alleles A23:17, A43:01, A29:11, A68:27:01, A01:23, B14:01:01, B15:10:01, B39:10:01, B45:07, B82:02:01 and C08:04:01 were notably more frequent in Cape Town compared to other populations reported in the literature. Class II loci had 21 different alleles of DPA1, 46 of DPB1, 27 of DQA1, 26 of DQB1, 41 of DRB1, 5 of DRB3, 4 of DRB4 and 6 of DRB5. The Cape Town cohort exhibited high degrees of HLA diversity and relatively high heterozygosity at most loci. Genetic distances between Cape Town and five other sub-Saharan African populations were also calculated and compared to European Americans.

    View details for PubMedID 30240896

  • BUILDING A HIGH RESOLUTION HAPLOTYPE DATABASE FOR 11 HUMAN LEUKOCYTE ANTIGEN LOCI FROM FAMILY TRIOS Kountouris, E., Levinson, D., Fernandez-Vina, M. A., Ollila, H., Mignot, E., Tsuang, M., Glatt, S., Li, M., Mindrinos, M. WILEY. 2018: 435?36
  • HLA ALLELE AND HAPLOTYPE FREQUENCIES CHARACTERIZED USING NEXT-GENERATION SEQUENCING METHODS IN UNRELATED WORLD-WIDE POPULATIONS: SUMMARY FROM THE 17TH INTERNATIONAL HLA AND IMMUNOGENETICS WORKSHOP Creary, L. E., Chang, C., Montero-Martin, G., Mallempati, K. C., Gangavarapu, S., Osoegawa, K., Vayntrub, T., Fernandez-Vina, M. A. WILEY. 2018: 327
  • HLA HAPLOTYPES IN A GREEK POPULATION BY NGS TECHNOLOGY Tarassi, K., Willis, A., Kitsiou, V., Osoegawa, K., Kouniaki, D., Athanassiades, T., Fernandez-Vina, M., Askar, M., Tsirogianni, A. WILEY. 2018: 412
  • HIGH-RESOLUTION CHARACTERIZATION OF ALLELIC AND HAPLOTYPIC HLA FREQUENCIES DISTRIBUTION IN A SPANISH POPULATION USING HIGH-THROUGHPUT NEXT-GENERATION SEQUENCING Montero-Martin, G., Creary, L. E., Mallempati, K., Gangavarapu, S., Vayntrub, T., Planelles, D., Vilches, C., Luis Caro, J., Jose Herrero-Mata, M., Sanchez-Gordo, F., Francisca Gonzalez-Escribano, M., Muro, M., Moya-Quiles, M. R., Gonzalez-Fernandez, R., Sanchez-Garcia, F., Gonzalo Ocejo-Vinyals, J., Balas, A., Luis Vicario, J., Marin, L., Fernandez-Vina, M. A. WILEY. 2018: 424?25
  • HIGH RESOLUTION HAPLOTYPE ANALYSES OF CLASSICAL HLA GENES IN FAMILIES FOR THE 17TH INTERNATIONAL HLA AND IMMUNOGENETICS WORKSHOP Osoegawa, K., Creary, L. E., Mallempati, K., Gangavarapu, S., Mack, S. J., Askar, M., Fernandez-Vina, M. WILEY. 2018: 330?31
  • BEHCET LIES IN THE EYE OF THE B-HOLDER Elfishawi, S., Mossallam, G., Elfishawi, M., Bruin, H., van de Pasch, L. L., Rozemuller, E. H., Zaky, K., Fernandez-Vina, M. A. WILEY. 2018: 460?61
  • THE RELEVANCE OF NGS TYPING IN UNRAVELING THE DIVERSITY OF 11 HLA LOCI TYPED IN THE MEXICAN MESTIZOS FROM OAXACA, MEXICO Munguia, A., Creary, L. E., Fernandez-Vina, M. A., Gonzalez, B., Flores-A, H., Gorodezky, C. WILEY. 2018: 440?41
  • Deconstruction of HLA-DRB1*04:01:01 and HLA-DRB1*15:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England) Creary, L. E., Mallempati, K. C., Gangavarapu, S., Caillier, S. J., Oksenberg, J. R., Fernandez-Vina, M. A. 2018: 1352458518770019

    Abstract

    BACKGROUND: The association between HLA-DRB1*15:01 with multiple sclerosis (MS) susceptibility is well established, but the contribution of the tightly associated HLA-DRB5*01:01 allele has not yet been completely ascertained. Similarly, the effects of HLA-DRB1*04:01 alleles and haplotypes, defined at the full-gene resolution level with MS risk remains to be elucidated.OBJECTIVES: To characterize the molecular architecture of class II HLA-DR15 and HLA-DR4 haplotypes associated with MS.METHODS: Next-generation sequencing was used to determine HLA-DQB1, HLA-DQA1, and HLA-DRB1/4/5 alleles in 1403 unrelated European-American patients and 1425 healthy unrelated controls. Effect sizes of HLA alleles and haplotypes on MS risk were measured by odds ratio (OR) with 95% confidence intervals.RESULTS: HLA-DRB1*15:01:01:01SG (OR=3.20, p<2.2E-16), HLA-DRB5*01:01:01 (OR=2.96, p<2.2E-16), and HLA-DRB5*01:01:01v1_STR1 (OR=8.18, p=4.3E-05) alleles all occurred at significantly higher frequencies in MS patients compared to controls. The most significant predis-posing haplotypes were HLA-DQB1*06:02:01~ HLA-DQA1*01:02:01:01SG~HLA-DRB1*15:01:01:01SG~HLA-DRB5*01:01:01 and HLA-DQB1*06:02:01~HLA-DQA1*01:02:01:01SG~HLA-DRB1*15:01:01:01SG~HLA-DRB5*01:01:01v1_STR1 (OR=3.19, p<2.2E-16; OR=9.30, p=9.7E-05, respectively). Analyses of the HLA-DRB1*04 cohort in the absence of HLA-DRB1*15:01 haplotypes revealed that the HLA-DQB1*03:01:01:01~HLA-DQA1*03:03:01:01~HLA-DRB1*04:01:01:01SG~HLA-DRB4*01:03:01:01 haplotype was protective (OR=0.64, p=0.028), whereas the HLA-DQB1*03:02:01~HLA-DQA1*03:01:01~HLA-DRB1*04:01:01:01SG~HLA-DRB4*01:03:01:01 haplotype was associated with MS susceptibility (OR=1.66, p=4.9E-03).CONCLUSION: HLA-DR15 haplotypes, including genomic variants of HLA-DRB5, and HLA-DR4 haplotypes affect MS risk.

    View details for PubMedID 29683085

  • Impact of HLA Alleles on Outcomes of Allogeneic Transplantation for B Cell Non-Hodgkin Lymphomas: A Center for International Blood and Marrow Transplant Research Analysis BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION William, B. M., Wang, T., Haagenson, M. D., Fleischhauer, K., Verneris, M., Hsu, K. C., de Lima, M. J., Fernandez-Vina, M., Spellman, S. R., Lee, S. J., Hill, B. T. 2018; 24 (4): 827?31

    Abstract

    Even in the modern era of targeted therapies, allogeneic hematopoietic stem cell transplantation (allo-HCT) can offer a chance of extended survival in B cell non-Hodgkin lymphoma (B-NHL) patients who relapse after or are deemed ineligible for autologous transplantation. A better understanding of the factors influencing the graft-versus-lymphoma (GVL) response would be useful in identifying B-NHL patients who may benefit from allo-HCT. Based on prior single-center reports, we hypothesized that certain HLA alleles, or haplotypes, may be associated with superior GVL compared with others after allo-HCT. To test this possibility we retrospectively evaluated whether the presence of HLA-A2, HLA-C1C1, HLA-DRB1*01:01, or HLA-DRB1*13 alleles or the presence of HLA-A1+, HLA-A2-, and HLA-B44- haplotypes is associated with outcomes in a cohort of 1314 HLA-8/8 matched sibling or unrelated donor HCT for relapsed/refractory B-NHL. We observed no significant association between any HLA allele or haplotype and overall survival or any of the secondary endpoints. In conclusion, this study represents the largest reported series of allo-HCT outcomes of B-NHL patients based on HLA type. Identification of other variables will be required to delineate the immunologic impact of donor-host interactions on outcomes of allo-HCT for B-NHL.

    View details for DOI 10.1016/j.bbmt.2017.11.003

    View details for Web of Science ID 000430640800026

    View details for PubMedID 29155319

    View details for PubMedCentralID PMC5902644

  • Effect of nonpermissive HLA-DPB1 mismatches after unrelated allogeneic transplantation with in vivo T-cell depletion BLOOD Oran, B., Saliba, R. M., Carmazzi, Y., de Lima, M., Rondon, G., Ahmed, S., Alousi, A., Andersson, B. S., Anderlini, P., Alvarez, M., Bashir, Q., Ciurea, S., Fernandez-Vina, M., Hosing, C., Kebriaei, P., Korbling, M., Cano, P., Khouri, I., Marin, D., Nieto, Y., Olson, A., Popat, U., Rezvani, K., Qazilbash, M., Shpall, E. J., Champlin, R. E., Cao, K. 2018; 131 (11): 1248?57

    Abstract

    We investigated the impact of donor-recipient HLA-DPB1 matching on outcomes of allogeneic hematopoietic stem cell transplantation with in vivo T-cell depletion using antithymocyte globulin (ATG) for patients with hematological malignancies. All donor-recipient pairs had high-resolution typing for HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, HLA-DPB1, and HLA-DRB3/4/5 and were matched at HLA-A, HLA-B, HLA-C, and HLA-DRB1. HLA-DPB1 mismatches were categorized by immunogenicity of the DPB1 matching using the DPB T-cell epitope tool. Of 1004 donor-recipient pairs, 210 (21%) were DPB1 matched, 443 (44%) had permissive mismatches, 184 (18%) had nonpermissive mismatches, in graft-versus-host (GVH) direction, and 167 (17%) had nonpermissive mismatches in host-versus-graft (HVG) direction. Compared with HLA-DPB1 permissive mismatched pairs, nonpermissive GVH mismatched pairs had the highest risk for grade II to IV acute graft-versus-host disease (aGVHD) (hazard ratio [HR], 1.4; P = .01) whereas matched pairs had the lowest risk (HR, 0.5; P < .001). Grade III to IV aGVHD was only increased with HLA-DPB1 nonpermissive GVH mismatched pairs (HR, 2.3; P = .005). The risk for disease progression was lower with any HLA-DPB1 mismatches, permissive or nonpermissive. However, the favorable prognosis of HLA-DPB1 mismatches on disease progression was observed only in peripheral blood stem cell recipients who were in the intermediate-risk group by the Disease Risk Index (HR, 0.4; P = .001) but no other risk groups. Our results suggest avoidance of nonpermissive GVH HLA-DPB1 mismatches for lowering the risk for grade II to IV and III to IV aGVHD. Permissive or nonpermissive HVG HLA-DPB1 mismatches may be preferred over HLA-DPB1 matches in the intermediate-risk patients to decrease the risk for disease progression.

    View details for PubMedID 29386198

  • Collection and storage of HLA NGS genotyping data for the 17th International HLA and Immunogenetics Workshop Chang, C., Osoegawa, K., Milius, R. P., Maiers, M., Xiaoa, W., Fernandez-Vina, M., Mack, S. J. ELSEVIER SCIENCE INC. 2018: 77?86

    Abstract

    For over 50?years, the International HLA and Immunogenetics Workshops (IHIW) have advanced the fields of histocompatibility and immunogenetics (H&I) via community sharing of technology, experience and reagents, and the establishment of ongoing collaborative projects. Held in the fall of 2017, the 17th IHIW focused on the application of next generation sequencing (NGS) technologies for clinical and research goals in the H&I fields. NGS technologies have the potential to allow dramatic insights and advances in these fields, but the scope and sheer quantity of data associated with NGS raise challenges for their analysis, collection, exchange and storage. The 17th IHIW adopted a centralized approach to these issues, and we developed the tools, services and systems to create an effective system for capturing and managing these NGS data. We worked with NGS platform and software developers to define a set of distinct but equivalent NGS typing reports that record NGS data in a uniform fashion. The 17th IHIW database applied our standards, tools and services to collect, validate and store those structured, multi-platform data in an automated fashion. We have created community resources to enable exploration of the vast store of curated sequence and allele-name data in the IPD-IMGT/HLA Database, with the goal of creating a long-term community resource that integrates these curated data with new NGS sequence and polymorphism data, for advanced analyses and applications.

    View details for PubMedID 29247682

    View details for PubMedCentralID PMC5805642

  • Multiplex family with GAD65-Abs neurologic syndromes NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION Belbezier, A., Joubert, B., Montero-Martin, G., Fernandez-Vina, M., Fabien, N., Rogemond, V., Mignot, E., Honnorat, J. 2018; 5 (1): e416

    Abstract

    Neurologic autoimmune syndromes associated with anti-glutamate acid decarboxylase 65 antibodies (GAD65-Abs) are rare and mostly sporadic.We describe a niece and her aunt with GAD65-Abs neurologic syndromes. High-resolution HLA typing of Class I and Class II alleles was performed using next-generation sequencing.The proband had cerebellar ataxia and probable limbic encephalitis features, whereas her niece had stiff-person syndrome. Both had a high titer of GAD65-Abs in serum and CSF and showed signs of inflammation in CSF. Both affected members carried the same rare recombinant DRB1*15:01:01?DQA1*01:02:01?DQB1*05:02:01 haplotype, which may or may not be involved in disease susceptibility. Of interest, other unaffected members of the family either had the same HLA haplotype but normal serum GAD65-Abs or had different HLA types but a high titer of serum GAD65-Abs without neurologic symptoms, suggesting cumulative effects.This unique association strengthens the concept that hereditary factors, possibly including specific HLA haplotypes, play a role in neurologic syndromes associated with GAD65-Abs.

    View details for PubMedID 29379821

  • Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients BONE MARROW TRANSPLANTATION Andersson, B. S., Thall, P. F., Valdez, B. C., Milton, D. R., Al-Atrash, G., Chen, J., Gulbis, A., Chu, D., Martinez, C., Parmar, S., Popat, U., Nieto, Y., Kebriaei, P., Alousi, A., de Lima, M., Rondon, G., Meng, Q. H., Myers, A., Kawedia, J., Worth, L. L., Fernandez-Vina, M., Madden, T., Shpall, E. J., Jones, R. B., Champlin, R. E. 2017; 52 (4): 580-587
  • MHC Class I Chain-Related Gene A (MICA) Donor-Recipient Mismatches and MICA-129 Polymorphism in Unrelated Donor Hematopoietic Cell Transplantations Has No Impact on Outcomes in Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, or Myelodysplastic Syndrome: A Center for International Blood and Marrow Transplant Research Study BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Askar, M., Sobecks, R., Wang, T., Haagenson, M., Majhail, N., Madbouly, A., Thomas, D., Zhang, A., Fleischhauer, K., Hsu, K., Verneris, M., Lee, S. J., Spellman, S. R., Fernandez-Vina, M. 2017; 23 (3): 436-444

    Abstract

    Single-center studies have previously reported associations of MHC Class I Chain-Related Gene A (MICA) polymorphisms and donor-recipient MICA mismatching with graft-versus-host disease (GVHD) after unrelated donor hematopoietic cell transplantation (HCT). In this study, we investigated the association of MICA polymorphism (MICA-129, MM versus MV versus VV) and MICA mismatches after HCT with 10/10 HLA-matched (n?=?552) or 9/10 (n?=?161) unrelated donors. Included were adult patients with a first unrelated bone marrow or peripheral blood HCT for acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome that were reported to the Center for International Blood and Marrow Transplant Research between 1999 and 2011. Our results showed that neither MICA mismatch nor MICA-129 polymorphism were associated with any transplantation outcome (P?

    View details for DOI 10.1016/j.bbmt.2016.11.021

    View details for PubMedID 27987385

  • HLA Amino Acid Polymorphisms and Kidney Allograft Survival. Transplantation Kamoun, M., McCullough, K. P., Maiers, M., Fernandez Vina, M. A., Li, H., Teal, V., Leichtman, A. B., Merion, R. M. 2017

    Abstract

    The association of HLA mismatching with kidney allograft survival has been well established. We examined whether amino acid (AA) mismatches (MMs) at the antigen recognition site of HLA molecules represent independent and incremental risk factors for kidney graft failure (GF) beyond those MMs assessed at the antigenic (2-digit) specificity.Data on 240 024 kidney transplants performed between 1987 and 2009 were obtained from the Scientific Registry of Transplant Recipients. We imputed HLA-A, -B, and -DRB1 alleles and corresponding AA polymorphisms from antigenic specificity through the application of statistical and population genetics inferences. GF risk was evaluated using Cox proportional-hazards regression models adjusted for covariates including patient and donor risk factors and HLA antigen MMs.We show that estimated AA MMs at particular positions in the peptide-binding pockets of HLA-DRB1 molecule account for a significant incremental risk that was independent of the well-known association of HLA antigen MMs with graft survival. A statistically significant linear relationship between the estimated number of AA MMs and risk of GF was observed for HLA-DRB1 in deceased donor and living donor transplants. This relationship was strongest during the first 12 months after transplantation (hazard ratio, 1.30 per 15 DRB1 AA MM; P < 0.0001).This study shows that independent of the well-known association of HLA antigen (2-digit specificity) MMs with kidney graft survival, estimated AA MMs at peptide-binding sites of the HLA-DRB1 molecule account for an important incremental risk of GF.

    View details for DOI 10.1097/TP.0000000000001670

    View details for PubMedID 28221244

  • HLA-mismatched unrelated donor transplantation using TLI-ATG conditioning has a low risk of GVHD and potent antitumor activity. Blood advances Spinner, M. A., Fernández-Viña, M., Creary, L. E., Quinn, O., Elder, L., Arai, S., Johnston, L. J., Meyer, E. H., Miklos, D. B., Muffly, L. S., Negrin, R. S., Shizuru, J. A., Weng, W. K., Laport, G. G., Strober, S., Lowsky, R., Rezvani, A. R. 2017; 1 (17): 1347?57

    Abstract

    Many patients lack a fully HLA-matched donor for hematopoietic cell transplantation (HCT), and HLA mismatch is typically associated with inferior outcomes. Total lymphoid irradiation and antithymocyte globulin (TLI-ATG) is a nonmyeloablative conditioning regimen that is protective against graft-versus-host disease (GVHD), and we hypothesized that the protective effect would extend beyond HLA-matched donors. We report outcomes for all consecutively transplanted patients at Stanford University from December 2001 through May 2015 who received TLI-ATG conditioning and HCTs from 8 to 9 out of 10 HLA-mismatched unrelated donors (MMUDs, N = 72) compared with 10 out of 10 HLA-matched unrelated donors (MUDs, N = 193). The median age of the patients was 60 years with a median follow-up of 2 years, and there was a similar distribution of lymphoid and myeloid malignancies in both cohorts. There were no significant differences between MMUD and MUD cohorts in overall survival (46% vs 46% at 5 years, P = .86), disease-free survival (38% vs 28% at 5 years, P = .25), nonrelapse mortality (17% vs 12% at 2 years, P = .34), acute GVHD grades III-IV (6% vs 3% at day +100, P = .61), or chronic GVHD (39% vs 35% at 5 years, P = .49). There was a trend toward less relapse in the MMUD cohort (45% vs 60% at 5 years, hazard ratio: 0.71, P = .094), which was significant for patients with lymphoid malignancies (29% vs 57% at 5 years, hazard ratio: 0.55, P = .044). Achieving full donor chimerism was strongly associated with lower relapse rates. TLI-ATG conditioning may overcome the traditionally poorer outcome associated with HLA-mismatched donors and may be particularly well suited for patients with lymphoid malignancies who lack HLA-matched donors.

    View details for PubMedID 29296777

  • Human leukocyte antigen supertype matching after myeloablative hematopoietic cell transplantation with 7/8 matched unrelated donor allografts: a report from the Center for International Blood and Marrow Transplant Research HAEMATOLOGICA Lazaryan, A., Wang, T., Spellman, S. R., Wang, H., Pidala, J., Nishihori, T., Askar, M., Olsson, R., Oudshoorn, M., Abdel-Azim, H., Yong, A., Gandhi, M., Dandoy, C., Savani, B., Hale, G., Page, K., Bitan, M., Reshef, R., Drobyski, W., Marsh, S. G., Schultz, K., Mueller, C. R., Fernandez-Vina, M. A., Verneris, M. R., Horowitz, M. M., Arora, M., Weisdorf, D. J., Lee, S. J. 2016; 101 (10): 1267-1274

    Abstract

    The diversity of the human leukocyte antigen (HLA) class I and II alleles can be simplified by consolidating them into fewer supertypes based on functional or predicted structural similarities in epitope-binding grooves of HLA molecules. We studied the impact of matched and mismatched HLA-A (265 versus 429), -B (230 versus 92), -C (365 versus 349), and -DRB1 (153 versus 51) supertypes on clinical outcomes of 1934 patients with acute leukemias or myelodysplasia/myeloproliferative disorders. All patients were reported to the Center for International Blood and Marrow Transplant Research following single-allele mismatched unrelated donor myeloablative conditioning hematopoietic cell transplantation. Single mismatched alleles were categorized into six HLA-A (A01, A01A03, A01A24, A02, A03, A24), six HLA-B (B07, B08, B27, B44, B58, B62), two HLA-C (C1, C2), and five HLA-DRB1 (DR1, DR3, DR4, DR5, DR9) supertypes. Supertype B mismatch was associated with increased risk of grade II-IV acute graft-versus-host disease (hazard ratio =1.78, P=0.0025) compared to supertype B match. Supertype B07-B44 mismatch was associated with a higher incidence of both grade II-IV (hazard ratio=3.11, P=0.002) and III-IV (hazard ratio=3.15, P=0.01) acute graft-versus-host disease. No significant associations were detected between supertype-matched versus -mismatched groups at other HLA loci. These data suggest that avoiding HLA-B supertype mismatches can mitigate the risk of grade II-IV acute graft-versus-host disease in 7/8-mismatched unrelated donor hematopoietic cell transplantation when multiple HLA-B supertype-matched donors are available. Future studies are needed to define the mechanisms by which supertype mismatching affects outcomes after alternative donor hematopoietic cell transplantation.

    View details for DOI 10.3324/haematol.2016.143271

    View details for PubMedID 27247320

  • Haploidentical Natural Killer Cells Infused before Allogeneic Stem Cell Transplantation for Myeloid Malignancies: A Phase I Trial BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Lee, D. A., Denman, C. J., Rondon, G., Woodworth, G., Chen, J., Fisher, T., Kaur, I., Fernandez-Vina, M., Cao, K., Ciurea, S., Shpall, E. J., Champlin, R. E. 2016; 22 (7): 1290-1298

    Abstract

    Allogeneic stem cell transplantation is an effective treatment for high-risk myeloid malignancies, but relapse remains the major post-transplantation cause of treatment failure. Alloreactive natural killer (NK) cells mediate a potent antileukemic effect and may also enhance engraftment and reduce graft-versus-host disease (GVHD). Haploidentical transplantations provide a setting in which NK cell alloreactivity can be manipulated, but they are associated with high rates of GVHD. We performed a phase I study infusing escalating doses of NK cells from an HLA haploidentical-related donor-selected for alloreactivity when possible-as a component of the preparative regimen for allotransplantation from a separate HLA-identical donor. The goal of infusing third-party alloreactive NK cells was to augment the antileukemic effect of the transplantation without worsening GVHD and, thus, improve the overall outcome of hematopoietic transplantation. Twenty-one patients with high-risk acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myelogenous leukemia refractory or beyond first remission received a preparative regimen with busulfan and fludarabine followed by infusion of apheresis-derived, antibody-selected, and IL-2-activated NK cells. Doses were initially based on total nucleated cell (TNC) content and later based on CD56(+) cells to reduce variability. CD56(+) content ranged from .02 to 8.32 × 10(6)/kg. IL-2, .5 × 10(6) units/m(2) subcutaneously was administered daily for 5 days in the final cohort (n = 10). CD3(+) cells in the NK cell product were required to be < 10(5)/kg. Median relapse-free, overall, and GVHD-free/relapse-free survival for all patients enrolled was 102, 233, and 89 days, respectively. Five patients are alive, 5 patients died of transplantation-related causes, and 11 patients died of relapse. Despite the small sample size, survival was highly associated with CD56(+) cells delivered (P = .022) and development of ? grade 3 GVHD (P = .006). There were nonsignificant trends toward higher survival rates in those receiving NK cells from KIR ligand-mismatched donors and KIR-B haplotype donors. There was no association with disease type, remission at time of transplantation, or KIR content. GVHD was not associated with TNC, CD56(+), or CD3(+) cells infused in the NK cell product or the stem cell product. This trial demonstrates a lack of major toxicity attributable to third-party NK cell infusions delivered in combination with an HLA-compatible allogeneic transplantation. The infusion of haploidentical alloreactive NK cells was well tolerated and did not interfere with engraftment or increase the rate of GVHD after allogeneic hematopoietic transplantation. Durable complete remissions occurred in 5 patients at high risk for disease recurrence. This approach is being further developed in a phase I/II trial with ex vivo-expanded NK cells to increase the NK cell dose with the objective of reducing relapse and improving the outcome of allogeneic hematopoietic transplantation for AML/MDS.

    View details for DOI 10.1016/j.bbmt.2016.04.009

    View details for PubMedID 27090958

  • Diversity in exon 5 of HLA-C*04:01:01G is significant in anthropological studies HUMAN IMMUNOLOGY Dunn, P. P., Lamb, G., Selwyn, C., Compton, J., Yang, E., Maiers, M., Fernandez-Vina, M. 2016; 77 (5): 426-428

    Abstract

    Polymorphisms in Human Leukocyte Antigen (HLA) class I genes are generally considered to be relevant only if they reside in exons 2 and 3 or if they affect the expression of the allele. HLA-C(?)04:82 differs from the common HLA-C(?)04:01:01 by having a 9 nucleotide, or 3 amino acid duplication, in exon 5. Having observed HLA-C(?)04:82 in a New Zealand Maori stem cell patient, we have attempted to examine the prevalence of this allele in different ethnicities. Although our studies are in a limited number of patients and donors, they have revealed that, in the Pacific region, HLA-C(?)04:82 appears to be the most common allele of the HLA-C(?)04:01:01G group of alleles, notably in Filippinos and in Maori/Polynesians. In these populations this allele has characteristic HLA-ABCDRB1 haplotypes. Thus, our studies have shown that polymorphisms outside of the clinically important exons can be considered to be relevant in anthropological studies.

    View details for DOI 10.1016/j.humimm.2016.03.007

    View details for Web of Science ID 000375741700008

    View details for PubMedID 27018403

  • High levels of anti-tuberculin (IgG) antibodies correlate with the blocking of T-cell proliferation in individuals with high exposure to Mycobacterium tuberculosis INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES Feris, E. J., Encinales, L., Awad, C., Stern, J. N., Tabansky, I., Jimenez-Alvarez, L., Ramirez-Martinez, G., Cruz-Lagunas, A., Bobadilla, K., Marquez, E., Granados-Montiel, J., Rodriguez-Reyna, T. S., Fernandez-Vina, M., Granados, J., Zuniga, J., Yunis, E. J. 2016; 43: 21-24

    Abstract

    To determine the effect of anti-tuberculin antibodies in the T-cell proliferation in response to tuberculin and Candida antigens in individuals with different levels of tuberculosis (TB) risk.Sixteen high-risk TB individuals, 30 with an intermediate TB risk (group A), and 45 with a low TB risk (group B), as well as 49 control individuals, were studied. Tuberculin skin test (TST) results were analyzed and serum levels of antibodies (IgG and IgM) against purified protein derivative (PPD) were measured by ELISA. Tuberculin and Candida antigens were used to stimulate T-cell proliferation in the presence of human AB serum or autologous serum.High levels of anti-tuberculin IgG antibodies were found to be significantly associated with the blocking of T-cell proliferation responses in cultures stimulated with tuberculin but not with Candida antigens in the presence of autologous serum. This phenomenon was particularly frequent in high-risk individuals with high levels of anti-tuberculin IgG antibodies in the autologous serum when compared to the other risk groups, which exhibited lower levels of anti-tuberculin antibodies.Although cellular immunity plays a central role in the protection against TB, humoral immunity is critical in the control of Mycobacterium tuberculosis infection in high-risk individuals with latent TB infection.

    View details for DOI 10.1016/j.ijid.2015.12.004

    View details for Web of Science ID 000369789900005

    View details for PubMedID 26686942

  • The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy BLOOD Kollman, C., Spellman, S. R., Zhang, M., Hassebroek, A., Anasetti, C., Antin, J. H., Champlin, R. E., Confer, D. L., DiPersio, J. F., Fernandez-Vina, M., Hartzman, R. J., Horowitz, M. M., Hurley, C. K., Karanes, C., Maiers, M., Mueller, C. R., Perales, M., Setterholm, M., Woolfrey, A. E., Yu, N., Eapen, M. 2016; 127 (2): 260-267

    Abstract

    There are >24 million registered adult donors, and the numbers of unrelated donor transplantations are increasing. The optimal strategy for prioritizing among comparably HLA-matched potential donors has not been established. Therefore, the objective of the current analyses was to study the association between donor characteristics (age, sex, parity, cytomegalovirus serostatus, HLA match, and blood group ABO match) and survival after transplantation for hematologic malignancy. The association of donor characteristics with transplantation outcomes was examined using either logistic or Cox regression models, adjusting for patient disease and transplantation characteristics associated with outcomes in 2 independent datasets: 1988 to 2006 (N = 6349; training cohort) and 2007 to 2011 (N = 4690; validation cohort). All donor-recipient pairs had allele-level HLA typing at HLA-A, -B, -C, and -DRB1, which is the current standard for selecting donors. Adjusting for patient disease and transplantation characteristics, survival was better after transplantation of grafts from young donors (aged 18-32 years) who were HLA matched to recipients (P < .001). These findings were validated for transplantations that occurred between 2007 and 2011. For every 10-year increment in donor age, there is a 5.5% increase in the hazard ratio for overall mortality. Increasing HLA disparity was also associated with worsening survival. Donor age and donor-recipient HLA match are important when selecting adult unrelated donors. Other donor characteristics such as sex, parity, and cytomegalovirus serostatus were not associated with survival. The effect of ABO matching on survival is modest and must be studied further before definitive recommendations can be offered.

    View details for DOI 10.1182/blood-2015-08-663823

    View details for PubMedID 26527675

  • Minimum information for reporting next generation sequence genotyping (MIRING): Guidelines for reporting HLA and KIR genotyping via next generation sequencing HUMAN IMMUNOLOGY Mack, S. J., Milius, R. P., Gifford, B. D., Sauter, J., Hofmann, J., Osoegawa, K., Robinson, J., Groeneweg, M., Turenchalk, G. S., Adai, A., Holcomb, C., Rozemuller, E. H., Penning, M. T., Heuer, M. L., Wang, C., Salit, M. L., Schmidt, A. H., Parham, P. R., Mueller, C., Hague, T., Fischer, G., Fernandez-Vina, M., Hollenbach, J. A., Norman, P. J., Maiers, M. 2015; 76 (12): 954-962

    Abstract

    The development of next-generation sequencing (NGS) technologies for HLA and KIR genotyping is rapidly advancing knowledge of genetic variation of these highly polymorphic loci. NGS genotyping is poised to replace older methods for clinical use, but standard methods for reporting and exchanging these new, high quality genotype data are needed. The Immunogenomic NGS Consortium, a broad collaboration of histocompatibility and immunogenetics clinicians, researchers, instrument manufacturers and software developers, has developed the Minimum Information for Reporting Immunogenomic NGS Genotyping (MIRING) reporting guidelines. MIRING is a checklist that specifies the content of NGS genotyping results as well as a set of messaging guidelines for reporting the results. A MIRING message includes five categories of structured information - message annotation, reference context, full genotype, consensus sequence and novel polymorphism - and references to three categories of accessory information - NGS platform documentation, read processing documentation and primary data. These eight categories of information ensure the long-term portability and broad application of this NGS data for all current histocompatibility and immunogenetics use cases. In addition, MIRING can be extended to allow the reporting of genotype data generated using pre-NGS technologies. Because genotyping results reported using MIRING are easily updated in accordance with reference and nomenclature databases, MIRING represents a bold departure from previous methods of reporting HLA and KIR genotyping results, which have provided static and less-portable data. More information about MIRING can be found online at miring.immunogenomics.org.

    View details for DOI 10.1016/j.humimm.2015.09.011

    View details for Web of Science ID 000366437900012

    View details for PubMedID 26407912

    View details for PubMedCentralID PMC4674382

  • Very high resolution single pass HLA genotyping using amplicon sequencing on the 454 next generation DNA sequencers: Comparison with Sanger sequencing HUMAN IMMUNOLOGY Yamamoto, F., Hoeglund, B., Fernandez-Vina, M., Tyan, D., Rastrou, M., Williams, T., Moonsamy, P., Goodridge, D., Anderson, M., Erlich, H. A., Holcomb, C. L. 2015; 76 (12): 910-916

    View details for DOI 10.1016/j.humimm.2015.05.002

    View details for Web of Science ID 000366437900006

    View details for PubMedID 26037172

  • HLA Mismatch Is Associated with Worse Outcomes after Unrelated Donor Reduced-Intensity Conditioning Hematopoietic Cell Transplantation: An Analysis from the Center for International Blood and Marrow Transplant Research. Biology of blood and marrow transplantation Verneris, M. R., Lee, S. J., Ahn, K. W., Wang, H., Battiwalla, M., Inamoto, Y., Fernandez-Vina, M. A., Gajewski, J., Pidala, J., Munker, R., Aljurf, M., Saber, W., Spellman, S., Koreth, J. 2015; 21 (10): 1783-1789

    Abstract

    Over the past 2 decades, reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC HCT) has increased substantially. Many patients do not have fully HLA-matched donors, and the impact of HLA mismatch on RIC HCT has not been examined in large cohorts. We analyzed 2588 recipients of 8/8 HLA-high resolution matched (n = 2025) or single-locus mismatched (n = 563) unrelated donor (URD) RIC HCT from 1999 to 2011. Overall survival (OS) was the primary outcome. Secondary endpoints included treatment-related mortality (TRM), relapse, disease-free survival (DFS), and acute/chronic graft-versus-host disease (GVHD). Adjusted 1- and 3-year OS was better in 8/8- versus 7/8-matched recipients (54.7% versus 48.8%, P = .01, and 37.4% versus 30.9%, P = .005, respectively). In multivariate models 7/8 URD RIC HCT recipients had more grades II to IV acute GVHD (RR = 1.29, P = .0034), higher TRM (RR = 1.52, P < .0001), and lower DFS (RR = 1.12, P = .0015) and OS (RR = 1.25, P = .0001), with no difference in relapse or chronic GVHD. In subgroup analysis, inferior transplant outcomes were noted regardless of the HLA allele mismatched. Previously reported permissive mismatches at HLA-C (C*03:03/C*03:04) and HLA-DP1 (based on T cell-epitope matching) were not associated with better outcomes. Although feasible, single-locus mismatch in RIC URD HCT is associated with inferior outcomes.

    View details for DOI 10.1016/j.bbmt.2015.05.028

    View details for PubMedID 26055300

  • Better allele-level matching improves transplant-related mortality after double cord blood transplantation HAEMATOLOGICA Oran, B., Cao, K., Saliba, R. M., Rezvani, K., de Lima, M., Ahmed, S., Hosing, C. M., Popat, U. R., Carmazzi, Y., Kebriaei, P., Nieto, Y., Rondon, G., Willis, D., Shah, N., Parmar, S., Olson, A., Moore, B., Marin, D., Mehta, R., Fernandez-Vina, M., Champlin, R. E., Shpall, E. J. 2015; 100 (10): 1361-1370

    Abstract

    Cord blood transplant requires less stringent human leukocyte antigen matching than unrelated donors. In 133 patients with hematologic malignancies who engrafted after double cord blood transplantation with a dominant unit, we studied the effect of high resolution testing at 4 loci (-A, -B, -C, -DRB1) for its impact on 2-year transplant-related mortality. Ten percent of the dominant cord blood units were matched at 7-8/8 alleles using HLA-A, -B, -C, and -DRB1; 25% were matched at 6/8, 40% at 5/8, and 25% at 4/8 or less allele. High resolution typing at 4 loci showed that there was no 2-year transplant-related mortality in 7-8/8 matched patients. Patients with 5-6/8 matched dominant cord blood units had 2-year transplant-related mortality of 39% while patients with 4/8 or less matched units had 60%. Multivariate regression analyses confirmed the independent effect of high resolution typing on the outcome when adjusted for age, diagnosis, CD34(+) cell dose infused, graft manipulation and cord to cord matching. The worst prognostic group included patients aged over 32 years with 4/8 or less matched cord blood units compared with patients who were either younger than 32 years old independent of allele-level matching, or aged over 32 years but with 5-6/8 matched cord blood units (Hazard Ratio 2.2; 95% confidence interval: 1.3-3.7; P<0.001). Patients with 7-8/8 matched units remained the group with the best prognosis. Our data suggest that high resolution typing at 4 loci and selecting cord blood units matched at at least 5/8 alleles may reduce transplant-related mortality after double cord blood transplantation.

    View details for DOI 10.3324/haematol.2015.127787

    View details for PubMedID 26250579

  • Limited Variation in BK Virus T-Cell Epitopes Revealed by Next-Generation Sequencing. Journal of clinical microbiology Sahoo, M. K., Tan, S. K., Chen, S. F., Kapusinszky, B., Concepcion, K. R., Kjelson, L., Mallempati, K., Farina, H. M., Fernández-Viña, M., Tyan, D., Grimm, P. C., Anderson, M. W., Concepcion, W., Pinsky, B. A. 2015; 53 (10): 3226-3233

    Abstract

    BK virus (BKV) infection and end-organ disease remains a formidable challenge to the hematopoietic cell transplant (HCT) and kidney transplant fields. As BKV-specific treatments are limited, immunologic-based therapies may be a promising and novel therapeutic option for transplant recipients with persistent BKV infection. Here, we describe a whole-genome, deep sequencing methodology and bioinformatics pipeline that identifies BKV variants across the genome and at BKV-specific HLA-A2, HLA-B0702, and HLA-B08 restricted CD8 T-cell epitopes. BKV whole genomes were amplified using long-range PCR with four inverse primer sets and fragmentation libraries were sequenced on the Ion Torrent PGM. An error model and variant calling algorithm were developed to accurately identify rare variants. 65 samples from 18 pediatric HCT and kidney recipients with quantifiable BKV DNAemia underwent whole-genome sequencing. Limited genetic variation was observed. The median number of amino acid variants identified per sample was 8 (range 2-37, interquartile range 10), with the majority of variants (77%) detected at a frequency of less than 5%. When normalized for length, there was no statistical difference in the median number of variants across all genes. Similarly, the predominant virus population within samples harbored T-cell epitopes similar to the reference BKV strain that was matched for BKV genotype. Despite the conservation of epitopes, low-level variants in T-cell epitopes were detected in 77.7% (14/18) of patients. Understanding epitope variation across the whole genome provides insight into the virus-immune interface and may help guide the development of protocols for novel immunologic-based therapies.

    View details for DOI 10.1128/JCM.01385-15

    View details for PubMedID 26202116

  • Impact of KIR and HLA Genotypes on Outcomes after Reduced-Intensity Conditioning Hematopoietic Cell Transplantation. Biology of blood and marrow transplantation Sobecks, R. M., Wang, T., Askar, M., Gallagher, M. M., Haagenson, M., Spellman, S., Fernandez-Vina, M., Malmberg, K., Müller, C., Battiwalla, M., Gajewski, J., Verneris, M. R., Ringdén, O., Marino, S., Davies, S., Dehn, J., Bornhäuser, M., Inamoto, Y., Woolfrey, A., Shaw, P., Pollack, M., Weisdorf, D., Milller, J., Hurley, C., Lee, S. J., Hsu, K. 2015; 21 (9): 1589-1596

    Abstract

    Natural killer cells are regulated by killer cell immunoglobulin-like receptor (KIR) interactions with HLA class I ligands. Several models of natural killer cell reactivity have been associated with improved outcomes after myeloablative allogeneic hematopoietic cell transplantation (HCT), but this issue has not been rigorously addressed in reduced-intensity conditioning (RIC) unrelated donor (URD) HCT. We studied 909 patients undergoing RIC-URD HCT. Patients with acute myeloid leukemia (AML, n = 612) lacking ? 1 KIR ligands experienced higher grade III to IV acute graft-versus-host disease (GVHD) (HR, 1.6; 95% CI, 1.16 to 2.28; P = .005) compared to those with all ligands present. Absence of HLA-C2 for donor KIR2DL1 was associated with higher grade II to IV (HR, 1.4; P = .002) and III to IV acute GVHD (HR, 1.5; P = .01) compared with HLA-C2(+) patients. AML patients with KIR2DS1(+), HLA-C2 homozygous donors had greater treatment-related mortality compared with others (HR, 2.4; 95% CI, 1.4 to 4.2; P = .002) but did not experience lower relapse. There were no significant associations with outcomes for AML when assessing donor-activating KIRs or centromeric KIR content or for any donor-recipient KIR-HLA assessments in patients with myelodysplastic syndrome (n = 297). KIR-HLA combinations in RIC-URD HCT recapitulate some but not all KIR-HLA effects observed in myeloablative HCT.

    View details for DOI 10.1016/j.bbmt.2015.05.002

    View details for PubMedID 25960307

  • Impact of KIR and HLA Genotypes on Outcomes after Reduced-Intensity Conditioning Hematopoietic Cell Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Sobecks, R. M., Wang, T., Askar, M., Gallagher, M. M., Haagenson, M., Spellman, S., Fernandez-Vina, M., Malmberg, K., Mueller, C., Battiwalla, M., Gajewski, J., Verneris, M. R., Ringden, O., Marino, S., Davies, S., Dehn, J., Bornhaeuser, M., Inamoto, Y., Woolfrey, A., Shaw, P., Pollack, M., Weisdorf, D., Milller, J., Hurley, C., Lee, S. J., Hsu, K. 2015; 21 (9): 1589-1596

    Abstract

    Natural killer cells are regulated by killer cell immunoglobulin-like receptor (KIR) interactions with HLA class I ligands. Several models of natural killer cell reactivity have been associated with improved outcomes after myeloablative allogeneic hematopoietic cell transplantation (HCT), but this issue has not been rigorously addressed in reduced-intensity conditioning (RIC) unrelated donor (URD) HCT. We studied 909 patients undergoing RIC-URD HCT. Patients with acute myeloid leukemia (AML, n = 612) lacking ? 1 KIR ligands experienced higher grade III to IV acute graft-versus-host disease (GVHD) (HR, 1.6; 95% CI, 1.16 to 2.28; P = .005) compared to those with all ligands present. Absence of HLA-C2 for donor KIR2DL1 was associated with higher grade II to IV (HR, 1.4; P = .002) and III to IV acute GVHD (HR, 1.5; P = .01) compared with HLA-C2(+) patients. AML patients with KIR2DS1(+), HLA-C2 homozygous donors had greater treatment-related mortality compared with others (HR, 2.4; 95% CI, 1.4 to 4.2; P = .002) but did not experience lower relapse. There were no significant associations with outcomes for AML when assessing donor-activating KIRs or centromeric KIR content or for any donor-recipient KIR-HLA assessments in patients with myelodysplastic syndrome (n = 297). KIR-HLA combinations in RIC-URD HCT recapitulate some but not all KIR-HLA effects observed in myeloablative HCT.

    View details for DOI 10.1016/j.bbmt.2015.05.002

    View details for Web of Science ID 000360255900009

    View details for PubMedCentralID PMC4537837

  • Complement-Binding Donor-Specific Anti-HLA Antibodies and Risk of Primary Graft Failure in Hematopoietic Stem Cell Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Ciurea, S. O., Thall, P. F., Milton, D. R., Barnes, T. H., Kongtim, P., Carmazzi, Y., Lopez, A. A., Yap, D. Y., Popat, U., Rondon, G., Lichtiger, B., Aung, F., Afshar-Kharghan, V., Ma, Q., Fernandez-Vina, M., Champlin, R. E., Cao, K. 2015; 21 (8): 1392-1398

    Abstract

    Detection of donor-specific anti-HLA antibodies (DSA) has been associated with graft rejection in all forms of transplantation. The mechanism by which DSA increase the risk of graft failure remains unclear. We hypothesized that complement-binding DSA are associated with engraftment failure in hematopoietic stem cell transplantation (HSCT) and analyzed 122 haploidentical transplant recipients tested prospectively for DSA. Retrospective analysis to detect C1q binding DSA (C1q+DSA) was performed on 22 allosensitized recipients. Twenty-two of 122 patients (18%) had DSA, 19 of which were women (86%). Seven patients with DSA (32%) rejected the graft. Median DSA level at transplant for patients who failed to engraft was 10,055 mean fluorescence intensity (MFI) versus 2065 MFI for those who engrafted (P = .007). Nine patients with DSA were C1q positive in the initial samples with median DSA levels of 15,279 MFI (range, 1554 to 28,615), compared with 7 C1q-negative patients with median DSA levels of 2471 MFI (range, 665 to 12,254) (P = .016). Of 9 patients who were C1q positive in the initial samples, 5 patients remained C1q positive at time of transplant (all with high DSA levels [median, 15,279; range, 6487 to 22,944]) and experienced engraftment failure, whereas 4 patients became C1q negative pretransplant and all engrafted the donor cells (P = .008). In conclusion, patients with high DSA levels (>5000 MFI) and complement-binding DSA antibodies (C1q positive) appear to be at much higher risk of primary graft failure. The presence of C1q+DSA should be assessed in allosensitized patients before HSCT. Reduction of C1q+DSA levels might prevent engraftment failure in HSCT.

    View details for DOI 10.1016/j.bbmt.2015.05.001

    View details for Web of Science ID 000358557700008

    View details for PubMedCentralID PMC4506716

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