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 co-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 170 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. Also he served as Co-Chair of the Immunobiology Committee of the CIBMTR. He serves as the Liaison between the American Society for Histocompatibility and Immunogenetics to the National Marrow Donor Program. 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 is a member of the WHO Nomenclature Committee for Factors of the HLA System; he has been designated as Chairman of the next (17th) International Histocompatibility Workshop. He is Section Editor of Human Immunology and an Advisory Board Member of the International Journal of Immunogenetics. Recently he was invited by the Secretary of Health and Human Services to serve on the Advisory Council on Blood Stem Cell Transplantation (ACBSCT) of the U.Sr of the International Journal of Immunogenetics.

Academic Appointments


Teaching

2014-15 Courses


Publications

All Publications


  • 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

  • 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

  • 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

  • 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

  • Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation BLOOD Fernandez-Vina, 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 Web of Science ID 000335838100027

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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 Web of Science ID 000304881700065

    View details for PubMedID 22589303

  • 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

  • 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

  • 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

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