J A Madrigal

Anthony Nolan Research Institute, Londinium, England, United Kingdom

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Publications (223)865.04 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: HLA-B∗57:01 is a well-known and cost-effective pharmacogenetic marker for abacavir hypersensitivity. As with other HLA alleles, there is widespread variation in its frequency across populations. The Costa Rica Central Valley Population (CCVP) is the major population in this country. The frequency of HLA-B∗57:01 in this population has not been described yet. Thus, our aim was to determine the frequency of this allele in the CCVP. 200 unrelated healthy volunteer donors born in the CCVP were typed. HLA-B∗57-positive samples identified by HLA intermediate resolution typing methods were further typed by SBT to high resolution. An HLA-B∗57:01 carrier frequency of 5.00% was determined in this sample. This frequency is relatively high in comparison to reports from other populations in Latin America. These results suggest that there is a considerable frequency of HLA-B∗57:01 in the CCVP and that pharmacogenetic testing for HIV+ patients who are going to receive abacavir-based treatment should be considered in this country.
    Human immunology. 10/2014;
  • S T Cox, J A Madrigal, A Saudemont
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    ABSTRACT: The major histocompatibility complex (MHC) class I-related chain A (MICA) and B (MICB) are ligands for the natural killer group 2, member D (NKG2D) activating receptor expressed on natural killer (NK) cells, natural killer T (NKT) cells, CD8+ T cells and γδ T cells. Natural killer group 2, member D (NKG2D) ligand expression is stress-related and upregulated by infected or oncogenic cells leading to cytolysis. MICA and MICB genes display considerable polymorphism among individuals and studies have investigated allelic association with disease and relevance of MICA in transplantation, with variable success. It is now known that promoters of MICA and MICB are polymorphic with some polymorphisms associating with reduced expression. We sequenced International Histocompatibility Workshop (IHW) cell line DNA to determine promoter types and alleles encoded by exons 2-6. We found 8 of 12 known MICA promoter polymorphisms and although promoter P7 dominated, other promoters associated with the same allele. For example, MICA*002:01 had promoters P3, P4 or P7 and the common MICA*008:01/04 type had P1, P6 or P7. Similarly, we sequenced 8 of 12 known MICB promoter haplotypes. Some coding region defined MICB alleles had a single promoter, for example, MICB*002:01 and promoter P9, whereas the promiscuous MICB*005 allele had promoters P1, P2, P5, P6, P10 or P12. The results indicate potential for variation in expression of MICA and MICB ligands between individuals with the same allelic types. If differential expression by polymorphic MICA and MICB promoters is confirmed by functional studies, involvement of these genes in disease susceptibility or adverse transplantation outcomes may require knowledge of both promoter and allelic types to make meaningful conclusions.
    Tissue Antigens 06/2014; · 2.93 Impact Factor
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    ABSTRACT: Genomic sequence of HLA-A*02:95 identified in an Anthony Nolan volunteer donor.
    Tissue Antigens 06/2014; · 2.93 Impact Factor
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    ABSTRACT: Background It is of clinical relevance to recognize donors who are unlikely to meet the requested stem cell dose for transplantation, as this group may benefit from an alternative mobilization regimen. This study was performed to evaluate the frequency of unrelated donor peripheral blood stem cell (PBSC) collections that meet the target yield and the impact of donor factors on this.Study Design and Methods All sequential PBSC collections facilitated by the national registry (n = 323) from January through December 2011 were analyzed. Donor factors analyzed included age, sex, weight, and presence of a central line.ResultsIn univariate analyses, we found that reaching the target yield was significantly associated with a higher donor weight (85.6 kg vs. 75.3 kg, p < 0.001), male donor sex (55% vs. 19%, p < 0.001), a positive difference in weight between donor and recipient (4.3 kg vs. −8 kg, p < 0.001), and a higher volume of blood processed (13.8 L vs. 11.9 L, p < 0.001). After stepwise binary logistic regression, sex (p < 0.001) and difference between donor and recipient weight (p < 0.005) remained significantly associated with target yield being met after 1 day of collection.Conclusions This study shows than women and donors who are lighter than their recipient have a decreased likelihood of meeting the transplant physician's requested dose. New strategies to improve mobilization in such donors are needed. These findings may also impact future donor recruitment strategies.
    Transfusion 06/2014; · 3.53 Impact Factor
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    ABSTRACT: Description of a novel RAET1E/ULBP4 allele characterized by sequence-based typing and cloning: RAET1E*011.
    Tissue Antigens 05/2014; · 2.93 Impact Factor
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    Aurore Saudemont, J Alejandro Madrigal
    Haematologica 02/2014; 99(2):203-5. · 5.94 Impact Factor
  • A Billen, J A Madrigal, B E Shaw
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    ABSTRACT: Donation of haematopoietic stem cells, either through BM or PBSC collection, is a generally safe procedure for healthy donors although adverse reactions are a definite risk. The invaluable source of donation and its central role in transplantation implies that every effort should be made to alleviate possible difficulties the donor encounters. The physical and psychological reactions to donation have been established for some time, but less is known about the factors that are associated with a poorer donation experience. In this article, we provide an overview of the physical and psychological donation experience and focus attention on demographic, physical and psychological factors that may influence this donation experience. Understanding that toxicity profiles vary with certain donor characteristics is crucial as this knowledge could influence practice in numerous ways including the modification of joining and recruitment policies and the improvement of supportive measures and donor follow-up procedures. Although this review deals with both unrelated and related donors (RDs), there is a relative paucity of regulation of RD care and we call for more attention to this area. Owing to the relative rarity of donation in each country, a global effort to collect donor outcome data is needed.Bone Marrow Transplantation advance online publication, 27 January 2014; doi:10.1038/bmt.2013.227.
    Bone marrow transplantation 01/2014; · 3.00 Impact Factor
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    ABSTRACT: Despite over 20 million unrelated donors being listed worldwide, donor attrition at the confirmatory typing (CT) stage of donor acquisition is a key source of delay. Anthony Nolan undertook a study of CT requests from 2010 to 2011 to identify factors associated with attrition. Of 7541 CT requests, 38.2% were cancelled for donor reasons. Of these, 19.4% were personal, 34.1% medical, 36% no contact, 7.9% emigrated and 2.6% others. African (odds ratio (OR) 2.78, P<0.001), African-Caribbean (OR 3.07, P<0.001), Asian (OR 2.65, P<0.001), Jewish (OR 1.54, P=0.009) and Mediterranean (OR=2.38, P<0.001) donors were more likely not to be available compared to Caucasian donors. Female donors were also more likely not to be available (OR=1.32, P<0.001): primarily due to pregnancy. Older donors were less likely to be available in univariate analysis, but this association was not significant after controlling for other factors. Blood donors and those recruited within the past five years had lower rates of attrition. Accumulation of additional attrition-associated characteristics for a given donor was associated with progressively greater odds of attrition (OR 1.99, 2.52, 3.4 and 5.53, respectively, for 1, 2, 3 and 4 risk factors, P<0.001). Donor registries must develop evidence-driven strategies to recruit and retain the most reliable donors.Bone Marrow Transplantation advance online publication, 13 January 2014; doi:10.1038/bmt.2013.206.
    Bone marrow transplantation 01/2014; · 3.00 Impact Factor
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    ABSTRACT: Hematopoietic stem cells (HSC) are rare, multipotent cells characterized by their ability to self-renew and to generate all blood cells throughout life. Major advances have been made in the area of HSC research as a result of the development of different techniques that allowed HSC identification, purification, and analysis of biological functions. This chapter presents methods that are currently used to analyze HSC functions in vitro based on their characteristics.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1109:65-72. · 1.29 Impact Factor
  • Katy Latham, Ann-Margaret Little, J Alejandro Madrigal
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    ABSTRACT: The selection of a related or an unrelated hematopoietic stem cell donor for a patient requires accurate matching of human leukocyte antigen (HLA) genes in order to maximize the beneficial effects of the transplant. There are various different factors a laboratory must consider in order to achieve an HLA type including the number of samples being processed, level of resolution to be achieved, cost of providing the various tests, and turnaround time required. Each method has its advantages and disadvantages, and in most laboratories, a combination of methods may be used.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1109:73-85. · 1.29 Impact Factor
  • Richard Charles Duggleby, J Alejandro Madrigal
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    ABSTRACT: Allogeneic hematopoietic stem cell therapy (HSCT) remains one of the few curative treatments for high-risk hematological malignancies (high-risk leukemia, myelodysplastic syndromes, advanced myeloproliferative disorders, high-risk lymphomas, and multiple myeloma) and is currently applied in more than 15,000 patients per year in Europe. Following HSCT, patients experience a period of reconstitution of the immune system, which seems to be highly dependent on conditioning, immunosuppression regimes, and the level of adverse events the patients experience. During this reconstitution period, the patient is immune compromised and susceptible to opportunistic infections and disease relapse. Consequently, a large number of clinical studies have been devoted to monitoring the recovery of the immune system following HSCT in the hopes of determining which cellular subsets are indicative of a favorable outcome. In this chapter we review the methods that have been employed to monitor the immune reconstitution and what clinical observations have been made. Of particular interest is the regulatory T cell (Treg) subset, which has been associated with tolerance and has been the subject of recent clinical trials as a possible cellular therapy for rejection reactions. Finally we will detail a proposed methodology for the flow cytometric assessment of cellular reconstitution post-HSCT.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1109:159-86. · 1.29 Impact Factor
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    ABSTRACT: Identification of the antigen presenting molecule HLA-DRB1*03:49 by group-specific sequence-based typing.
    Tissue Antigens 11/2013; 82(5):357-8. · 2.93 Impact Factor
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    ABSTRACT: In 2005, the National Institutes of Health (NIH) consensus conference published a series of papers recommending methods to improve the conduct of clinical trials in chronic GVHD. Although the NIH recommendations were primarily aimed at strengthening research, several papers addressed issues relevant for clinical practice, particularly diagnosis, severity scoring, and ancillary and supportive care practices. We conducted an international survey to assess the uptake of these recommendations, identify barriers to greater use and document the use and perceived effectiveness of available treatments. The response rate for the American survey of 1387 practitioners was 21.8%, and it was 24.6% for 407 centers surveyed in Europe, Asia, Australia and Africa. Most respondents were familiar with the NIH consensus recommendations (94-96%) and used them in practice. Multiple barriers to greater use were reported. Besides lack of time (55-62%), unfamiliarity with the recommendations, scarcity of evidence supporting the impact of recommendations on outcomes, insufficient training/experience in chronic GVHD management and inaccessibility of subspecialists were also endorsed. Systemic corticosteroids were reported to be the most effective treatment for chronic GVHD, but many others were perceived to have moderate or great success. Therapeutic management of steroid-refractory chronic GVHD was identified as the highest priority for research.Bone Marrow Transplantation advance online publication, 19 August 2013;. doi:10.1038/bmt.2013.129.
    Bone marrow transplantation 08/2013; · 3.00 Impact Factor
  • Bone marrow transplantation 07/2013; · 3.00 Impact Factor
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    ABSTRACT: Approximately 1 in 20 unrelated donors are asked to make a second donation of hematopoietic progenitor cells, the majority to the same patient. Anthony Nolan undertook a study of subsequent haematopoietic progenitor cell donations made by its donors from 2005 to 2011, with the aim of predicting those donors more likely to be called for a second donation, assessing rates of serious adverse reactions and examining harvest yields. This was not a study of factors predictive of second allografts. 2591 donations were made during this time; 120 (4.6%) were subsequent donations. The median time between donations was 179 days (range 21-4016). Indications for second allogeneic transplant included primary graft failure (11.7%), secondary graft failure (53.2%), relapse (30.6%) and others (1.8%). On multivariate analysis, bone marrow harvest at first donation was associated with subsequent donation requests (odds ratio 2.00, p=0.001). The rate of serious adverse reactions in donors making a subsequent donation appeared greater than in those making a first donation (relative risk=3.29, p=0.005). Harvest yields per kilogram recipient body weight were equivalent between donations, although females appeared to have a lower yield at the subsequent donation. Knowledge of these factors will help unrelated donor registries to counsel their donors.
    Haematologica 06/2013; · 5.94 Impact Factor
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    ABSTRACT: NK cell cytolysis of infected or transformed cells can be mediated by engagement of the activating immunoreceptor NKG2D with one of eight known ligands (MICA, MICB and RAET1E-N) and is essential for innate immunity. As well as diversity of NKG2D ligands having the same function, allelic polymorphism and ethnic diversity has been reported. We previously determined HLA class I allele and haplotype frequencies in Kolla South American Indians who inhabit the northwest provinces of Argentina, and were found to have a similar restricted allelic profile to other South American Indians and novel alleles not seen in other tribes. In our current study, we characterized retinoic acid early transcription-1 (RAET1) alleles by sequencing 58 unrelated Kolla people. Only three of six RAET1 ligands were polymorphic. RAET1E was most polymorphic with five alleles in the Kolla including an allele we previously described, RAET1E∗009 (allele frequency (AF) 5.2%). Four alleles of RAET1L were also found and RAET1E∗002 was most frequent (AF=78%). Potential functional diversity only affected RAET1E and RAET1L, which were in linkage disequilibrium indicating a selective advantage. The results suggest that limited RAET1 polymorphism in the Kolla was not detrimental to human survival but still necessary and may affect disease susceptibility or severity.
    Human immunology 02/2013; · 2.55 Impact Factor
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    ABSTRACT: BACKGROUND: Conditions for maintaining hematopoietic progenitor cells (HPCs) before cryopreservation remain controversial. An understanding of the impact of time and temperature during nonfrozen storage can contribute to the maintenance of the quality of products, improving transplantation outcomes. The objective of this study was to determine the influence on cell potency of thawed products from three sources of HPCs after prolonged storage at different temperatures before cryopreservation. STUDY DESIGN AND METHODS: Viable cell counts by flow cytometry and colony-forming unit (CFU) recoveries were assessed on cord blood (CB), mobilized peripheral blood stem cell (PBSC), and bone marrow (BM) samples over 72 hours using two different storage conditions, refrigerated (4-8°C) or room temperature (19-22°C). To determine the effects of delayed freezing on progenitor recoveries, paired samples were evaluated before and after cryopreservation. RESULTS: All samples maintained at refrigerated temperatures resulted in higher recoveries than those at room temperature in all variables assessed. Specifically, when assessing for CFU yields after thawing, the impact of time on BM resulted in a significant loss as soon as 24 hours (n = 10, 36.4 ± 28.0%, p = 0.003). This decrease was also observed for PBSCs and CB but at 48 hours of fresh storage (PBSCs n = 11, 32.7 ± 26.2%, p = 0.006; CB n = 10, 39.6 ± 26.4%, p = 0.001). CONCLUSION: Our data suggest that HPC products are better maintained at refrigerated temperatures before cryopreservation. Delaying cryopreservation should be minimized to avoid significant losses in cell potency.
    Transfusion 12/2012; · 3.53 Impact Factor
  • S T Cox, J A Madrigal, A Saudemont
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    ABSTRACT: Discovery of three novel alleles of RAET1E/ULBP4 by sequence-based typing: RAET1E*008, RAET1E*009 and RAET1E*010.
    Tissue Antigens 07/2012; 80(4):390-2. · 2.93 Impact Factor
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    ABSTRACT: The risks after unrelated-donor haemopoietic-cell transplantation with matched HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 alleles between donor and recipient (10/10 matched) can be decreased by selection of unrelated donors who also match for HLA-DPB1; however, such donors are difficult to find. Classification of HLA-DPB1 mismatches based on T-cell-epitope groups could identify mismatches that might be tolerated (permissive) and those that would increase risks (non-permissive) after transplantation. We did a retrospective study to compare outcomes between permissive and non-permissive HLA-DPB1 mismatches in unrelated-donor haemopoietic-cell transplantation. HLA and clinical data for unrelated-donor [corrected] transplantations submitted to the International Histocompatibility Working Group in haemopoietic-cell transplantation were analysed retrospectively. HLA-DPB1 T-cell-epitope groups were assigned according to a functional algorithm based on alloreactive T-cell crossreactivity patterns. Recipients and unrelated donors matching status were classified as HLA-DPB1 match, non-permissive HLA-DPB1 mismatch (those with mismatched T-cell-epitope groups), or permissive HLA-DPB1 mismatch (those with matched T-cell-epitope groups). The clinical outcomes assessed were overall mortality, non-relapse mortality, relapse, and severe (grade 3-4) acute graft-versus-host disease (aGvHD). Of 8539 transplantations, 5428 (64%) were matched for ten of ten HLA alleles (HLA 10/10 matched) and 3111 (36%) for nine of ten alleles (HLA 9/10 matched). Of the group overall, 1719 (20%) were HLA-DPB1 matches, 2670 (31%) non-permissive HLA-DPB1 mismatches, and 4150 (49%) permissive HLA-DPB1 mismatches. In HLA 10/10-matched transplantations, non-permissive mismatches were associated with a significantly increased risk of overall mortality (hazard ratio [HR] 1·15, 95% CI 1·05-1·25; p=0·002), non-relapse mortality (1·28, 1·14-1·42; p<0·0001), and severe aGvHD (odds ratio [OR] 1·31, 95% CI 1·11-1·54; p=0·001), but not relapse (HR 0·89, 95% CI 0·77-1·02; p=0·10), compared with permissive mismatches. There were significant differences between permissive HLA-DPB1 mismatches and HLA-DPB1 matches in terms of non-relapse mortality (0·86, 0·75-0·98; p=0·03) and relapse (1·34, 1·17-1·54; p<0·0001), but not for overall mortality (0·96, 0·87-1·06; p=0·40) or aGvHD (OR 0·84, 95% CI 0·69-1·03; p=0·09). In the HLA 9/10 matched population, non-permissive HLA-DPB1 mismatches also increased the risk of overall mortality (HR 1·10, 95% CI 1·00-1·22; p=0·06), non-relapse mortality (1·19, 1·05-1·36; p=0·007), and severe aGvHD (OR 1·37, 95% CI 1·13-1·66; p=0·002) compared with permissive mismatches, but the risk of relapse was the same in both groups (HR 0·93, 95% CI 0·78-1·11; p=0·44). Outcomes for HLA 10/10-matched transplantations with non-permissive HLA-DPB1 mismatches did not differ substantially from those for HLA 9/10-matched transplantations with permissive HLA-DPB1 mismatches or HLA-DPB1 matches. T-cell-epitope matching defines permissive and non-permissive HLA-DPB1 mismatches. Avoidance of an unrelated donor with a non-permissive T-cell-epitope mismatch at HLA-DPB1 might provide a practical clinical strategy for lowering the risks of mortality after unrelated-donor haemopoietic-cell transplantation. National Institutes of Health; Associazione Italiana per la Ricerca sul Cancro; Telethon Foundation; Italian Ministry of Health; Cariplo Foundation; National Cancer Institute; National Heart, Lung and Blood Institute; National Institute of Allergy and Infectious Diseases; Office of Naval Research; IRGHET Paris; Swedish Cancer Society; Children's Cancer Foundation; Swedish Research Council; Cancer Society in Stockholm; Karolinska Institutet; and Leukemia and Lymphoma Society.
    The Lancet Oncology 02/2012; 13(4):366-74. · 25.12 Impact Factor
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    E. Arrieta-Bolanos, J. Alejandro Madrigal, B. E. Shaw
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    ABSTRACT: Hematopoietic stem cell transplantation (HSCT) is a medical procedure used to treat malignant and nonmalignant haematological diseases, congenital immunodeficiency syndromes, solid tumours and metabolic diseases. Despite its usefulness, several major complications, such as graft-versus-host disease, can negatively affect patients treated with HSCT. Apart from clinical factors well known to affect the outcome of HSCT, patient and donor genetics have been shown to play an important role in the susceptibility to post-transplant complications. Histocompatibility as determined by the human leucocyte antigen (HLA) system has been a major genetic determinant of the success of HSCT. Non-HLA immunogenetics are increasingly recognized to play a part in the events related to transplantation. Cytokine genes, and their receptors, bear a considerable amount of polymorphism. One of the genes that may play an important role on the outcome of allogeneic HSCT is TGFB1, which encodes transforming growth factor, betaeta 1 (TGF-beta1). TGF-beta1 is a pleiotropic cytokine, which plays a central role in the development, homeostasis and responses of the immune system. Several functional polymorphisms in TGFB1 have been identified, and these are known to cause alterations in cytokine secretion in several settings. The present review will focus on the current knowledge surrounding the effect of polymorphisms within TGFB1 on the outcome of HSCT.
    International Journal of Immunogenetics 01/2012; · 1.36 Impact Factor

Publication Stats

3k Citations
865.04 Total Impact Points


  • 1995–2014
    • Anthony Nolan Research Institute
      • Clinical Research Group
      Londinium, England, United Kingdom
  • 2001–2012
    • Nottingham Trent University
      Nottigham, England, United Kingdom
  • 2010
    • University of Costa Rica
      • Centro de Investigación en Hematología y Trastornos Afines (CIHATA)
      San José, San José, Costa Rica
  • 1999–2009
    • Royal Free London NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2003–2008
    • University College London
      • • Division of Infection and Immunity
      • • Division of Medicine
      London, ENG, United Kingdom
  • 1998
    • Venezuelan Institute for Scientific Research
      Caracas, Distrito Federal, Venezuela
  • 1992–1997
    • Stanford Medicine
      • Department of Microbiology and Immunology
      Stanford, California, United States
  • 1991–1995
    • Stanford University
      • • Department of Structural Biology
      • • Department of Microbiology and Immunology
      Stanford, CA, United States
  • 1989
    • Imperial College London
      Londinium, England, United Kingdom