J A Madrigal

Anthony Nolan Research Institute, Londinium, England, United Kingdom

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Publications (230)899.07 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: NK cells play a key role in innate elimination of virally infected or neoplastic cells but they can be circumvented by immunoevasive mechanisms enabling viral spread or tumour progression. Engagement of the NKG2D activating receptor with soluble forms of its ligand is one such mechanism of inducing NK cell hyporesponsiveness. Interestingly, this immunoevasive strategy among others is described at the maternal-fetal interface where tolerance of the semi-allogeneic fetus is required to allow successful human pregnancy. Understanding of maternal-fetal tolerance is increasing but mechanisms preventing alloreactivity of fetal immune cells against the maternal host are less well understood. The study of umbilical cord blood has enabled insight of the fetal immune system, which appears immature and inert. We have found that soluble NKG2D ligands (sNKG2DLs) are present in cord blood plasma (CBP) and associate with adult NK cell hyporesponsiveness demonstrated by reduced CD107a expression and secretion of IFN-γ upon stimulation. The capacity of NK cells to kill K562 cells or proliferate was also reduced by incubation with CBP; however, physical removal of sNKG2DL from CBP restored K562 lytic function and NKG2D expression. Therefore, our results strongly suggest sNKG2DLs are expressed in CBP as a mechanism of fetal-maternal tolerance in human pregnancy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 05/2015; DOI:10.1002/eji.201444990 · 4.52 Impact Factor
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    ABSTRACT: Background and Objectives Advantages of using cord blood (CB) over other sources of haematopoietic progenitor cells, such as bone marrow, include the ability to cryopreserve and bank the samples until requested for a transplant. Cryopreservation requires the addition of a cryoprotectant to prevent the formation of intracellular ice during freezing. Dimethyl sulphoxide (DMSO) is commonly used at a concentration of 10% (v/v); however, there is evidence to suggest this chemical is toxic to cells as well as to patients after infusion.Materials and Methods The toxic effects of DMSO were assessed through cell viability and in vitro functional assays in fresh and post-thaw CB samples before determining the maximum exposure time and optimal concentration for cryopreservation.ResultsA dose-dependent toxicity of DMSO was observed in fresh samples with 40% removing all viable and functional haematopoietic progenitor cells (HPC). In fresh and post-thaw analysis, minimal toxic effect was observed when cryopreservation was delayed for up to 1 h after 10% DMSO addition. After thawing, DMSO washout was superior to dilution or unmanipulated when maintained for long periods (advantage observed 1 h after thawing). Finally, the optimum concentration for cryopreserving CB was found to be 7·5 to 10% with detrimental effects observed outside of this range.Conclusion These results support the use of 7·5–10% as the optimal DMSO concentration and the maximum exposure time should be limited to <1 h prior to freezing and 30 min post-thaw.
    Vox Sanguinis 04/2015; DOI:10.1111/vox.12267 · 3.30 Impact Factor
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    ABSTRACT: In this study, we have characterized two novel polymorphism of the 5' promoter sequence of MICA gene, MICA-P13 and MICA-P14, by sequence-based typing and cloning. © 2015 John Wiley & Sons Ltd.
    International Journal of Immunogenetics 03/2015; 42(3). DOI:10.1111/iji.12194 · 1.34 Impact Factor
  • Esteban Arrieta-Bolanos, J Alejandro Madrigal, Bronwen E Shaw
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    ABSTRACT: Transforming growth factor β-1, encoded by the TGFB1 gene, is a cytokine that plays a central role in many physiologic and pathogenic processes with pleiotropic effects. Regulatory activity for this gene has been shown for 3.0 kb between positions -2665 and +423 from its translational start site. At least 17 TGFB1 regulatory region and exon 1 alleles have been defined on the basis of 18 polymorphic sites. Polymorphisms in TGFB1's regulatory region have been associated with differential levels of expression of this cytokine and to genetic risk in cancer and transplantation. In this report, we present 19 novel TGFB1 regulatory region and exon 1 alleles: p018-p036. Amplification of TGFB1's regulatory region was performed with an in-house protocol, and novel alleles were defined by either allele-specific amplification and/or molecular cloning of the amplicons, followed by sequencing in isolation. Three of these novel alleles (p018, p019, and p020) are shown to be formed by novel combinations of the aforementioned known polymorphic positions. Another 16 novel alleles are shown to carry additional known and unknown single-nucleotide polymorphisms. Polymorphism in TGFB1's regulatory region could have an impact on important processes, including embryogenesis, hematopoiesis, carcinogenesis, angiogenesis, fibrosis, immune responses, and transplantation, making its characterization necessary. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
    Tissue Antigens 03/2015; 85(6). DOI:10.1111/tan.12555 · 2.35 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2015; 21(2):S309-S310. DOI:10.1016/j.bbmt.2014.11.493 · 3.35 Impact Factor
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    ABSTRACT: The physical reactions to hematopoietic stem cell donation have been extensively studied, but less is known about factors that predict poorer donation experiences. The aim of this prospective study was to examine demographic and health-related quality of life (HRQOL) factors that might be associated with recovery and side effects. We also described the changes in HRQOL during the donation process. In total, 275 peripheral blood stem cell (PBSC) and 37 bone marrow (BM) consecutive donors completed the SF-36 questionnaire predonation and 4 weeks, and 3 months postdonation. Predonation HRQOL markers were the strongest predictors of time to recovery. Poorer predonation physical health was associated with longer recovery (P = .017) and certain side effects in PBSC donors. Poorer predonation mental health was associated with longer recovery in BM donors (P = .03) and pain after PBSC donation (P = .003). Physical HRQOL scores declined significantly from predonation to 4 weeks postdonation. This was shown both for PBSC and BM donors (P < .001 and P = .009, respectively), but the decline was much greater for BM donors. There was a return to predonation HRQOL values 3 months after donation in both groups with values well above the mean of the general population (P < .001). Copyright © 2014 American Society for Blood and Marrow Transplantation. All rights reserved.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2014; 21(2). DOI:10.1016/j.bbmt.2014.10.028 · 3.35 Impact Factor
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    ABSTRACT: Allo-SCT using unrelated donors is a curative treatment for patients with hematological disorders. The best donor is one matched for 10/10 HLA alleles, however studies have shown an additional survival benefit when considering other genetic factors. It has been shown that a six-nucleotide insertion/deletion polymorphism in the CASP8 gene promoter results in reduced susceptibility of T lymphocytes to undergo apoptosis. In 186 SCT recipients, we found a significantly better OS in those who received a transplant from a WT/WT donor compared with donors with a deletion (3 years: 52 vs 34%; P=0.03; multivariate analysis; RR 0.61; 95% CI 0.38-0.98, P=0.04). This was more marked when both the patient and the donor had a deletion (3 years OS: 62% compared with 36%, P=0.01). As the majority of these patients received Alemtuzumab during conditioning, we went on to analyze the in vitro effect of the polymorphism on Alemtuzumab-induced apoptosis. We showed statistically significantly higher percentages of apoptotic naïve CD4 (P<0.0005) and CD8 (P<0.0005) T cells in WT/WT donors in comparison with donors with a deletion. These data imply an unrecognized role for the CASP8 promoter polymorphism on survival following unrelated SCT particularly in the context of T-cell depletion with Alemtuzumab.Bone Marrow Transplantation advance online publication, 27 October 2014; doi:10.1038/bmt.2014.238.
    Bone Marrow Transplantation 10/2014; 50(2). DOI:10.1038/bmt.2014.238 · 3.47 Impact Factor
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    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; DOI:10.1016/j.humimm.2014.09.011 · 2.28 Impact Factor
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    ABSTRACT: The new HLA-A*74:23 allele differs from the closest allele A*74:01 by a nucleotide change in exon 3 at codon 97 (ATG to ATA).
    Tissue Antigens 10/2014; DOI:10.1111/tan.12470 · 2.35 Impact Factor
  • 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; 84(3). DOI:10.1111/tan.12400 · 2.35 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; 84(3). DOI:10.1111/tan.12397 · 2.35 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; 54(11). DOI:10.1111/trf.12720 · 3.57 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; DOI:10.1111/tan.12383 · 2.35 Impact Factor
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    Aurore Saudemont, J Alejandro Madrigal
    Haematologica 02/2014; 99(2):203-5. DOI:10.3324/haematol.2013.101295 · 5.87 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; DOI:10.1038/bmt.2013.227 · 3.47 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; DOI:10.1038/bmt.2013.206 · 3.47 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. DOI:10.1007/978-1-4614-9437-9_5 · 1.29 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. DOI:10.1007/978-1-4614-9437-9_4 · 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. DOI:10.1007/978-1-4614-9437-9_10 · 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. DOI:10.1111/tan.12203 · 2.35 Impact Factor

Publication Stats

4k Citations
899.07 Total Impact Points


  • 1996–2015
    • Anthony Nolan Research Institute
      • Clinical Research Group
      Londinium, England, United Kingdom
  • 2014
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
  • 2008–2013
    • Royal Free Academy of PMC
      Londinium, England, United Kingdom
  • 2001–2011
    • Nottingham Trent University
      Nottigham, England, United Kingdom
  • 1995–2009
    • Royal Free London NHS Foundation Trust
      • Department of Haematology
      Londinium, England, United Kingdom
  • 1992–1997
    • Stanford Medicine
      • • Department of Cardiothoracic Surgery
      • • Department of Microbiology and Immunology
      Stanford, California, United States
  • 1992–1995
    • Stanford University
      • • Department of Structural Biology
      • • Department of Microbiology and Immunology
      Palo Alto, California, United States