ORCID Profile
0000-0001-9653-3298
Current Organisation
Murdoch University
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Publisher: Frontiers Media SA
Date: 12-01-2020
DOI: 10.3389/FPHAR.2020.573573
Abstract: Delayed drug hypersensitivity reactions are clinically erse reactions that vary from isolated benign skin conditions that remit quickly with no or symptomatic treatment, drug discontinuation or even continued drug treatment, to the other extreme of severe cutaneous adverse reactions (SCARs) that are associated with presumed life-long memory T-cell responses, significant acute and long-term morbidity and mortality. Diagnostic “in clinic” approaches to delayed hypersensitivity reactions have included patch testing (PT), delayed intradermal testing (IDT) and drug challenges for milder reactions. Patch and IDT are, in general, performed no sooner than 4–6 weeks after resolution of the acute reaction at the maximum non-irritating concentrations. Functional in vitro and ex vivo assays have largely remained the province of research laboratories and include lymphocyte transformation test (LTT) and cytokine release enzyme linked ImmunoSpot (ELISpot) assay, an emerging diagnostic tool which uses cytokine release, typically IFN-γ, after the patient’s peripheral blood mononuclear cells are stimulated with the suspected drug(s). Genetic markers such as human leukocyte antigen have shown recent promise for both pre-prescription screening as well as pre-emptive and diagnostic testing strategies.
Publisher: Elsevier BV
Date: 02-2021
Publisher: Frontiers Media SA
Date: 16-04-2021
DOI: 10.3389/FGENE.2021.641905
Abstract: Adverse drug reactions (ADRs) remain associated with significant mortality. Delayed hypersensitivity reactions (DHRs) that occur greater than 6 h following drug administration are T-cell mediated with many severe DHRs now associated with human leukocyte antigen (HLA) risk alleles, opening pathways for clinical prediction and prevention. However, incomplete negative predictive value (NPV), low positive predictive value (PPV), and a large number needed to test (NNT) to prevent one case have practically prevented large-scale and cost-effective screening implementation. Additional factors outside of HLA contributing to risk of severe T-cell-mediated DHRs include variation in drug metabolism, T-cell receptor (TCR) specificity, and, most recently, HLA-presented immunopeptidome-processing efficiencies via endoplasmic reticulum aminopeptidase (ERAP). Active research continues toward identification of other highly polymorphic factors likely to impose risk. These include those previously associated with T-cell-mediated HLA-associated infectious or auto-immune disease such as Killer cell immunoglobulin-like receptors (KIR), epistatically linked with HLA class I to regulate NK- and T-cell-mediated cytotoxic degranulation, and co-inhibitory signaling pathways for which therapeutic blockade in cancer immunotherapy is now associated with an increased incidence of DHRs. As such, the field now recognizes that susceptibility is not simply a static product of genetics but that in iduals may experience dynamic risk, skewed toward immune activation through therapeutic interventions and epigenetic modifications driven by ecological exposures. This review provides an updated overview of current and proposed genetic factors thought to predispose risk for severe T-cell-mediated DHRs.
Publisher: Wiley
Date: 17-07-2021
DOI: 10.1002/CPT.2343
Abstract: The human leukocyte antigen (HLA) system is the most polymorphic in the human genome that has been associated with protection and predisposition to a broad array of infectious, autoimmune, and malignant diseases. More recently over the last two decades, HLA class I alleles have been strongly associated with T‐cell‐mediated drug hypersensitivity reactions. In the case of abacavir hypersensitivity and HLA‐B*57:01, the 100% negative predictive value and low number needed to test to prevent a single case has led to a durable and effective global preprescription screening strategy. However, HLA associations are still undefined for most drugs clinically associated with different delayed drug hypersensitivity phenotypes, and an HLA association relevant to one population is not generalizable across ethnicities. Furthermore, while a specific risk HLA allele is necessary for drug‐induced T‐cell activation, it is not sufficient. The low and incomplete positive predictive value has hindered efforts at clinical implementation for many drugs but has provided the impetus to understand the mechanisms of HLA class I restricted T‐cell‐mediated drug hypersensitivity reactions. Current research has focused on defining the contribution of additional elements of the adaptive immune response and other genetic and ecologic risk factors that contribute to drug hypersensitivity risk. In this review we focus on new insights into immunological, pharmacological, and genetic mechanisms underpinning HLA‐associated drug reactions and the implications for future translation into clinical care.
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.JAIP.2022.04.027
Abstract: Delayed drug hypersensitivities are CD8
Publisher: Wiley
Date: 26-08-2022
DOI: 10.1111/TAN.14767
Abstract: HLA (HLA) alleles are risk factors for CD8+ T‐cell‐mediated drug hypersensitivity reactions. However, as most HLA associations are incompletely predictive and/or involve risk alleles at low frequency, costly sequence‐based typing can elude an economically productive cost: benefit ratio for clinical validation studies and diagnostic and/or preventative screening. Hence rapid and low‐cost detection assays are now required, both for single alleles but also across risk loci associated with broader multi‐disease risk exemplified by associations with erse alleles in HLA‐B*35, including HLA‐B * 35 : 01 and green tea‐ or co‐trimoxazole‐induced liver injury. Here, we developed a cost‐effective ( $10USD) qPCR assay for rapid ( .5 h) clinical detection of HLA‐B * 35 alleles. The assay was validated using 430 DNA s les with previous American society for histocompatibility and immunogenetics‐accredited sequence‐based high‐resolution HLA typing, positively detecting all HLA‐B * 35 allelic variants in our cohort, and as expected by primer design, the six s les that expressed low‐frequency B * 78 : 01 . The assay did not result in positive detection for any negative control allele. With expected detection of B * 35 and B * 78 , our assay sensitivity (95% CI, 95.07%–100.00%) and specificity (95% CI, 98.97%–100.00%) of 100% using as low as 10 ng of DNA provides a reliable HLA‐B * 35 screening tool for clinical validation and HLA–risk‐based prevention and diagnostics.
Publisher: Wiley
Date: 18-07-2014
Publisher: Elsevier BV
Date: 2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2013
DOI: 10.1002/HEP.26077
Abstract: The role of the adaptive immune system in adverse drug reactions that target the liver has not been defined. For flucloxacillin, a delay in the reaction onset and identification of human leukocyte antigen (HLA)-B*57:01 as a susceptibility factor are indicative of an immune pathogenesis. Thus, we characterize flucloxacillin-responsive CD4+ and CD8+ T cells from patients with liver injury and show that naive CD45RA+CD8+ T cells from volunteers expressing HLA-B*57:01 are activated with flucloxacillin when dendritic cells present the drug antigen. T-cell clones expressing CCR4 and CCR9 migrated toward CCL17 and CCL 25, and secreted interferon-gamma (IFN-γ), T helper (Th)2 cytokines, perforin, granzyme B, and FasL following drug stimulation. Flucloxacillin bound covalently to selective lysine residues on albumin in a time-dependent manner and the level of binding correlated directly with the stimulation of clones. Activation of CD8+ clones with flucloxacillin was processing-dependent and restricted by HLA-B*57:01 and the closely related HLA-B*58:01. Clones displayed additional reactivity against β-lactam antibiotics including oxacillin, cloxacillin, and dicloxacillin, but not abacavir or nitroso sulfamethoxazole. This work defines the immune basis for flucloxacillin-induced liver injury and links the genetic association to the iatrogenic disease.
Publisher: Elsevier BV
Date: 02-0012
Publisher: Wiley
Date: 17-07-2020
DOI: 10.1111/BCP.14433
Publisher: Wiley
Date: 23-12-2019
DOI: 10.1111/ALL.14127
Abstract: Delayed-type, T cell-mediated, drug hypersensitivity reactions are a serious unwanted manifestation of drug exposure that develops in a small percentage of the human population. Drugs and drug metabolites are known to interact directly and indirectly (through irreversible protein binding and processing to the derived adducts) with HLA proteins that present the drug-peptide complex to T cells. Multiple forms of drug hypersensitivity are strongly linked to expression of a single HLA allele, and there is increasing evidence that drugs and peptides interact selectively with the protein encoded by the HLA allele. Despite this, many in iduals expressing HLA risk alleles do not develop hypersensitivity when exposed to culprit drugs suggesting a nonlinear, multifactorial relationship in which HLA risk alleles are one factor. This has prompted a search for additional susceptibility factors. Herein, we argue that immune regulatory pathways are one key determinant of susceptibility. As expression and activity of these pathways are influenced by disease, environmental and patient factors, it is currently impossible to predict whether drug exposure will result in a health benefit, hypersensitivity or both. Thus, a concerted effort is required to investigate how immune dysregulation influences susceptibility towards drug hypersensitivity.
Publisher: Oxford University Press (OUP)
Date: 20-10-2020
Abstract: Exposure to tolvaptan is associated with a significant risk of liver injury in a small fraction of patients with autosomal dominant polycystic kidney disease. The observed delayed onset of liver injury of between 3 and 18 months after commencing tolvaptan treatment, along with rapid recurrence of symptoms following re-challenge is indicative of an adaptive immune attack. This study set out to assess the intrinsic immunogenicity of tolvaptan and pathways of drug-specific T-cell activation using in vitro cell culture platforms. Tolvaptan (n = 7), as well as oxybutyric (DM-4103, n = 1) and hydroxybutyric acid (DM-4107, n = 18) metabolite-specific T-cell clones were generated from tolvaptan naive healthy donor peripheral blood mononuclear cells. Tolvaptan and DM-4103 T-cell clones could also be activated with DM-4107, whereas T-cell clones originally primed with DM-4107 were highly specific to this compound. A signature cytokine profile (IFN-γ, IL-13, granzyme B, and perforin) for almost all T-cell clones was identified. Mechanistically, compound-specific T-cell clone activation was dependent on the presence of soluble drug and could occur within 4 h of drug exposure, ruling out a classical hapten mechanism. However, antigen processing dependence drug presentation was indicated in many T-cell clones. Collectively these data show that tolvaptan-associated liver injury may be attributable to an adaptive immune attack upon the liver, with tolvaptan- and metabolite-specific T cells identified as candidate effector cells in such etiology.
Publisher: American Chemical Society (ACS)
Date: 15-11-2017
DOI: 10.1021/ACS.CHEMRESTOX.6B00333
Abstract: The workshop on "New Approaches to Investigate Drug-Induced Hypersensitivity" was held on June 5, 2014 at the Foresight Center, University of Liverpool. The aims of the workshop were to (1) discuss our current understanding of the genetic, clinical, and chemical basis of small molecule drug hypersensitivity, (2) highlight the current status of assays that might be developed to predict potential drug immunogenicity, and (3) identify the limitations, knowledge gaps, and challenges that limit the use of these assays and utilize the knowledge gained from the workshop to develop a pathway to establish new and improved assays that better predict drug-induced hypersensitivity reactions during the early stages of drug development. This perspective reviews the clinical and immunological bases of drug hypersensitivity and summarizes various experts' views on the different topics covered during the meeting.
Publisher: Informa UK Limited
Date: 15-12-2014
DOI: 10.1517/17425255.2015.992780
Abstract: Adverse drug reactions with an immune pathogenesis are a problem in the clinic and an impediment to drug development. T lymphocytes are believed to play a role in the pathogenesis however, the nature of the drug interaction with immune receptors remains an area of debate. This article reviews recent advances in our understanding of drug hypersensitivity focusing specifically on the way in which drugs are displayed in MHC molecules. Most drugs associated with a high incidence of reactions have been shown to form protein-reactive metabolites. Hence, the relationship between drug metabolism and T-cell activation is discussed in detail. The role of metabolism in pathogenesis of immunological drug reactions has only been studied with a small number of drugs where synthetic metabolites are available for functional studies. In each case, metabolite-responsive T cells have been detected. However, the field is skewed by the fact that most research is conducted using the parent compound in metabolically inert cell systems. We propose that research efforts are directed towards the synthesis of drug metabolites and/or drug-protein conjugates. Furthermore, analytical methods need to be developed to relate metabolite exposure to the T-cell response. For now, our understanding of the chemical basis of drug hypersensitivity is incomplete.
Publisher: Springer Science and Business Media LLC
Date: 16-02-2022
Publisher: Wiley
Date: 18-07-2014
Publisher: American Chemical Society (ACS)
Date: 21-10-2020
Publisher: Elsevier BV
Date: 08-2021
Publisher: Elsevier BV
Date: 09-2020
Publisher: Oxford University Press (OUP)
Date: 16-09-2016
Abstract: A number of serious adverse drug reactions are caused by T cells. An association with HLA alleles has been identified with certain reactions, which makes it difficult to develop standardized preclinical tests to predict chemical liability. We have recently developed a T cell priming assay using the drug metabolite nitroso sulfamethoxazole (SMX-NO). We now report on reproducibility of the assay, establishment of a biobank of PBMC from 1000 HLA-typed volunteers, and generation of antigen-specific responses to a panel of compounds. Forty T cell priming assays were performed with SMX-NO 5 gave weak responses (1.5-1.9) and 34 showed good (SI 2.0-3.9) or strong responses (SI > 4.0) using readouts for proliferation and cytokine release. Thus, SMX-NO can be used as a model reagent for in vitro T cell activation. Good to strong responses were also generated to haptenic compounds (amoxicillin, piperacillin and Bandrowski's base) that are not associated with an HLA risk allele. Furthermore, responses were detected to carbamazepine (in HLA-B*15:02 donors), flucloxacillin (in 1 HLA-B*57:01 donor) and oxypurinol (in HLA-B*58:01 donors), which are associated with HLA-class I-restricted forms of hypersensitivity. In contrast, naïve T cell priming to ximelagatran, lumiracoxib, and lapatinib (HLA-class II-restricted forms of hypersensitivity) yielded negative results. Abacavir, which activates memory T cells in patients, did not activate naïve T cells from HLA-B*57:01 donors. This work shows that the priming assay can be used to assess primary T cell responses to drugs and to study mechanisms T cell priming for drugs that display HLA class I restriction. Additional studies are required to investigate HLA-class II-restricted reactions.
Publisher: The American Association of Immunologists
Date: 15-03-2014
Abstract: Activation of PD-1 on T cells is thought to inhibit Ag-specific T cell priming and regulate T cell differentiation. Thus, we sought to measure the drug-specific activation of naive T cells after perturbation of PD-L1/2/PD-1 binding and investigate whether PD-1 signaling influences the differentiation of T cells. Priming of naive CD4+ and CD8+ T cells against drug Ags was found to be more effective when PD-L1 signaling was blocked. Upon restimulation, T cells proliferated more vigorously and secreted increased levels of IFN-γ, IL-13, and IL-22 but not IL-17. Naive T cells expressed low levels of PD-1 however, a transient increase in PD-1 expression was observed during drug-specific T cell priming. Next, drug-specific responses from in vitro primed T cell clones and clones from hypersensitive patients were measured and correlated with PD-1 expression. All clones were found to secrete IFN-γ, IL-5, and IL-13. More detailed analysis revealed two different cytokine signatures. Clones secreted either FasL/IL-22 or granzyme B. The FasL/IL-22–secreting clones expressed the skin-homing receptors CCR4, CCR10, and CLA and migrated in response to CCL17/CCL27. PD-1 was stably expressed at different levels on clones however, PD-1 expression did not correlate with the strength of the Ag-specific proliferative response or the secretion of cytokines/cytolytic molecules. This study shows that PD-L1/PD-1 binding negatively regulates the priming of drug-specific T cells. ELISPOT analysis uncovered an Ag-specific FasL/IL-22–secreting T cell subset with skin-homing properties.
Publisher: Elsevier BV
Date: 05-2022
Publisher: Oxford University Press (OUP)
Date: 12-01-2019
Abstract: Telaprevir, a protease inhibitor, was used alongside PEGylated interferon-α and ribavirin to treat hepatitis C viral infections. The triple regimen proved successful however, the appearance of severe skin reactions alongside competition from newer drugs restricted its use. Skin reactions presented with a delayed onset indicative of a T-cell mediated reaction. Thus, the aim of this study was to investigate whether telaprevir and/or its diastereomer, which is generated in humans, activates T-cells. Telaprevir in its S-configured therapeutic form and the R-diastereomer were cultured directly with peripheral blood mononuclear cells from healthy donors prior to the generation of T-cell clones by serial dilution. Drug-specific CD4+ and CD8+ T-cell clones responsive to telaprevir and the R-diastereomer were generated and characterized in terms of phenotype and function. The clones proliferated with telaprevir and diastereomer concentrations of 5-20 µM and secreted IFN-γ, IL-13, and granzyme B. In contrast, the telaprevir M11 metabolite did not stimulate T-cells. The CD8+ T-cell response was MHC I-restricted and dependent on the presence of soluble drug. Flow cytometric analysis showed that clones expressed chemokine receptors CCR4 (skin homing) and CXCR3 (migration to peripheral tissue) and 1 of 3 distinct TCR Vβs TCR Vβ 2, 5.1, or 22. These data show the propensity of both R- and S-forms of telaprevir to generate skin-homing cytotoxic T-cells that may induce the adverse reactions observed in human patients.
Publisher: The American Association of Immunologists
Date: 15-08-2017
Abstract: Drug hypersensitivity involves the activation of T cells in an HLA allele–restricted manner. Because the majority of in iduals who carry HLA risk alleles do not develop hypersensitivity, other parameters must control development of the drug-specific T cell response. Thus, we have used a T cell–priming assay and nitroso sulfamethoxazole (SMX-NO) as a model Ag to investigate the activation of specific TCR Vβ subtypes, the impact of programmed death -1 (PD-1), CTL-associated protein 4 (CTLA4), and T cell Ig and mucin domain protein-3 (TIM-3) coinhibitory signaling on activation of naive and memory T cells, and the ability of regulatory T cells (Tregs) to prevent responses. An expansion of the TCR repertoire was observed for nine Vβ subtypes, whereas spectratyping revealed that SMX-NO–specific T cell responses are controlled by public TCRs present in all in iduals alongside private TCR repertoires specific to each in idual. We proceeded to evaluate the extent to which the activation of these TCR Vβ–restricted Ag-specific T cell responses is governed by regulatory signals. Blockade of PD-L1/CTLA4 signaling d ened activation of SMX-NO–specific naive and memory T cells, whereas blockade of TIM-3 produced no effect. Programmed death-1, CTLA4, and TIM-3 displayed discrete expression profiles during drug-induced T cell activation, and expression of each receptor was enhanced on iding T cells. Because these receptors are also expressed on Tregs, Treg-mediated suppression of SMX-NO–induced T cell activation was investigated. Tregs significantly d ened the priming of T cells. In conclusion, our findings demonstrate that distinct TCR Vβ subtypes, dysregulation of coinhibitory signaling pathways, and dysfunctional Tregs may influence predisposition to hypersensitivity.
Publisher: Frontiers Media SA
Date: 17-06-2021
DOI: 10.3389/FGENE.2021.642012
Abstract: Type B adverse drug reactions (ADRs) are iatrogenic immune-mediated syndromes with mechanistic etiologies that remain incompletely understood. Some of the most severe ADRs, including delayed drug hypersensitivity reactions, are T-cell mediated, restricted by specific human leukocyte antigen risk alleles and sometimes by public or oligoclonal T-cell receptors (TCRs), central to the immunopathogenesis of tissue-damaging response. However, the specific cellular signatures of effector, regulatory, and accessory immune populations that mediate disease, define reaction phenotype, and determine severity have not been defined. Recent development of single-cell platforms bringing together advances in genomics and immunology provides the tools to simultaneously examine the full transcriptome, TCRs, and surface protein markers of highly heterogeneous immune cell populations at the site of the pathological response at a single-cell level. However, the requirement for advanced bioinformatics expertise and computational hardware and software has often limited the ability of investigators with the understanding of diseases and biological models to exploit these new approaches. Here we describe the features and use of a state-of-the-art, fully integrated application for analysis and visualization of multiomic single-cell data called Visual Genomics Analysis Studio (VGAS). This unique user-friendly, Windows-based graphical user interface is specifically designed to enable investigators to interrogate their own data. While VGAS also includes tools for sequence alignment and identification of associations with host or organism genetic polymorphisms, in this review we focus on its application for analysis of single-cell TCR–RNA–Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE)-seq, enabling holistic cellular characterization by unbiased transcriptome and select surface proteome. Critically, VGAS does not require user-directed coding or access to high-performance computers, instead incorporating performance-optimized hidden code to provide application-based fast and intuitive tools for data analyses and production of high-resolution publication-ready graphics on standard specification laptops. Specifically, it allows analyses of comprehensive single-cell TCR sequencing (scTCR-seq) data, detailing (i) functional pairings of α–β heterodimer TCRs, (ii) one-click histograms to display entropy and gene rearrangements, and (iii) Circos and Sankey plots to visualize clonality and dominance. For unbiased single-cell RNA sequencing (scRNA-seq) analyses, users extract cell transcriptome signatures according to global structure via principal component analysis, t-distributed stochastic neighborhood embedding, or uniform manifold approximation and projection plots, with overlay of scTCR-seq enabling identification and selection of the immunodominant TCR-expressing populations. Further integration with similar sequence-based detection of surface protein markers using oligo-labeled antibodies (CITE-seq) provides comparative understanding of surface protein expression, with differential gene or protein analyses visualized using volcano plot or heatmap functions. These data can be compared to reference cell atlases or suitable controls to reveal discrete disease-specific subsets, from epithelial to tissue-resident memory T-cells, and activation status, from senescence through exhaustion, with more finite transcript expression displayed as violin and box plots. Importantly, guided tutorial videos are available, as are regular application updates based on the latest advances in bioinformatics and user feedback.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2018
DOI: 10.1097/ACI.0000000000000459
Abstract: Defining predisposition to allergic drug reactions has largely focussed on HLA associations, but other genetic and nongenetic factors are also likely to be involved. Polymorphic genetic variants in cytokine genes, including IL-10, and co-signalling pathways, including CTLA4, have been associated with allergic drug reactions, but the effect size is lower than with HLA alleles and most associations have not been replicated. Although TCR specificity seems to be important for CBZ-induced SJS/TEN in South East Asian patients, a distinct repertoire may not play a role in reactions to other drugs. New mass spectrometric techniques allowing for the identification of naturally eluted peptides from drug-exposed HLA alleles will allow for the antigenic source of T-cell activation to be defined and may shed light on the influence of disease. Indeed, preliminary data highlight the propensity of drug-responsive T cells to cross-react with T cells primed to viral antigens. Furthermore, the environment can epigenetically influence regulatory gene expression, suggesting that an in idual's family exposure history may alter immune thresholds and tip the balance toward activation. It is likely that predisposition to allergic drug reactions is multifaceted in most cases. This will require the study of large numbers of patients to detect genetic factors that have a lower effect size than HLA alleles. This should be accompanied by detailed clinical phenotyping of patients and the assessment of the immunological phenotype with respect to the presence and type of drug antigen-responsive T cells.
Publisher: Wiley
Date: 15-04-2019
DOI: 10.1111/ALL.13769
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-05-2021
DOI: 10.1097/ACI.0000000000000754
Abstract: An update of the pharmacogenetic risk factors associated with T-cell-mediated delayed hypersensitivity reactions. Recent HLA associations relevant to our understanding of immunopathogenesis and clinical practice include HLA-B ∗ 13:01 with co-trimoxazole-induced SCAR, and HLA-A ∗ 32:01 with vancomycin-DRESS, for which an extended HLA class II haplotype is implicated in glycopeptide antibiotic cross-reactivity. Hypoactive variants of ERAP1, an enzyme-trimming peptide prior to HLA loading, are now associated with protection from abacavir-hypersensitivity in HLA-B ∗ 57:01+ patients, and single-cell sequencing has defined the skin-restricted expansion of a single, public and drug-reactive dominant TCR across patients with HLA-B ∗ 15:02-restricted carbamazepine-induced SJS/TEN. More recent strategies for the use of HLA and other risk factors may include risk-stratification, early diagnosis, and diagnosis in addition to screening. HLA is necessary but insufficient as a risk factor for the development of most T-cell-mediated reactions. Newly emerged genetic and ecological risk factors, combined with HLA-restricted response, align with underlying immunopathogenesis and drive towards enhanced strategies to improve positive-predictive and negative-predictive values. With large population-matched cohorts, genetic studies typically focus on populations that have been readily accessible to research studies, but it is now imperative to address similar risk in globally relevant and understudied populations.
Publisher: Elsevier BV
Date: 02-2022
Publisher: Elsevier BV
Date: 08-2017
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Andrew Gibson.