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Single-cell transcriptomics reveal polyclonal memory T-cell responses in skin with positive abacavir patch test results.
Redwood AJ, Rwandamuriye F, Chopra A, Leary S, Ram R, McDonnell W, Konvinse K, White K, Pavlos R, Koelle DM, Mallal S, Phillips EJ
(2019) J Allergy Clin Immunol 144: 1413-1416.e7
MeSH Terms: Aged, Anti-HIV Agents, Arthralgia, CD8-Positive T-Lymphocytes, Dideoxynucleosides, Drug Hypersensitivity, Drug-Related Side Effects and Adverse Reactions, Gene Expression Profiling, HLA-B Antigens, Headache, Humans, Immunologic Memory, Lymphocyte Activation, Male, Myalgia, Patch Tests, Single-Cell Analysis, Skin
Added March 30, 2020
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18 MeSH Terms
Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions.
Nicoletti P, Barrett S, McEvoy L, Daly AK, Aithal G, Lucena MI, Andrade RJ, Wadelius M, Hallberg P, Stephens C, Bjornsson ES, Friedmann P, Kainu K, Laitinen T, Marson A, Molokhia M, Phillips E, Pichler W, Romano A, Shear N, Sills G, Tanno LK, Swale A, Floratos A, Shen Y, Nelson MR, Watkins PB, Daly MJ, Morris AP, Alfirevic A, Pirmohamed M
(2019) Clin Pharmacol Ther 106: 1028-1036
MeSH Terms: Adult, Anaplastic Lymphoma Kinase, Carbamazepine, Chemical and Drug Induced Liver Injury, Drug Hypersensitivity, Drug Hypersensitivity Syndrome, Europe, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-A Antigens, HLA-B Antigens, Humans, Male, Phenotype, Risk Factors, Stevens-Johnson Syndrome
Show Abstract · Added March 30, 2020
Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10-15.80; P = 1.2 × 10 ) and CBZ-DILI (OR = 7.3; 95% CI 2.47-23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10 ) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation.
© 2019 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.
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17 MeSH Terms
Prevention and Diagnosis of Severe T-Cell-Mediated Adverse Drug Reactions: Are We There Yet?
Redwood A, Trubiano J, Phillips EJ
(2019) J Allergy Clin Immunol Pract 7: 228-230
MeSH Terms: Administration, Cutaneous, Drug Hypersensitivity, HLA-B Antigens, Humans, Skin, T-Lymphocytes
Added March 30, 2020
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Controversies in drug allergy: Testing for delayed reactions.
Phillips EJ, Bigliardi P, Bircher AJ, Broyles A, Chang YS, Chung WH, Lehloenya R, Mockenhaupt M, Peter J, Pirmohamed M, Roujeau JC, Shear NH, Tanno LK, Trubiano J, Valluzzi R, Barbaud A
(2019) J Allergy Clin Immunol 143: 66-73
MeSH Terms: Animals, Asian Continental Ancestry Group, Carbamazepine, Dideoxynucleosides, HLA-B Antigens, HLA-B15 Antigen, Humans, Skin Tests, Stevens-Johnson Syndrome
Show Abstract · Added March 30, 2020
Controversies exist with regard to in vivo approaches to delayed immunologically mediated adverse drug reactions, such as exanthem (maculopapular eruption), drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and fixed drug eruptions. In particular, widespread differences exist between regions and practice on the availability and use of intradermal and patch testing, the standard drug concentrations used, the use of additional drugs in intradermal and patch testing to help determine cross-reactivity, the timing of testing in relation to the occurrence of the adverse drug reaction, the use of testing in specific phenotypes, and the use of oral challenge in conjunction with delayed intradermal and patch testing to ascertain drug tolerance. It was noted that there have been advances in the science of delayed T cell-mediated reactions that have shed light on immunopathogenesis and provided a mechanism of preprescription screening in the case of HLA-B*57:01 and abacavir hypersensitivity and HLA-B*15:02 and carbamazepine Stevens-Johnson syndrome/toxic epidermal necrolysis in Southeast Asian subjects. Future directions should include the collaboration of large international networks to develop and standardize in vivo diagnostic approaches, such as skin testing and patch testing, combined with ex vivo and in vitro laboratory approaches.
Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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Sequence-based HLA-A, B, C, DP, DQ, and DR typing of 496 adults from San Diego, California, USA.
Moore E, Grifoni A, Weiskopf D, Schulten V, Arlehamn CSL, Angelo M, Pham J, Leary S, Sidney J, Broide D, Frazier A, Phillips E, Mallal S, Mack SJ, Sette A
(2018) Hum Immunol 79: 821-822
MeSH Terms: Adolescent, Adult, Alleles, California, Female, Gene Frequency, Genotype, Genotyping Techniques, HLA-A Antigens, HLA-B Antigens, HLA-C Antigens, HLA-DP Antigens, HLA-DQ Antigens, HLA-DR Antigens, Histocompatibility Testing, Humans, Linkage Disequilibrium, Male, Middle Aged, Sequence Analysis, DNA, T-Lymphocytes, Young Adult
Show Abstract · Added March 30, 2020
DNA sequence-based typing at the HLA-A, -B, -C, -DPB1, -DQA1, -DQB1, and -DRB1 loci was performed on 496 healthy adult donors from San Diego, California, to characterize allele frequencies in support of studies of T cell responses to common allergens. Deviations from Hardy Weinberg proportions were detected at each locus except A and C. Several alleles were found in more than 15% of individuals, including the class II alleles DPB1∗02:01, DPB1∗04:01, DQA1∗01:02, DQA1∗05:01, DQB1∗03:01, and the class I allele A∗02:01. Genotype data will be available in the Allele Frequencies Net Database (AFND 3562).
Copyright © 2018. Published by Elsevier Inc.
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Active suppression rather than ignorance: tolerance to abacavir-induced HLA-B*57:01 peptide repertoire alteration.
Phillips EJ, Mallal SA
(2018) J Clin Invest 128: 2746-2749
MeSH Terms: Animals, Dideoxynucleosides, Drug Hypersensitivity, Drug Tolerance, HLA-B Antigens, Mice, Mice, Transgenic, Peptides
Show Abstract · Added March 30, 2020
The discovery of HLA-B*57:01-associated abacavir hypersensitivity is a translational success story that eliminated adverse reactions to abacavir through pretreatment screening and defined a mechanistic model of an altered peptide repertoire. In this issue of the JCI, Cardone et al. have developed an HLA-B*57:01-transgenic mouse model and demonstrated that CD4+ T cells play a key role in mediating tolerance to the dramatically altered endogenous peptide repertoire induced by abacavir and postulate a known mechanism by which CD4+ T cells suppress DC maturation. This report potentially explains why 45% of HLA-B*57:01 carriers tolerate abacavir and provides a framework for future studies of HLA-restricted, T cell-mediated drug tolerance and hypersensitivity.
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Sequence-based HLA-A, B, C, DP, DQ, and DR typing of 159 individuals from the Worcester region of the Western Cape province of South Africa.
Grifoni A, Sidney J, Carpenter C, Phillips E, Mallal S, Scriba TJ, Sette A, Lindestam Arlehamn CS
(2018) Hum Immunol 79: 143-144
MeSH Terms: Databases, Genetic, Gene Frequency, Genotype, HLA-A Antigens, HLA-B Antigens, HLA-C Antigens, HLA-DQ Antigens, HLA-DR Antigens, Humans, Lymphocyte Activation, Mycobacterium tuberculosis, Sequence Analysis, DNA, South Africa, T-Lymphocytes, Tuberculosis
Show Abstract · Added March 30, 2020
DNA sequence-based typing at the HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1, and -DRB3/4/5 loci was performed on samples provided by 159 individuals from the Worcester region of the Western Cape province of South Africa. The purpose of the study was to characterize allele frequencies in the local population, to support studies of T cell immunity against pathogens, including Mycobacterium tuberculosis. There are no detectable deviations from Hardy Weinberg proportions for the HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, and -DRB1 loci. A minor deviation was detected at the HLA-DQB1 locus due to an excess of homozygotes. The genotype data are available in the Allele Frequencies Net Database under identifier 3425.
Copyright © 2018. Published by Elsevier Inc.
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Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update.
Phillips EJ, Sukasem C, Whirl-Carrillo M, Müller DJ, Dunnenberger HM, Chantratita W, Goldspiel B, Chen YT, Carleton BC, George AL, Mushiroda T, Klein T, Gammal RS, Pirmohamed M
(2018) Clin Pharmacol Ther 103: 574-581
MeSH Terms: Anticonvulsants, Carbamazepine, Drug-Related Side Effects and Adverse Reactions, HLA-B Antigens, Humans, Oxcarbazepine, Pharmacogenetics
Show Abstract · Added March 30, 2020
The variant allele HLA-B*15:02 is strongly associated with greater risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients treated with carbamazepine or oxcarbazepine. The variant allele HLA-A*31:01 is associated with greater risk of maculopapular exanthema, drug reaction with eosinophilia and systemic symptoms, and SJS/TEN in patients treated with carbamazepine. We summarize evidence from the published literature supporting these associations and provide recommendations for carbamazepine and oxcarbazepine use based on HLA genotypes.
© 2018 American Society for Clinical Pharmacology and Therapeutics.
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Sequence-based HLA-A, B, C, DP, DQ, and DR typing of 714 adults from Colombo, Sri Lanka.
Grifoni A, Weiskopf D, Lindestam Arlehamn CS, Angelo M, Leary S, Sidney J, Frazier A, Phillips E, Mallal S, Mack SJ, Tippalagama R, Goonewardana S, Premawansa S, Premawansa G, Wijewickrama A, De Silva AD, Sette A
(2018) Hum Immunol 79: 87-88
MeSH Terms: Adult, Animals, Ethnic Groups, Female, Gene Frequency, Genotype, HLA-A Antigens, HLA-B Antigens, HLA-C Antigens, HLA-DP Antigens, HLA-DQ Antigens, HLA-DR Antigens, Healthy Volunteers, Histocompatibility Testing, Humans, Male, Mice, Sequence Analysis, DNA, Sri Lanka, T-Lymphocytes
Show Abstract · Added March 30, 2020
DNA sequence-based typing at the HLA-A, -B, -C, -DPB1, -DQA1, -DQB1, and -DRB1 loci was performed on 714 healthy adult blood bank donors from Colombo, Sri Lanka, to characterize allele frequencies in support of studies on T cell immunity against pathogens, including Dengue virus. Deviations from Hardy Weinberg proportions were not detected at any locus. Several alleles were found in >30% of individuals, including the class II alleles DPB1 * 04:01, DPB1 * 02:01, DQB1 * 06:01 and DRB1 * 07:01, and the class I alleles A * 33:03 and A * 24:02. Genotype data will be available in the Allele Frequencies Net Database.
Copyright © 2018 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
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HLAs: Key regulators of T-cell-mediated drug hypersensitivity.
Redwood AJ, Pavlos RK, White KD, Phillips EJ
(2018) HLA 91: 3-16
MeSH Terms: B-Lymphocytes, Dideoxynucleosides, Drug Hypersensitivity, HLA-B Antigens, Humans, Immunity, Cellular, Risk Factors, T-Lymphocytes
Show Abstract · Added March 30, 2020
Adverse drug reactions (ADR) can be broadly categorised as either on-target or off-target. On-target ADRs arise as a direct consequence of the pharmacological properties of the drug and are therefore predictable and dose-dependent. On-target ADRs comprise the majority (>80%) of ADRs, relate to the drug's interaction with its known pharmacological target and are a result of a complex interplay of genetic and ecologic factors. In contrast, off-target ADRs, including immune-mediated ADRs (IM-ADRs), are due to unintended pharmacological interactions such as inadvertent ligation of host cell receptors or non-pharmacological interactions mediated through an adaptive immune response. IM-ADRs can be classified according to the primary immune cell involved and include B-cell-mediated (Gell-Coombs type I-III reactions) and T-cell-mediated (Gell-Coombs type IV or delayed hypersensitivity) reactions. IM-ADRs mediated by T cells are associated with phenotypically distinct clinical diagnoses and can vary from a mild delayed rash to a life-threatening cutaneous, systemic or organ disease, such as Stephen Johnson syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms and drug-induced liver disease. T-cell-mediated ADRs are strongly linked to the carriage of particular HLA risk alleles which are in the case of abacavir hypersensitivity and HLA-B*57:01 has led to translation into the clinic as a routine screening test. In this review, we will discuss the immunogenetics and pathogenesis of IM-ADRs and how HLA associations inform both pre-drug screening strategies and mechanistic understanding.
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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