Single cell transcriptomics reveal polyclonal memory T cell responses in abacavir patch test positive skin

Capsule Summary. Single-cell responses in HLA-B*57:01 abacavir patch test positive skin remote to the acute hypersensitivity reaction demonstrate polyclonal T-cell activation and proliferation characterized by a transcriptional and cellular response consistent with memory responses to altered peptides

7th Drug hypersensitivity meeting: part two

No abstract availabl

Antibiotic allergy in pediatrics

The overlabeling of pediatric antibiotic allergy represents a huge burden in society. Given that up to 10% of the US population is labeled as penicillin allergic, it can be estimated that at least 5 million children in this country are labeled with penicillin allergy. We now understand that most of the cutaneous symptoms that are interpreted as drug allergy are likely viral induced or due to a drug–virus interaction, and they usually do not represent a long-lasting, drug-specific, adaptive immune response to the antibiotic that a child received. Because most antibiotic allergy labels acquired in childhood are carried into adulthood, the overlabeling of antibiotic allergy is a liability that leads to unnecessary long-term health care risks, costs, and antibiotic resistance. Fortunately, awareness of this growing burden is increasing and leading to more emphasis on antibiotic allergy delabeling strategies in the adult population. There is growing literature that is used to support the safe and efficacious use of tools such as skin testing and drug challenge to evaluate and manage children with antibiotic allergy labels. In addition, there is an increasing understanding of antibiotic reactivity within classes and side-chain reactions. In summary, a better overall understanding of the current tools available for the diagnosis and management of adverse drug reactions is likely to change how pediatric primary care providers evaluate and treat patients with such diagnoses and prevent the unnecessary avoidance of antibiotics, particularly penicillins

Single cell analysis of drug responsive T cells; identification of candidate drug reactive T cell receptors in abacavir and carbamazepine hypersensitivity

No abstract availabl

Characterization of TCR repertoire diversity and tissue distribution of drug-specific T cells in DRESS

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Cross-reactivity between vancomycin, teicoplanin and telavancin in HLA-A*32:01 positive vancomycin DRESS patients sharing an HLA-Class II haplotype

All fifteen patients with HLA-A*32:01 restricted vancomycin-induced DRESS, showed negative ex vivo responses to dalbavancin however two showed cross-reactivity to teicoplanin and telavancin. Adjunctive diagnostic testing should be considered to detect potential cross-reactivity amongst glycopeptides

Isolation of activated CD8+ T cells following drug stimulation: A first step toward evaluating the heterologous immunity model for pure T-cell mediated adverse drug reactions

No abstract availabl

Severe Delayed Cutaneous and Systemic Reactions to Drugs: A Global Perspective on the Science and Art of Current Practice

Most immune-mediated adverse drug reactions (IM-ADRs) involve the skin, and many have additional systemic features. Severe cutaneous adverse drug reactions (SCARs) are an uncommon, potentially life-threatening, and challenging subgroup of IM-ADRs with diverse clinical phenotypes, mechanisms, and offending drugs. T-cell–mediated immunopathology is central to these severe delayed reactions, but effector cells and cytokines differ by clinical phenotype. Strong HLA-gene associations have been elucidated for specific drug-SCAR IM-ADRs such as Stevens-Johnson syndrome/toxic epidermal necrolysis, although the mechanisms by which carriage of a specific HLA allele is necessary but not sufficient for the development of many IM-ADRs is still being defined. SCAR management is complicated by substantial short- and long-term morbidity/mortality and the potential need to treat ongoing comorbid disease with related medications. Multidisciplinary specialist teams at experienced units should care for patients. In the setting of SCAR, patient outcomes as well as preventive, diagnostic, treatment, and management approaches are often not generalizable, but rather context specific, driven by population HLA-genetics, the pharmacology and genetic risk factors of the implicated drug, severity of underlying comorbid disease necessitating ongoing treatments, and cost considerations. In this review, we update the basic and clinical science of SCAR diagnosis and managemen

Characterizing immune responses in severe T-cell mediated adverse drug reaction

Severe immune-mediated adverse drug reactions (IM-ADRs) significantly impact patient outcome and inflict substantial cost on healthcare and drug development. Many of these T-cell mediated reactions are now known to be class I and/or class II HLA restricted, however, the minority of patients carrying an HLA risk allele will develop an IM-ADR. To help define the specific immunopathogenesis of these T-cell mediated drug reactions, a biobank of cryopreserved PBMCs and blister fluid/skin biopsies has been developed from HLA class I and II genotyped patients with IM-ADRs (Stevens-Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN), abacavir hypersensitivity, and drug reaction with eosinophilia and systemic symptoms (DRESS)) at various time points from their acute reaction. Causative drugs included antibiotics, antiretrovirals, anticonvulsants and allopurinol. Overnight gamma interferon ELISpot assay proved sensitive to identify dose-dependent drug responses at different time points during and following the acute IM-ADR. We used intracellular cytokine staining and cell sorting to identify drug specific CD137+/CD69+ activated CD8+ and CD4+ T cells. Single cell and bulk TCR sequencing was performed to compare activated and non-activated populations of T cells in the presence and absence of drug. Immune responses differed according to the drug, clinical phenotype/tissue specificity, time from drug reaction, CD4+ and/or CD8+ dependency, and the oligoclonality of drug specific T-cell populations

Characterizing immune responses in severe T-cell mediated adverse drug reaction

Severe immune-mediated adverse drug reactions (IM-ADRs) significantly impact patient outcome and inflict substantial cost on healthcare and drug development. Many of these T-cell mediated reactions are now known to be class I and/or class II HLA restricted, however, the minority of patients carrying an HLA risk allele will develop an IM-ADR. To help define the specific immunopathogenesis of these T-cell mediated drug reactions, a biobank of cryopreserved PBMCs and blister fluid/skin biopsies has been developed from HLA class I and II genotyped patients with IM-ADRs (Stevens-Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN), abacavir hypersensitivity, and drug reaction with eosinophilia and systemic symptoms (DRESS)) at various time points from their acute reaction. Causative drugs included antibiotics, antiretrovirals, anticonvulsants and allopurinol. Overnight gamma interferon ELISpot assay proved sensitive to identify dose-dependent drug responses at different time points during and following the acute IM-ADR. We used intracellular cytokine staining and cell sorting to identify drug specific CD137+/CD69+ activated CD8+ and CD4+ T cells. Single cell and bulk TCR sequencing was performed to compare activated and non-activated populations of T cells in the presence and absence of drug. Immune responses differed according to the drug, clinical phenotype/tissue specificity, time from drug reaction, CD4+ and/or CD8+ dependency, and the oligoclonality of drug specific T-cell populations