demonstrated that PTs were most frequently positive for beta-lactams (primarily amoxicillin) and pristinamycin [112]. through which an antibiotic label gets assigned, acted on and maintained is still imprecise. Predicting T-cell-mediated ADRs via personalised approaches, including HLA-typing may pave Antitumor agent-2 future pathways to safer antimicrobial prescribing guidelines. Keywords: ELISpot, antibiotic allergy, severe cutaneous adverse reactions, patch testing, hypersensitivity, lymphocyte transformation test == Introduction == T-cell-mediated drug hypersensitivities are a group of immune-mediated (IM) adverse drug reactions (ADRs) of varying phenotype and severity. Descriptions of antimicrobial associated T-cell-mediated ADRs date back to the use of the first sulfa antimicrobials [1] and Antitumor agent-2 then almost a decade later to early preparations of penicillins [2, 3]. These IM-ADRs result in antimicrobial allergy labels that impact patient outcomes and antimicrobial usage [46]. For the diagnosis of antimicrobial allergy, the use of skin prick and intradermal testing (SPT/IDT) remain the mainstay of first-stage diagnosis for immediate reactions suspected to be IgE-mediated. This should be followed by an ingestion challenge which, in combination with SPT/IDT, is still considered to be the gold standard [7]. However , in the setting Antitumor agent-2 of serious T-cell-mediated ADRs, both patch testing, a more established test for the diagnosis of delayed reactions, and SPT/IDT lack the 100% negative predictive value necessary to re-challenge patients to drugs either orally or systemically following negative testing [8]. In this review, we will address the current understanding of antimicrobial cross-reactivity and the ready availability of and evidence for IM-ADRin vitro, in vivoandex vivodiagnostics. The epidemiology of serious T-cell-mediated reactions varies according to the region studied and is driven by genetic predisposition to these reactions. In general, given the high prevalence of antibiotic use, 50% or more of severe cutaneous adverse reactions (SCAR) globally are associated with antimicrobials, commonly penicillins, glycopeptides and sulphonamide antibiotics and antiretrovirals [5, 9, 10]. The most serious of these reactions include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustolosis (AGEP). Additionally , abacavir, a guanosine analogue nucleoside reverse transcriptase inhibitor (NRTI), is associated with a severe HLA-B*57: 01-restricted, CD8+ T-cell-mediated hypersensitivity reaction (AHS) which is characterized clinically by fever, malaise, gastrointestinal symptoms and late onset of rash (70%) a median of 8 days after initiation of dosing. In the setting of multiple implicated antimicrobials, the cause of SCAR and other IM-ADRs is often unclear despite application of published causality assessments [11, 12]. == Effector immunology of T-cell-mediated Antitumor agent-2 ADRs == IM-ADRs can be classified by the revised Gell and Coombs classification (Table 1)[13]. This review focuses on Type IV, T-cell-dependent IM-ADRs. The pathogenesis of T-cell-mediated immune responses has been long debated, yet the presence of allergen-specific T lymphocytes is an observation in most drug-allergy reactions. Whiteet al. reviewed the current mechanistic hypotheses of T-cell-dependent IM-ADRs namely (i) pharmacological interaction of drugs with immune receptors Cav1.3 (the p-i concept), (ii) the hapten/pro-hapten model and (iii) the altered peptide repertoire model (Figure 1)[4]. The cellular and cytokine response within IM-ADRs vary (Table 1). Antitumor agent-2 == Table 1 . == T-cell-mediated ADR classification, pathogenesis and phenotype guide References:[13] Abbreviations: Th1, Type 1 T helper cells, Th2, Type 2 T helper cells; Th17, Type 17 T helper cells; IL, interleukin; DHR, Drug hypersensitivity reaction; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; MPE, maculopapular exanthema; DRESS, drug reaction with eosinophilia and systemic symptoms; HSS, hypersensitivity syndrome; FDE, fixed drug eruption; EM, erythema multiforme; DILI, drug induced liver injury; AGEP, acute generalised exanthematous pustolosis; GM-CSF, granulocyte monocyte colony-stimulating factor; PMN, polymorphonuclear cell. Not classically described by Gell and Coombs criteria of T cell-mediated.