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Drug hypersensitivity reactions ( DHRs) may be caused by immunologic and non-immunologic mechanisms. According to the World Allergy Organization, drug allergy ( DA) encompasses the subgroup of immunologic DHRs which are mediated either by specific antibodies or specific T lymphocytes. Due to the immunologic memory, DA reactions bear an increased risk for dramatically enhanced reactions on re-exposure. Some current concepts of DA were described decades ago. Drug allergies to soluble macromolecular protein drugs such as biopharmaceuticals are predominantly T cell-dependent drug-specific antibody responses leading to IgE-or IgG-mediated allergy. However, most drugs are too small to be directly recognized by specific B and T cells. Immune reactions to low-molecular drugs have been explained by the hapten model: a hapten drug can bind covalently to soluble autologous proteins (e.g. serum albumin). Resulting compounds may then be recognized by matching B cell receptors ( BCRs) and induce a specific T cell-dependent IgE-or IgG-antibody production. Drug haptens may bind to extra- or intracellular proteins, which are processed and presented by various professional antigen-presenting cells ( APCs). Depending on the APC, they may induce not only specific antibody production, but also non-immediate T cell-mediated DA. More recently, a supplementary effector mechanism for non-immediate DA to low-molecular drugs has been described, namely the pharmacological interaction of native low-molecular drugs with immune receptors (p-i-concept). Low-molecular drugs may directly and reversibly attach to immune receptors. These non-covalent interactions may modify the affinity between autologous major histocompatibility complex ( MHC), presented peptides and specifically primed T cell receptors ( TCRs) and thereby stimulate T cells. A special type of p-i-reaction has been recently described between the antiviral drug abacavir and the F pocket of HLA-B*57:01. This interaction causes an alteration of the MHC-presented self-peptide repertoire and may consecutively lead to a kind of auto-reactivity. Such types of reactions can explain the strong MHC- HLA associations which have been found for some T cell-mediated DHRs. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity may deprive patients of drug therapy, and occasionally no effective alternative treatment is available. Successful desensitization has been well documented in delayed drug hypersensitivity reactions. In certain situations, such as sulfonamide hypersensitivity in HIV-positive patients or hypersensitivity to antibiotics in patients with cystic fibrosis, published success rates reach 80%, and this procedure appears helpful for the patient management. A state of clinical tolerance may be achieved by the administration of increasing doses of the previously offending drug. However, in most cases, a pre-existent sensitization has not been proven by positive skin tests. Successful re-administration may have occurred in nonsensitized patients. A better understanding of the underlying mechanisms of desensitization is needed. Currently, desensitization in delayed hypersensitivity reactions is restricted to mild, uncomplicated exanthems and fixed drug eruptions. The published success rates vary depending on clinical manifestations, drugs, and applied protocols. Slower protocols tend to be more effective than rush protocols; however, underreporting of unsuccessful procedures is very probable. The decision to desensitize a patient must always be made on an individual basis, balancing risks and benefits. This paper reviews the literature and presents the expert experience of the Drug Hypersensitivity Interest Group of the European Academy of Allergy and Clinical Immunology. [ABSTRACT FROM AUTHOR]

BackgroundThe most frequent side-effects of drug therapy are skin eruptions. Their pathomechanism is rather unclear. ObjectiveIn this prospective study we investigated the T cell activation and drug specificity in different forms of drug-induced exanthemas from 22 patients. MethodsDuring acute drug allergy, liver parameters and T cell subset activation in the circulation (up-regulation of CD25 and HLA‐DR) were evaluated and skin biopsies of the acute lesion performed. After recovery, the causative drug was identified by lymphocyte transformation (LTT) and scratch-patch tests. ResultsSeventeen of 22 (17/22) patients had maculo-papular exanthema, 4/22 bullous exanthema and 1/22 urticaria. The causative drugs were mainly antibiotics, anti-epileptics and anti-hypertensives. Up-regulation of HLA‐DR on circulating CD4+ and/or CD8+ T cells was detected in 17 patients, being most marked in patients with bullous reactions or hepatic involvement. The LTT was positive in 14/21 analysed and the patch test in 7/15. All patients showed lymphocytic infiltration in the skin biopsy of the acute lesion. Generally CD4+ T cells dominated; a higher percentage of circulating CD8+ T cells was found in patients with bullous skin reactions or hepatic involvement. ConclusionOur data demonstrate activation and drug specificity of T cells in drug-induced skin eruptions. A predominant CD8+ T cell activation leads to more severe (bullous) skin symptoms or liver involvement, while predominant activation of CD4+ cells elicits mainly maculo-papular reactions. [ABSTRACT FROM AUTHOR]

Discusses how T cell recognition of drugs plays a role in immunologic and clinical features in drug allergy. Reason the diagnosis of drug allergy is difficult; Approach to a patient with suspected drug allergy that is useful for diagnostic procedures and helpful in advising patients to avoid further symptoms; Main reasons that may explain this neglect of T cells in drug allergy:

T cells recognize peptide and non-peptide antigens. Drugs represent typical examples of nonpeptide antigens. The majority of drug-specific T cells are αβ+ TCR T cells and are MHC class I or II restricted. Here we show the existence of drug (lidocaine)-specific T cell clones which proliferate in the presence of antigen-presenting cells (APC) with different HLA alleles. Two clones (SFT24 and E20) were analyzed in detail. They show a narrow dose-dependent proliferation to lidocaine, but not to procaine. With the use of a panel of HLA-typed allogeneic APC, we observed that certain allogeneic APC plus lidocaine lead to a similar, others to partial and some to no proliferation of the lidocaine-specific T cell clones. An APC-independent proliferation could be excluded since both clones proliferated only marginally without APC and increasing the number of APC resulted in a higher proliferation. Blocking experiments with anti-DP, -DQ and -DR antibodies showed that lidocaine is presented in a HLA-DR-restricted way both with autologous or allogeneic APC. Mouse fibroblasts transfected with an allogeneic HLA-DRB1*01 but not HLA-DR-negative mouse fibroblasts could serve as presenting cells. Fixation of APC did not hamper drug presentation, but pulsing of APC with the drug was not possible, indicating that processing is not required and that lidocaine binds in an unstable way to the MHC-peptide complex. This degenerate drug recognition has certain features of superantigen recognition, such as the ability of drugs to bind from the outside to multiple HLA-DR alleles. Such features of drug recognition may open new therapeutic possibilities to intervene with TCR-MHC interactions in a selective way. [ABSTRACT FROM PUBLISHER]

Drugs are non-peptide antigens that can be recognized by specific T cells. It has been thought for many years that small molecular compounds can only be stimulating for T cells after covalent binding to MHC-embedded peptides. As most drug-specific T cell clones can react to glutaraldehyde fixed antigen presenting cells (APC), recognition of drugs by specific T cells does not require prior uptake and processing of haptenated proteins by APC. In fact, activated T cell clones can recognize drugs associated with the MHC-peptide complex in a non-covalent way. Such a binding is reminiscent of superantigen stimulations of T cells. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various topics within the issue including the skin patch tests, the lymphocyte proliferation assay, and the test sensitivity in drug allergy diagnosis.