Delayed Drug Hypersensitivity Reactions

Drug-induced adverse reactions are a major health problem (1-3). Most adverse effects, so-called type A reactions, are due to the pharmacologic action of a drug. Idiosyncratic and immune-mediated side effects, which are not predictable, are called type B reactions (4). Drug hypersensitivity reactions (drug allergy) account for about one seventh of adverse reactions and manifest themselves in many diseases, some of which are severe (5, 6). The most common allergic reactions occur in the skin and are observed in about 2% to 3% of hospitalized patients (7-9). To correlate the clinical symptoms with the underlying immune mechanism, drug hypersensitivity and other immune reactions are frequently classified into 4 categories described by Coombs and Gell (10). Type I reactions are due to IgE mediation and mainly cause urticaria, anaphylaxis, and asthma; type II reactions are based on immunoglobulin-mediated cytotoxic mechanisms, accounting mainly for blood cell dyscrasias; type III reactions are immune complexmediated (for example, vasculitis); and type IV reactions are mediated by T cells, causing so-called delayed hypersensitivity (Table 1). Table 1. Relationship of Clinical Symptoms to Drug Reactivity This classification system has proven to be helpful in clinical practice and can guide diagnostic decisions. However, the term delayed hypersensitivity reactions, originally coined to describe T-cell reactions to tuberculin, became an umbrella term for various T-cellmediated immune mechanisms leading to clinically distinct diseases. Indeed, T cells have been found to differ in the cytokines they produce, which result in distinct disorders. T-helper 1 T cells activate macrophages by secreting large amounts of interferon drive the production of complement-fixing antibody isotypes, and costimulate proinflammatory responses (tumor necrosis factor-, interleukin [IL]-12) and CD8+ T-cell responses. T-helper 2 T cells secrete the cytokines IL-4 and IL-5 (11), which promote B-cell production of IgE and IgG4, macrophage deactivation, and mast-cell and eosinophil responses. CD8+ T cells can produce similarly polarized patterns of cytokines. Newer immunology textbooks have recognized this heterogeneity of T-cell function and consequently subdivide delayed hypersensitivity reactions into type IVa, type IVb, and type IVc reactions, which correspond to T-helper 1, T-helper 2, and cytotoxic reactions (Table 1) (12). T cells recognize small peptide antigens but are also involved in immune reactions to small chemicals. Indeed, the original description of cellular immunity is based on immune responses to haptens (13). The role of T cells in contact dermatitis elicited by small chemicals has been extensively documented (14, 15), and animal models have been used to dissect the immunopathogenesis (16, 17). Understanding of allergies to orally or parentally administered drugs has, in contrast, only slowly evolved, since clinical manifestations are extremely heterogeneous and animal models do not exist for most side effects. Nevertheless, the observation of T-cell infiltrates in drug-related allergic reactions that affect the skin, liver, and kidney, as well as drug-specific reactions found in vitro or indicated in the results of skin tests (16-21), strongly suggested T-cellmediated pathogenesis. This review presents newer concepts of the role of T cells in drug hypersensitivity, which evolved from the study of drug-specific T cells in various drug-induced hypersensitivity diseases. On the basis of in vitro analysis of drug-specific T-cell clones, novel methods of drug presentation to T cells can be defined, extending the hapten concept (22-24). Moreover, functional analysis of T-cell clones from the peripheral blood as well as from the affected tissue, together with immunohistologic analysis, reveals that distinct types of T-cell reactions can lead to different clinical forms of drug hypersensitivity reactions (25-28). How Do T Cells Recognize Drugs? T cells recognize the antigen by their antigen receptors, which are heterodimers of 2 chains designated as either T-cell receptors (the majority of T cells) or T-cell receptors (about 5% of circulating T cells). An enormous variety (>107) of T-cell receptors can be generated with distinct specificities because of different recombinations of genes related to T-cell receptors and the addition of N-region nucleotide insertions. Each T cell displays thousands of identical T-cell receptors, which bind a bimolecular complex displayed at the surface of another cell called an antigen-presenting cell. This complex consists of a fragment of a protein antigen (peptide) bound in the groove of a major MHC molecule (Figure 1). Two classes of MHC molecules present peptides of different origin and stimulate different T cells. Peptides that are derived from proteins synthesized and degraded in the cytosol are presented by MHC class I molecules and activate CD8+ T cells. The reactive CD8+ T cells secrete cytokines and are able to kill cells displaying foreign peptides derived from cytosolic pathogens, such as viruses. In contrast, MHC class II molecules present peptides derived from proteins degraded in endocytic vesicles. These structures interact with CD4+ T cells, which activate other immune effector cells as dictated by their cytokines (for example, macrophages, B cells, and CD8+ T cells) (11, 12). CD4+ T cells can also be cytotoxic (34). Figure 1. The hapten and prohapten concept and the noncovalent drug presentation to T cells. APC NO TCR The recognition of small molecules (such as drugs) by B cells and T cells is usually explained by the hapten concept. Haptens are small molecules (mostly <1000 Da) that are chemically reactive and thus able to undergo stable, covalent binding to a larger protein or peptide (13, 29, 30-33, 35, 36). This modification of a protein or peptide makes it immunogenic (Figure 1): Cell-bound or soluble immunoglobulins can recognize it directly, while T cells recognize a haptenpeptide fragment that is generated by intracellular processing of the haptenprotein complex and is presented to T cells by MHC molecules (Figure 1). Penicillin G is a typical hapten that tends to bind covalently to lysine groups within soluble or cell-bound proteins, thereby modifying them and eliciting B-cell and T-cell reactions (36). It is also possible that the hapten may bind directly to the immunogenic peptide presented by the MHC molecule itself or alter the MHC molecule directly. In this case, no processing is required (26, 37-39) (Figure 1). Alternatively, if the drug is not chemically reactive itself, it may represent a prohapten, which becomes reactive during metabolism (26-28, 34) (Figure 1). Sulfamethoxazole has been proposed as a typical example of a prohapten,since it is not chemically reactive but gains immunogenicity by intracellular metabolism. Cytochrome P450dependent metabolism can lead to sulfamethoxazolehydroxylamine, which becomes sulfamethoxazole-nitroso after oxidation, a chemically reactive compound that is able to bind covalently to proteins and peptides (Figure 1) (31, 37-40). The finding that keratinocytes might also process sulfamethoxazole to sulfamethoxazolehydroxylamine supports this concept and may explain the manifestation of drug allergy in the skin (38). Recently, a third possibility has been considered, namely a pharmacologic interaction of drugs with immune receptors (the pi concept) (Figure 1) (41-46). Chemically inert drugs, unable to covalently bind to peptides or proteins, may still activate certain T cells that happen to bear T-cell receptors that can interact with the drug. This model has been expanded by in vitro studies using T-cell clones specific for such drugs as sulfamethoxazole, lidocaine, mepivacaine, celecoxib, lamotrigine, carbamazepine, and p-phenylenediamine (41-43, 47-49). It relies on the following findings: Glutaraldehyde-fixed antigen-presenting cells, unable to process, can still present the drug and stimulate specific T cells (41); inhibited generation of reactive metabolites actually enhances the reactivity of T cells, suggesting that the inert drug but not the reactive metabolite is recognized (50); the drug is bound in a labile way since it can be washed away from the cell surface, in contrast to covalently bound drugs, which cannot (41, 42); and a drug-reactive T-cell clone reacts to the drug within seconds, before metabolism and processing can take place (42). This stimulation by inert drugs is MHC dependent, implying that for full stimulation of the T cell, the T-cell receptor needs to interact with the drug and the MHC molecule. This new concept has a major impact on our understanding of drug hypersensitivity and its distinct clinical manifestations (Figure 1, Table 1). Haptens are primarily immunogenic because of their chemical reactivity. They modify peptides and make them more or newly immunogenic. In contrast, chemical inert drugs are immunogenic only because of their structural features, which enable them to interact with immune receptors (certain T-cell receptors and possibly MHC). These structural features have never been considered in drug development but may account for a substantial portion of unforeseen side effects (51). The clinical symptoms elicited by drugs that are immunogenic because of their chemical or structural features may well differ. A hapten-like drug (for example, amoxicillin) is able to alter many different proteins, either soluble or cell-bound, and can even modify different MHC molecules and their embedded peptides directly (Figure 1). These distinct antigenic determinants can stimulate T cells and B cells and elicit more or less all types of immune reactions. Indeed, penicillins are reported to cause different antibody-mediated diseases, such as anaphylaxis or hemolytic anemia, but also various T-cellmediated reactions, such as maculopapular exanthema, drug-induced hypersensitivity syndrome, acute generalized