On the basis of clinical criteria, it has been postulated that many idiosyncratic adverse drug reactions are immune-mediated (Park et al., 1998; Pirmohamed et al., 1998). Research into this area is now providing some direct evidence to support the clinical impression. The mechanism by which a drug leads to an immune-mediated adverse reaction is explained by the hapten hypothesis (Park et al., 1998) (Figure 6.2). Central to the hapten hypothesis is the assumption that small molecules such as drugs (< 1000 Da) can be recognized as immunogens (i.e. a substance capable of eliciting a specific immune response) only when they become covalently bound to an autologous high molecular weight (> 50 000 Da) macromolecular carrier such as a protein (Park et al., 1987). The term hapten has been coined to describe such substances that are not immunogenic per se but become immuno-genic when conjugated to a macromolecular carrier (this has been termed signal 1). The type of hypersensitive reaction will be partly determined by the nature of the immune response and the site of antigen formation. The best understood reactions are the type I hypersensitivity reactions induced by penicillins and cephalosporins and mediated by IgE antibodies directed against a drug hapten conjugated to protein (Weiss and Adkinson, 1988; Pirmohamed et al., 1994). Severe anaphylac-tic reactions occur in only a minority of patients (1 in 2000); atopic patients are at increased risk, although the genetic basis of this and of the IgE response to penicillins remains to be elucidated.
Less well understood are the immunological mechanisms that underlie severe skin reactions such as Stevens-Johnson syndrome and immunoallergic hepatitis. There is clear chemical evidence from in vitro studies that the drugs associated with these reactions can undergo oxidative metabolism to chemically reactive metabolites that can haptenate proteins (Park et al., 1995). In addition, both humoral and cell-mediated responses directed against drug-induced antigen have been detected in patients, for example in halothane hepatitis (Pohl et al., 1990). With some compounds the immune response seems to be directed predominantly towards an autoantigen. For example, in tienilic acid-induced hepatitis, patients have circulating autoantibodies directed against the P450 isoform (CYP2C9), which is responsible for the bioactiva-tion of tienilic acid (Beaune and Bourdi, 1993).
The fundamental concept that protein-conjugation is an obligatory step in the process of immune recognition of drugs has however recently been challenged by the observation that T-cell clones from patients hypersensitive to a number of drugs undergo proliferation in an antigen-processing independent [but major histocompatibility complex (MHC) restricted] manner (Schnyder et al., 1997; Zanni et al., 1998). This requires labile, reversible binding of a drug to the MHCs on antigen-presenting cells. The presence of T-cell clones that proliferate only in response to the parent drug rather than the metabolite, and the rapid down-regulation in expression of the T-cell receptor upon stimulation are consistent with this mechanism. It is of course possible that both mechanisms may be important in the overall pathogenesis. For example, the hapten-dependent pathway may be more important for primary immune stimulation (sensitization), while the metabolism-independent pathway may be all that is necessary for secondary stimulation and elicita-tion of tissue damage (Pirmohamed and Park, 2001b). Further studies are needed to define the roles of the two pathways of drug (antigen) presentation in the pathogenesis of immunemediated adverse drug reactions.
Irrespective of the mechanism of antigen presentation, T cells are of fundamental importance in the immune response against a drug (Naisbitt et al., 2000a). The interaction between the T cell and the drug (antigen) in the groove of the MHC governs the immune response. MHC class I molecules bind the peptides of 8-10 amino acids and present to the CD8 + T cells (Pamer and Creswell, 1998). MHC class II molecules present longer peptide molecules (13 -17 amino acids) to CD4 + cells (Jensen, 1997). While class I molecules are found on all cell surfaces, class II molecules are only expressed on specialized antigen-presenting cells such as macrophages, but can become expressed on other cells such as keratinocytes in the presence of pro-inflammatory cytokines such as interferon gamma (Pichler and Yawalkar, 2000). The nature of the immune response is governed by differentiation of T cells into T helper-1 (TH1), T helper-2 (TH2), T cytotoxic-1 (TC1) or T cytotoxic-2 (TC2) subsets. TH1 and TC1 cells mediate cytotoxicity and local inflammatory reactions, while TH2 and TC2 cells stimulate B-cell dependent antibody production (Romagnani, 1999; Singh et al., 1999).
It is important to note that the presence of an antigen (i.e. signal 1) in the absence of co-stimulatory molecules will lead to tolerance and T-cell apoptosis (Naisbitt et al., 2000a). Although the role of surface molecules such as B7.1 and B7.2 as co-stimulatory molecules has long been known, the importance of cytokines has only been recognized recently. In addition to signal 1, two other signals are required to stimulate a full immune response (Curtsinger et al., 1999). Signal 2 is represented by a series of pro-inflammatory cytokines such as IL-2, TNF-a, and IFN-gamma that act indirectly on antigen presenting cells to up-regulate the expression of co-stimulatory molecules. Signal 3 represents polarizing cytokines that act directly on T cells. It is known that TH1 cells produce IL-12 and IFN-gamma, which promote the activation of macrophages and cellmediated immunity. By contrast, TH2 cells produce IL-4 and IL-13; these provide help for the humoral immune response by promoting IgG to IgE class switching.
An interesting hypothesis, termed the danger hypothesis, has recently been proposed in the field of immunology to explain the basis of self-tolerace (Matzinger, 1994; Anderson and Matzinger, 2000; Gallucci and Matzinger, 2001). This can also be applied to the mechanism of drug hypersensitivity (Park et al., 1998; Uetrecht, 1999). This hypothesis states that the immune system responds to most antigens with tolerance, and only in the presence of a danger signal will presentation of an antigen result in an immune response. The nature of the danger signals has not been accurately defined, but pro-inflammatory and polarizing cytokines, intracellu-lar contents resulting from cell necrosis and exogenous proteins including those derived from viruses, are all potential candidates (Gallucci and Matzinger, 2001). With respect to drug hypersensi-tivity, it can be hypothesized that the chemically reactive metabolite may not only provide signal 1 (by conjugating with a protein), but it could also provide the co-stimulatory signals 2 and 3 by activation of signalling pathways linked to oxida-tive stress and protein damage, including the secretion of cytokines (Park et al., 2001). Furthermore, the hypothesis also allows the possibility that the co-stimulatory molecules are completely independent of the drug, and could, for example, be concomitant viral infections (see below).
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