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B DelayedType ImmuneMediated Drug Reactions
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The clinical course of many CDRs suggests they are delayed-type immune-mediated drug reactions. Growing evidence indicates that T-cell recognition of drugs is a critical step in the generation of these responses (11). T-cells possess clonally distributed receptors (TCR) that recognize antigen on the cell surface when presented by products of the major histocompatibility complex (MHC) genes. This cell surface-dependent recognition is referred to as MHC-restricted antigen recognition. CD4+ T-helper cells recognize antigen presented by MHC Class II, while those antigens presented by MHC Class I are recognized by CD8+ cytotoxic T-cells (11).
Because most drugs are of low molecular weight, their recognition as antigens is believed to necessitate the haptenation discussed previously. Few agents are chemically reactive and able to covalently bind with proteins and, thereby, directly act as haptens. Most drugs that evoke a delayed-type immune-mediated reaction are believed to undergo bioactivation to generate haptens that are recognized by sensitized lymphocytes (12). Hence, many investigations have focused on the role of bioactivation of causative agents to reactive metabolites, which may in turn bind to critical macromolecules and initiate the immune cascade that eventually presents as a delayed-type immune-mediated CDR. Numerous studies have demonstrated that several sulfonamides, as well as the sulfone dapsone, can undergo biotransformation to form reactive N-hydroxylamine metabolites (13). These studies indicate that the ability to detoxify these reactive metabolites may be an important determinant in the development of CDR. Interestingly, several studies have suggested that the in vitro cytotoxicity of these hydroxylamines toward peripheral blood mononuclear cells can predict predisposition to delayed-type immune-mediated reactions toward sulfonamides (13).
The anticonvulsants phenytoin and carbamazepine (which are also among the highest CDR-producing drugs) can also be metabolized by liver microsomes to reactive metabolites that are cytotoxic and exhibit covalent binding to macromolecules (14, 15). It has also been demonstrated that lymphocytes isolated from patients with a history of a CDR to phenytoin or carbamazepine incubated with parent drug and liver microsomes exhibit a higher cell death than lymphocytes from patients without a history of such a reaction. This suggests that a defect in detoxifying enzymes may be an important predisposing factor for the development of CDRs to anticonvulsants (14, 15).
One question that arises from these observations is, how can reactive metabolites generated in the liver survive transit to the sites where delayed-type hypersensitivity is manifested (most commonly, the skin)? It has been proposed that circulating immune cells may catalyze the bioactivation of these agents (16, 17, and 18). Indeed, activated monocytes and neutrophils have been shown to convert numerous CDR-evoking drugs to reactive metabolites. Using aniline as a model compound, Wulferink et al. have demonstrated that prohaptens incubated with white bone marrow cells form neoantigens that are recognized by T-cells (16, 17, and 18).
Long recognized for its importance in the structural integrity of the skin, the epidermal keratinocyte is a key cell in the initiation and propagation of cutaneous immune reactions (19). Keratinocyte-derived cytokines provide essential signals for the migration of Langerhans cells, which are believed to be the predominant APC in the skin. Modulation of the expression of these keratinocyte-derived cytokines may, therefore, impact antigen presentation and, ultimately, T-cell activation (19).
Intercellular adhesion molecule-1 (ICAM-1; also known as CD54) plays an important role in cell-cell-mediated immune responses, including drawing cells to the local enviroment (20, 21, and 22). Common sensitizing agents, such as nickel, p-phenylenediamine, and urushiol (the antigen in poison ivy) have been shown to induce the expression of ICAM-1 in cultured human keratinocytes. Other investigators have provided evidence that this induction of ICAM-1 is secondary to oxidative stress. Induction of ICAM-1 upon exposure to reactive metabolites, which may in turn induce oxidative stress, might be expected to enhance lymphocyte infiltration, making it an important step in initiation of these CDRs (20, 21, and 22).
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