It is important to emphasize that cytokine interactions with target cells often result in the release of a cascade of different endogenous cytokines, which exert their effects sequentially or simultaneously. For example, IFN-γ exposure increases the number of cell-surface receptors on target cells for TNF-α. Therapy with IL-2 induces the production of TNF-α, while experimental therapy with IL-12 induces the production of IFN-γ.
The basic immune mechanism and the ways in which it can be suppressed or stimulated by drugs have been discussed in previous sections of this chapter. Drugs also activate the immune system in undesirable ways that are manifested as adverse drug reactions. These reactions are generally grouped in a broad classification as “drug allergy.” Indeed, many drug reactions such as those to penicillin, iodides, phenytoin, and sulfonamides are allergic in nature. These drug reactions are manifested as skin eruptions, edema, anaphylactoid reactions, glomerulonephritis, fever, and eosinophilia.
Drug reactions mediated by immune responses can have several different mechanisms. Thus, any of the four major types of hypersensitivity discussed earlier in this chapter (pages 981–983) can be associated with allergic drug reactions:
I: IgE-mediated acute allergic reactions to stings, pollens, and drugs, including anaphylaxis, urticaria, and angioedema. IgE is fixed to tissue mast cells and blood basophils, and after interaction with antigen the cells release potent mediators.
II: Drugs often modify host proteins, thereby eliciting antibody responses to the modified protein. These allergic responses involve IgG or IgM in which the antibody becomes fixed to a host cell, which is then subject to complement-dependent lysis or to antibody-dependent cellular cytotoxicity.
III: Drugs may cause serum sickness, which involves immune complexes containing IgG complexed with a foreign antigen and is a multisystem complement-dependent vasculitis that may also result in urticaria.
IV: Cell-mediated allergy is the mechanism involved in allergic contact dermatitis from topically applied drugs or induration of the skin at the site of an antigen injected intradermally.
In some drug reactions, several of these hypersensitivity responses may occur simultaneously. Some adverse reactions to drugs may be mistakenly classified as allergic or immune when they are actually genetic deficiency states or are idiosyncratic and not mediated by immune mechanisms (eg, hemolysis due to primaquine in glucose-6-phosphate dehydrogenase deficiency, or aplastic anemia caused by chloramphenicol). See Figure 55–6.
Type I (immediate) sensitivity allergy to certain drugs occurs when the drug, not capable of inducing an immune response by itself, covalently links to a host carrier protein (hapten). When this happens, the immune system detects the drug-hapten conjugate as “modified self” and responds by generating IgE antibodies specific for the drug-hapten. It is not known why some patients mount an IgE response to a drug while others mount IgG responses. Under the influence of IL-4, -5, and -13 secreted by Th2 cells, B cells specific for the drug secrete IgE antibody. The mechanism for IgE-mediated immediate hypersensitivity is diagrammed in Figure 55–5.