Enzyme-linked Immunossays for Detection of Anti-drug Antibodies

Abstract

Adverse reactions to drugs constitute a serious problem in clinical practice, with respect to both their unpredictability and their sometimes life-threatening consequences. A large proportion of adverse drug reactions (estimates range from 10–50%) are labelled as ‘allergic’ or ‘hypersensitivity’ reactions, with the implication that the reaction is mediated by a specific immune response directed against the drug. Such classification of adverse reactions is based largely on symptoms alone, which may include skin rashes, fever, taste disturbance, and occasionally more serious disorders such as anaphylaxis, kidney dysfunction and cytopenias, all of which certainly can be caused by hypersensitivity reactions. For example, anaphylactic reactions and skin inflammation can be caused by cross-linking of cell-bound IgE by antigen, leading to release of histamine and other mast-cell-dependent chemical mediators (type I hypersensitivity); blood cells can be destroyed by antibody-dependent cytotoxic reactions (type II); inflammatory reactions and kidney dysfunction can be caused by immune complex deposition (type III); and inflammatory tissue reactions can also be T-cell-mediated (type IV). However, although certain symptoms may point to an immune aetiology, an adverse drug reaction can only be classified with certainty as a ‘hypersensitivity reaction’ or ‘drug allergy’ when drug-specific antibodies or sensitized T cells can be demonstrated. Even so, convincing evidence that an adverse reaction is immunologically mediated will only be obtained when the severity of the reaction is shown to relate to levels of circulating or tissue antibody or sensitized T cells. Hence, diagnosis of drug hypersensitivity depends on the development and correct use of appropriate laboratory tests for humoral and cellular indices of specific immune responses. Only when these immunological parameters are monitored in a quantitative manner will it be possible to relate drug dosage, distribution, disposition and metabolism to the induction of hypersensitivity.