Immunopharmacology of hypersensitivity reactions to drugs
Drug hypersensitivity reactions are characterized by their unpredictability, lack of simple dose-dependency, host sensitivity, and potentially serious clinical outcome. They occur in a small proportion of patients, and usually the predisposing factors are unknown, although there is increasing evidence for genetic predisposition and disease being significant risk factors. The current understanding of the chemical basis of immune-mediated reactions is based on the hapten hypothesis, which requires drug bioactivation, covalent binding to proteins, followed by uptake, antigen processing, and a polyclonal immune response. The recently proposed “danger hypothesis” can be considered to be an essential addition to the hapten hypothesis. According to the danger hypothesis, the immune response to a drug-derived antigen requires the presence of co-stimulatory signals and cytokines, which propagate and determine the type of immune response. The “danger signal” might result from chemical, physical, or viral stress.
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References and Recommended Reading
- 6.Neuberger J, Kenna JG: Halothane hepatitis: a model of immunoallergic disease. In Liver Cells and Drugs. Edited by John Libbey. Montrouge, France: Eurotext; 1988:161–173.Google Scholar
- 9.Park BK, Pirmohamed M, Kitteringham NR: The role of drug disposition in drug hypersensitivity: a chemical, molecular and clinical perspective. Chem Res Toxicol 1998, 11:969–988. Detailed review of the mechanism of drug hypersensitivity reactions and the first article to relate LDdanger” and drug hypersensitivity.PubMedCrossRefGoogle Scholar
- 14.Naisbitt DJ, Gordon SF, Pirmohamed M, et al.: Antigenicity and immunogenicity of sulphamethoxazole: demonstration of metabolism-dependent haptenation and T-cell proliferation in vivo. Br J Pharmacol 2001, 133:295–305. This manuscript in conjunction with reference 15 describes a rodent model of drug immunogenicity and highlights the critical role of metabolism in the induction of a cellular immune response.PubMedCrossRefGoogle Scholar
- 15.NaisbittDJ, Farrell J, Gordon SF, et al.: Covalent binding of the nitroso metabolite of sulfamethoxazole leads to toxicity and major histocompatibility complex-restricted antigen presentation. Mol Pharmacol 2002, 62:628–637. Here the authors describe the relationship between drug metabolism, toxicity, and the induction of a drug metabolite-specific cellular immune response. Importantly, metabolite-specific T-cells do not cross-react with the parent drug.PubMedCrossRefGoogle Scholar
- 21.Reilly TP, Lash LH, Doll MA, et al.: A role for bioactivation and covalent binding within epidermal keratinocytes in sulfonamide-induced cutaneous drug reactions. J Invest Dermatol 2000, 114:1164–1173. Metabolic activation and covalent binding of the drug sulfamethoxazole in skin cells.PubMedCrossRefGoogle Scholar
- 22.Uetrecht J: Generation by phagocytes of reactive drug metabolites. Exp Hematol 1995, 23:778–814.Google Scholar
- 25.SchnyderB, Burkhart C, Schnyder-Frutig K, et al.: Recognition of sulfamethoxazole and its reactive metabolites by drug-specific CD4+ T cells from allergic individuals. J Immunol 2000, 164:6647–6654. The authors clone and characterize drug- and drug metabolite-specific T-cells from the same hypersensitive patients. Drug and drug metabolite presentations to T-cells were processing independent.PubMedGoogle Scholar
- 29.Curtsinger JM, Schmidt CS, Mondino A, et al.: Inflammatory cytokines provide a third signal for activation of naive CD4+ and CD8+ T cells. J Immunol 1999, 162:3256–3262. The authors define three signals (1. antigen, 2. co-stimulation, 3. polarizing cytokines) that are required for the induction of an efficient cellular immune response.PubMedGoogle Scholar
- 35.Lepoittevin JP, Leblond I: Hapten peptide T-cell receptor interactions: molecular basis for the recognition of haptens by Tlymphocytes. Eur J Dermatol 1997, 7:151–154.Google Scholar
- 42.Dorner BG, Scheffold A, Rolph MS, et al.: MIP-1alpha, MIP-1beta, RANTES, and ATAC/lymphotactin function together with IFN-gamma as type 1 cytokines. Proc Natl Acad Sci U S A 2002, 99:6181–6186. A recent article that studies the nature of cellular immune responses in terms of chemokine polarization.PubMedCrossRefGoogle Scholar
- 49.Mallal S, Nolan D, Witt C, et al.: Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse transcriptase inhibitor abacavir. Lancet 2002, 359:727–732. An important study that highlights that it may be possible to identify genetic predisposing factors to drug hypersensitivity even in a disease that is as highly complex and heterogeneous as HIV disease.PubMedCrossRefGoogle Scholar
- 50.Hetherington S, Hughes AR, Mosteller M, et al.: Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 2002, 359:1121–1122. An important study that highlights that it may be possible to identify genetic predisposing factors to drug hypersensitivity even in a disease that is as highly complex and heterogeneous as HIV diseasePubMedCrossRefGoogle Scholar