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Immunopharmacology of hypersensitivity reactions to drugs

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Abstract

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

  1. Pirmohamed M, Breckenridge AM, Kitteringham NR, Park BK: Adverse drug reactions. BMJ 1998, 316:1295–1298.

    PubMed  CAS  Google Scholar 

  2. Park BK, Pirmohamed M, Kitteringham NR: Idiosyncratic drug reactions: a mechanistic evaluation of risk factors. Br J Clin Pharmacol 1992, 34:377–395.

    PubMed  CAS  Google Scholar 

  3. Sullivan JR, Shear NH: The drug hypersensitivity syndrome: What is the pathogenesis? Arch Dermatol 2001, 137:357–364.

    PubMed  CAS  Google Scholar 

  4. Wong IC, Mawer GE, Sander JW: Factors influencing the incidence of lamotrigine-related skin rash. Ann Pharmacother 1999, 33:1037–1042.

    Article  PubMed  CAS  Google Scholar 

  5. Knowles SR, Uetrecht J, Shear NH: Idiosyncratic drug reactions: the reactive metabolite syndromes. Lancet 2000, 356:1587–1591.

    Article  PubMed  CAS  Google Scholar 

  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 

  7. Pohl LR, Kenna JG, Satoh H, Christ D: Neoantigens associated with halothane hepatitis. Drug Metab Rev 1989, 20:203–217.

    PubMed  CAS  Google Scholar 

  8. Kenna JG, Knight TL, van PeltFNAM: Immunity to halothane metabolite-modified proteins in halothane hepatitis. Ann NY Acad Sci 1993, 685:646–661.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

  10. Naisbitt DJ, Williams DP, Pirmohamed M, et al.: Reactive metabolites and their role in adverse drug reactions. Curr Opin Allergy Clin Immunol 2001, 1:317–325.

    PubMed  CAS  Google Scholar 

  11. Uetrecht JP: New concepts in immunology relevant to idiosyncratic drug reactions: the "danger hypothesis" and innate immune system. Chem Res Toxico. 1999, 12:387–395.

    Article  CAS  Google Scholar 

  12. Landsteiner K, Jacobs J: Studies on the sensitisation of animals with simple chemical compounds. J Exp Med 1935, 61:643–656.

    Article  CAS  PubMed  Google Scholar 

  13. Park BK, Coleman JW, Kitteringham NR: Drug disposition and drug hypersensitivity. Biochem Pharmacol 1987, 36:581–590.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google Scholar 

  16. Kalish RS, Askenase PW: Molecular mechanisms of CD8+ T cell-mediated delayed hypersensitivity: implications for allergies, asthma and autoimmunity. J Allergy Clin Immunol 1999, 103:192–199.

    Article  PubMed  CAS  Google Scholar 

  17. Naisbitt DJ, Gordon SF, Pirmohamed M, Park BK: Immunological principles of adverse drug reactions: the initiation and propagation of immune responses elicited by drug treatment. Drug Saf 2000, 23:483–507.

    Article  PubMed  CAS  Google Scholar 

  18. Gut J, Christen U, Huwyler J: Mechanisms of halothane toxicity: novel insights. Pharmacol Ther 1993, 58:133–155.

    Article  PubMed  CAS  Google Scholar 

  19. Njoku D, Laster MJ, Gong DH, et al.: Biotransformation of halothane, enflurane, isoflurane, and desflurane to trifluoroacetylated liver proteins: association between protein acylation and hepatic injury. Anesth Analg 1997, 84:173–178.

    Article  PubMed  CAS  Google Scholar 

  20. Baron JM, Holler D, Schiffer R, et al.: Expression of multiple cytochrome P450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes. J Invest Dermatol 2001, 116:541–548.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google Scholar 

  22. Uetrecht J: Generation by phagocytes of reactive drug metabolites. Exp Hematol 1995, 23:778–814.

    Google Scholar 

  23. Williams DP, Pirmohamed M, Naisbitt DJ, et al.: Induction of metabolism-dependent and-independent neutrophil apoptosis by clozapine. Mol Pharmacol 2000, 58:207–216.

    PubMed  CAS  Google Scholar 

  24. Zanni MP, von Greyerz S, Schnyder B, et al.:HLA-restricted, processing- and metabolism-independent pathway of drug recognition by human alpha beta T lymphocytes. J Clin Invest 1998, 102:1591–1598.

    Article  PubMed  CAS  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.

    PubMed  CAS  Google Scholar 

  26. Hertl M, Jugert F, Merk HF: CD8(+) dermal T-cells from a sulfamethoxazole-induced bullous exanthem proliferate in response to drug-modified liver-microsomes. Br J Dermatol 1995, 132:215–220.

    Article  PubMed  CAS  Google Scholar 

  27. Matzinger P: Tolerance, danger, and the extended family. Annu Rev Immunol 1994, 12:991–1045.

    PubMed  CAS  Google Scholar 

  28. Gallucci S, Lolkema M, Matzinger P: Natural adjuvants: endogenous activators of dendritic cells. Nat Med 1999, 5:1249–1255.

    Article  PubMed  CAS  Google 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.

    PubMed  CAS  Google Scholar 

  30. Descamps V, Valance A, Edlinger C, et al.: Association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms. Arch Dermatol 2001, 137:301–304.

    PubMed  CAS  Google Scholar 

  31. Pirmohamed M, Park BK: HIV and drug allergy. Curr Opin Allergy Clin Immunol 2001, 1:311–316.

    PubMed  CAS  Google Scholar 

  32. Baier-Bitterlich G, Fuchs D, Wachter H: Chronic immune stimulation, oxidative stress, and apoptosis in HIV infection. Biochem Pharmacol 1997, 53:755–763.

    Article  PubMed  CAS  Google Scholar 

  33. Schnyder B, Frutig K, Mauri-Hellweg D, et al.: T-cell-mediated cytotoxicity against keratinocytes in sulfamethoxazoleinduced skin reaction. Clin Exp Allergy 1998, 28:1412–1417.

    Article  PubMed  CAS  Google Scholar 

  34. Naldi L, Conforti A, Venegoni M, et al.: Cutaneous reactions to drugs. An analysis of spontaneous reports in four Italian regions. Br J Clin Pharmacol 1999, 48:839–846.

    Article  PubMed  CAS  Google 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.

    CAS  Google Scholar 

  36. Kimber I, Dearman RJ: Allergic contact dermatitis: the cellular effectors. Contact Dermatitis 2002, 46:1–5.

    Article  PubMed  Google Scholar 

  37. Kehren J, Desvignes C, Krasteva M, et al.: Cytotoxicity is mandatory for CD8+ T cell-mediated contact hypersensitivity. J Exp Med 1999, 189:779–786. The authors utilize gene knockout animals to investigate the molecular mechanisms of contact hypersensitivity.

    Article  PubMed  CAS  Google Scholar 

  38. Akiba H, Kehren J, Ducluzeau MT, et al.: Skin inflammation during contact hypersensitivity is mediated by early recruitment of CD8+ T cytotoxic 1 cells inducing keratinocyte apoptosis. J Immunol 2002, 168:3079–3087.

    PubMed  CAS  Google Scholar 

  39. Friedmann PS, Strickland I, Pirmohamed M, Park BK: Investigation of mechanisms in toxic epidermal necrolysis induced by carbamazepine. Arch Dermatol 1994, 130:598–604.

    Article  PubMed  CAS  Google Scholar 

  40. Madden S, Maggs JL, Park BK: Bioactivation of carbamazepine in the rat in vivo: evidence for the formation of reactive arene oxide(s). Drug Metab Dispos 1996, 24:469–479.

    PubMed  CAS  Google Scholar 

  41. Maggs JL, Naisbitt DJ, Tettey JN, et al.: Metabolism of lamotrigine to a reactive arene oxide intermediate. Chem Res Toxicol 2000, 13:1075–1081.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

  43. Yawalkar N, Hari Y, Frutig K, et al.: T cells isolated from positive epicutaneous test reactions to amoxicillin and ceftriaxone are drug specific and cytotoxic. J Invest Dermatol 2000, 115:647–652.

    Article  PubMed  CAS  Google Scholar 

  44. Hashizume H, Takigawa M, Tokura Y: Characterization of drug-specific T cells in phenobarbital-induced eruption. J Immunol 2002, 168:5359–5368. An ex vivo study characterizing drug antigen-specific T cells from patients hypersensitive to the anticonvulsant henobarbital.

    PubMed  CAS  Google Scholar 

  45. Batchelor JR, Welsh KI, Tinoco RM, et al.: Hydralazine-induced systemic lupus erythematosus: influence of HLA-DR and sex on susceptibility. Lancet 1980, 1:1107–1109.

    Article  PubMed  CAS  Google Scholar 

  46. Pirmohamed M, Park BK: Genetic susceptibility to adverse drug reactions. Trends Pharmacol Sci 2001, 22:298–305.

    Article  PubMed  CAS  Google Scholar 

  47. Green VJ, Pirmohamed M, Kitteringham NR, et al.: Genetic analysis of microsomal epoxide hydrolase in patients with carbamazepine hypersensitivity. Biochem Pharmacol 1995, 50:1353–1359.

    Article  PubMed  CAS  Google Scholar 

  48. Pirmohamed M, Lin K, Chadwick D, Park BK: TNF-alpha promoter region gene polymorphisms in carbamazepine-hypersensitive patients. Neurology 2001, 56:890–896.

    PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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 disease

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street, L69 3GE, Liverpool, UK

    Dean J. Naisbitt PhD, Munir Pirmohamed MD & B. Kevin Park PhD

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  1. Dean J. Naisbitt PhD
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  2. Munir Pirmohamed MD
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  3. B. Kevin Park PhD
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Naisbitt, D.J., Pirmohamed, M. & Park, B.K. Immunopharmacology of hypersensitivity reactions to drugs. Curr Allergy Asthma Rep 3, 22–29 (2003). https://doi.org/10.1007/s11882-003-0006-9

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