Abstract
The immunotoxic effects of drugs are divided into immunosuppression, immunostimulation, hypersensitivity and autoimmunity. The major adverse consequences of immunosuppression are infectious complications and virus-induced malignancies. Flu-like reactions, more frequent autoimmune diseases and hypersensitivity reactions to unrelated allergens, and inhibition of drug-metabolising enzymes are the adverse effects related to immunostimulation. Hypersensitivity reactions are the most frequent immunotoxic effects of drugs. They include immune-mediated (‘allergic’) and non immune-mediated (‘pseudoallergic’) reactions. Drug-induced autoimmune reactions, either systemic or organ-specific, are seemingly rare. A review of drug-induced immunotoxic effects demonstrates that immunotoxicity is a significant cause of morbidity and even mortality.
As immunotoxicologists have long focused on immunosuppression, the nonclinical immunotoxicity safety assessment of unexpected immunosuppression is based on a number of relatively well standardised and validated animal models and assays. However, there is no general consensus regarding the minimal requirement for this assessment. Many different assays can be used to extend the assessment case by case. Few animal models and assays have been validated for use in the nonclinical safety assessment of unexpected immunostimulation. The situation is worse regarding the prediction of hypersensitivity and autoimmune reactions. Our limited understanding of the molecular and cellular mechanisms of immunotoxicity accounts, at least partly, for this situation.
Recent guidelines for the immunotoxicity safety assessment of drugs, even though conflicting on several points, will serve as an impetus not only to refine current animal models and assays, but also to search for better alternatives. The new data generated will have to be interpreted and extended to animal species other than just rodents. Likewise, animal results will have to be compared with findings in humans. The search for immunological endpoints that can be used in several animal species and in humans will therefore become essential. Specific endpoints and clinical criteria that can be included in clinical trials to further investigate the potential for immunotoxicity of new drugs will have to be defined.
Because immunotoxicity plays a key role in drug-induced adverse effects, the role of immunotoxicology in drug safety assessment is indisputable and the systematic nonclinical as well as clinical immunotoxicity assessment of every new drug is deemed essential.
Similar content being viewed by others
References
Meylers L. Cytostatic drugs. In: Meylers L, editor. Side-effects of drugs. 2nd ed. Amsterdam: Excerpta Medica, 1966: 472–494
Vos JG. Immune suppression as related to toxicology. CRC Crit Rev Toxicol 1977; 5: 67–101
Descotes J. From clinical to animal toxicology: linking animal research and risk assessment in man. Toxicol Lett 2003; 140-141: 3–10
CPMP. Note for guidance on repeated dose toxicity testing. CPMP/SWP/1042/99, 2000 [online]. Available from URL:http://www.emea.eu.int/pdfs/human/swp/104299en.pdf [Accessed 2005 Jan 14]
CPMP FDA. Guidance for industry: immunotoxicology evaluation of investigational new drugs, 2002 [online]. Available from URL:http://www.fda.gov/cder/guidance/4945fnl.pdf [Accessed 2005 Jan 14]
Descotes J. Health consequences of immunotoxic effects. In: Descotes J, editor. Immunotoxicology of drugs and chemicals. 3rd ed. Amsterdam: Elsevier Science, 2004: 55–126
Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998; 338: 1741–51
Schmidt A, Oberbauer R. Bacterial and fungal infections after kidney transplantation. Curr Opin Urol 1999; 9: 45–9
Klein NC, Go CH, Cunha BA. Infections associated with steroid use. Infect Dis Clin North Am 2001, 432
Boerbooms AM, Kerstens PJ, van Loenhout JW, et al. Infections during low-dose methotrexate treatment in rheumatoid arthritis. Semin Arthritis Rheum 1995; 24: 411–21
Kroesen S, Widmer AF, Tyndall A, et al. Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-α therapy. Rheumatology 2003; 42: 617–21
Nakanishi Y, Shigematsu N, Kurita Y, et al. Respiratory involvement and immune status in Yusho patients. Environ Health Perspect 1985; 59: 31–6
Vial T, Descotes J. Immunosuppressive drugs and cancer. Toxicology 2003; 185: 229–40
Wilson LD. Skin cancers after organ transplantation. N Engl J Med 2003; 349: 612–4
Murray PG, Young LS. Epstein-Barr virus infection: basis of malignancy and potential for therapy. Expert Rev Mol Med 2001; 3: 1–20
Verma SC, Robertson ES. Molecular biology and pathogenesis of Kaposi sarcoma-associated herpesvirus. FEMS Microbiol Lett 2003; 222: 155–63
Georgescu L, Paget SA. Lymphoma in patients treated with rheumatoid patients: what is the evidence of link with methotrexate? Drug Saf 1999; 20: 475–87
Brown SL, Greene MH, Gershon SK, et al. Tumor necrosis factor antagonist therapy and lymphoma development: twentysix cases reported to the Food and Drug Administration. Arthritis Rheum 2002; 46: 3151–8
Descotes J. Adverse consequences of chemical immunomodulation. Clin Res Pr Drug Regul Aff 1985; 3: 45–52
Vial T, Choquet-Kastylevsky G, Descotes J. Adverse effects of immunotherapeutics involving the immune system. Toxicology 2002;174: 3–11
Vial T, Descotes J. Immune-mediated side-effects of cytokines in humans. Toxicology 1995; 105: 31–57
Cheifetz A, Smedley M, Martin S, et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 2003; 98: 1315–24
Krause I, Valesini G, Scrivo R, et al. Autoimmune aspects of cytokine and anticytokine therapies. Am J Med 2003; 115: 390–7
Shulman KL, Thompson JA, Benyunes MC, et al. Adverse reactions to intravenous contrast media in patients treated with interleukin-2. J Immunother 1993; 13: 208–12
Heywood GR, Rosenberg SA, Weber JS. Hypersensitivity reactions to chemotherapy agents in patients receiving chemoimmunotherapy with high-dose interleukin 2. J Natl Cancer Inst 1995; 87: 915–22
Renton KW. Hepatic drug metabolism and immunostimulation. Toxicology 2000; 142: 173–8
Hassan M, Nilsson C, Olsson H, et al. The influence of interferon-α on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite in patients with multiple myeloma. Eur J Pharmacol 1999; 63: 163–70
Descotes J, Choquet-Kastylevsky G. The Gell and Coombs classification: is it still valid? Toxicology 2001; 158: 43–9
Naisbitt DJ, Williams DP, Pirmohamed M, et al. Reactive metabolites and their role in drug reactions. Curr Opin Allergy Clin Immunol 2001; 1: 317–25
Britschgi M, von Greyerz S, Burkhart C, et al. Molecular aspects of drug recognition by specific T cells. Curr Drug Targets 2003; 4: 1–11
Choquet-Kastylevsky G, Vial T, Descotes J. Drug allergy diagnosis in humans: possibilities and pitfalls. Toxicology 2001; 158: 1–10
Zuberbier T. Pseudoallergy or nonallergic hypersensitivity. Allergy 1999; 54: 397–8
Mathews KP. Clinical spectrum of allergic and pseudoallergic drug reactions. J Allergy Clin Immunol 1984; 74: 558–66
Withington DE, Patrick JA, Reynolds F. Histamine release by morphine and diamorphine in man. Anaesthesia 1993; 48: 26–9
Wallace MR, Mascola JR, Oldfield EC. Red man syndrome: incidence, etiology, and prophylaxis. J Infect Dis 1991; 164: 1180–5
Szebeni J, Muggia FM, Alving CR. Complement activation by Cremophor EL as a possible contributor to hypersensitivity to paclitaxel: an in vitro study. J Natl Cancer Inst 1998; 90: 300–6
Hoffmeister HM, Heller W. Radiographic contrast media and the coagulation and complement systems. Invest Radiol 1996; 31: 591–5
Nettis E, Colanardi MC, Ferrannini A, et al. Update on sensitivity to nonsteroidal antiinflammatory drugs. Curr Drug Targets Immune Endocr Metabol Disord 2001; 1: 233–40
Vial T, Nicolas B, Descotes J. Drug-induced autoimmunity: experience of the French Pharmacovigilance system. Toxicology 1997; 119: 23–7
Pichler WJ. Drug-induced autoimmunity. Curr Opin Allergy Clin Immunol 2003; 3: 249–53
Rubin RL. Etiology and mechanisms of drug-induced lupus. Curr Opin Rheumatol 1999; 11: 357–63
Haustein UF, Haupt B. Drug-induced scleroderma and sclerodermiform conditions. Clin Dermatol 1998; 16: 353–66
Vial T, Pont J, Pham E, et al. Cefaclor-associated serum sickness-like disease: eight cases and review of the literature. Ann Pharmacother 1992; 26: 910–4
Penn AS, Low BW, Jaffe IA, et al. Drug-induced autoimmune myasthenia gravis. Ann N Y Acad Sci 1998; 841: 433–49
Kuper CF, Harleman JH, Richter-Reichelm HB, et al. Histopathologic approaches to detect changes indicative of immunotoxicity. Toxicol Pathol 2000; 28: 454–66
Putman E, Van Loveren H, Bode G, et al. Assessment of the immunotoxic potential of human pharmaceuticals: a workshop report. Drug Inf J 2002; 36: 417–27
Luster MI, Portier C, Pait DG, et al. Risk assessment in immunotoxicology: II. relationships between immune and host resistance tests. Fundam Appl Toxicol 1994; 21: 71–82
Schulte A, Althoff J, Ewe S, et al. Two immunotoxicity ring studies according to OECD TG 407-comparison of data on cyclosporin A and hexachlorobenzene. Regul Toxicol Pharmacol 2002; 36: 12–21
Gore ER, Gower J, Kurali E, et al. Primary antibody response to keyhole limpet hemocyanin in rat as a model for immunotoxicity evaluation. Toxicology 2004; 197: 23–35
Descotes J. Nonclinical evaluation of unexpected immunosuppression. In: Descotes J, editor. Immunotoxicology of drugs and chemicals. 3rd ed. Amsterdam: Elsevier Science, 2004: 163–203
Dean JH, Padarathsingh ML, Jerrells TR. Assessment of immunobiological effects induced by chemicals, drugs and food additives: I. tier testing and screening approach. Drug Chem Toxicol 1979; 2: 5–17
Thomas PT, Sherwood RL. Host resistance models in immunotoxicology. In: Smialowicz RJ, Holsapple MP, editors. Experimental immunotoxicology. Boca Raton: CRC Press, 1996: 29–45
Henry SP, Taylor J, Midgley L, et al. Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a 4-week study in CD-1 mice. Antisense Nucleic Acid Drug Dev 1997; 7: 473–81
Farine JC. Animal models of autoimmune disease in immunotoxicity assessment. Toxicology 1997; 119: 29–35
Oshiro Y, Morris DL. TNF-α release from human peripheral blood mononuclear cells to predict the proinflammatory properties of cytokines and growth factors. J Pharmacol Toxicol Methods 1997; 37: 55–9
Kimber I, Maurer T. Toxicology of contact hypersensitivity. London: Taylor & Francis, 1996
Doull J. Factors influencing toxicology. In: Casarett LJ, Doull J, editors. Toxicology: the basis science of poisons. New York: MacMillan, 1975: 133–150
Choquet-Kastylevski G, Descotes J. Value of animal models for predicting hypersensitivity reactions to medicinal products. Toxicology 1998; 129: 27–35
Kimber I, Dearman RJ, Basketter DA, et al. The local lymph node assay: past, present and future. Contact Dermatitis 2002; 47: 315–28
Vial T, Descotes J. Contact sensitization assays in guinea-pigs: are they predictive of the potential for systemic allergic reactions? Toxicology 1994; 93: 63–75
Weaver JL, Staten D, Swann J, et al. Detection of systemic hypersensitivity to drugs using standard guinea pig assays. Toxicology 2003; 193: 203–17
Hisatomi A, Kimura M, Maeda M, et al. Toxicity of polyoxyethylene hydrogenated castor oil 60 (HCO-60) in experimental animals. J Toxicol Sci 1993; 18Suppl. 3: 1–9
Monneret G, Gutowski MC, Bienvenu J. Detection of allergen-induced basophil activation by expression of CD63 antigen using a tricolour flow cytometric method. Clin Exp Immunol 1999; 115: 393–6
Benoit Y, Chadenson O, Ducloux B, et al. Hypersensitivity reactions to Althesin infusion: measurement of complement involvement. Anaesthesia 1983; 38: 1079–81
Descotes J. Autoimmunity and toxicity testing. Toxicol Lett 2000; 112-113: 461–5
Verdier F, Patriarca C, Descotes J. Autoantibodies in conventional toxicity testing. Toxicology 1997; 119: 51–8
Ravel G, Descotes J. The popliteal lymph node assay: facts and perspectives. J Appl Toxicol. In press
De Waal EJ, Timmerman HH, Dortant PM, et al. Investigation of a screening battery for immunotoxicity of pharmaceuticals within a 28-day oral toxicity study using azathioprine and cyclosporin A as model compounds. Regul Toxicol Pharmacol 1995; 21: 327–38
The ICICIS Group of Investigators. Report of validation study of assessment of direct immunotoxicity in the rat: International Collaborative Immunotoxicity Study. Toxicology 1998; 125: 183–201
Luster MI, Portier C, Pait DG, et al. Risk assessment in immunotoxicology: I. Sensitivity and predictability of immune tests. Fundam Appl Toxicol 1992; 18: 200–10
Loveless SE, Ladics GS, Gerberick GF, et al. Further evaluation of the local lymph node assay in the final phase of an international collaborative trial. Toxicology 1996; 108: 141–52
Descotes J. Regulating immunotoxicity evaluation: issues and needs. Arch Toxicol Suppl 1998; 20: 293–39
Pennie WD, Kimber I. Toxicogenomics: transcript profiling and potential application to chemical allergy. Toxicol In Vitro 2002; 16: 319–26
Bugelski PJ, Herzyk DJ, Rehm S, et al. Preclinical development of keliximab, a primatized anti-CD4 monoclonal antibody, in human CD4 transgenic mice: characterization of the model and safety studies. Hum Exp Toxicol 2000; 19: 230–43
Vandebriel RJ, Van Loveren H, Meredith C. Altered cytokine (receptor) mRNA expression as a tool in immunotoxicology. Toxicology 1998; 130: 43–67
Haley PJ. Species differences in the structure and function of the immune system. Toxicology 2003; 188: 49–71
Buhles WC. Application of immunologic methods in clinical trials. Toxicology 1998; 129: 73–89
Mikuls TR, Moreland LW. Benefit-risk assessment of infliximab in the treatment of rheumatoid arthritis. Drug Saf 2003; 26: 23–32
Descotes J. Immunotoxicology: health aspects and regulatory issues. Trends Pharmacol Sci 1986; 7: 1–4
Acknowledgements
No sources of funding were used to assist in the preparation of this study. The author has no conflicts of interest that are directly relevant to the content of this study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Descotes, J. Immunotoxicology. Drug-Safety 28, 127–136 (2005). https://doi.org/10.2165/00002018-200528020-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002018-200528020-00004