Immunotoxicology: A Brief History

  • Kenneth L. Hastings
Part of the Methods in Molecular Biology book series (MIMB, volume 1803)


Immunotoxicological research and testing have evolved from early studies of anaphylaxis to the robust and diverse field of immunotoxicology as we know it today. Early studies connecting immune dysfunction with exposure to exogenous agents focused on adverse reactions to immunogenic agents present in vaccines. Over time, work done by immunologists and pathologists leads to descriptions of characteristics of immunogenic agents as well as mechanisms by which anaphylaxis occurs and an understanding of the concept of immunosuppression. These myriad achievements greatly improved public health and led the field of immunotoxicology, which addresses all aspects of adverse immunological responses following exposure to exogenous agents as well as the development of testing paradigms to understand immunological responses of designed agents such as drugs and biologics.

Key words

Testing Guidelines Anaphylaxis Immunopathology 


  1. 1.
  2. 2.
    Von Pirquet C, Schick B (1906) Serum sickness. München Med Wchnshr 53:1457Google Scholar
  3. 3.
    Portier P, Richet C (1902) De l’action anaphylactique de certains venins. CR Séances Soc Bio 54:170Google Scholar
  4. 4.
    Auer J (1911) Lethal cardiac anaphylaxis in the rabbit. J Exp Med 14:476–496CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Feinberg SM, Feinberg AR, Moran CF (1953) Penicillin anaphylaxis, nonfatal and fatal reactions. J Am Med Assoc 152:114–119CrossRefPubMedGoogle Scholar
  6. 6.
    Solensky R (2003) Hypersensitivity reactions to betalactamantibiotics. Clin Rev Allergy Immunol 24:201–220CrossRefPubMedGoogle Scholar
  7. 7.
    Landsteiner K, Jacobs J (1935) Studies on the sensitization of animals with simple chemical compounds. J Exp Med 61:643–656CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Landsteiner K, Jacobs J (1936) Studies on the sensitization of animals with simple chemical compounds. J Exp Med 64:625–639CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Levine BB (1964) Studies on the immunological mechanisms of penicillin allergy. I. Antigenic specificities of Guinea-pig skin sensitizing rabbit anti-benzylpenicillin antibodies. Immunology 7:527–541PubMedPubMedCentralGoogle Scholar
  10. 10.
    Ovary Z, Benacerraf B, Bloch KJ (1963) Properties of Guinea pig 7S antibodies. II. Identification of antibodies involved in passive cutaneous and systemic anaphylaxis. J Exp Med 117:951–964CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ovary Z (1958) Passive cutaneous anaphylaxis in the mouse. J Immunol 81:355–357PubMedGoogle Scholar
  12. 12.
    Dearman RJ, Stone S, Caddick HT, Basketter DA, Kimber I (2003) Evaluation of protein allergenic potential in mice: dose-response analyses. Clin Exp Allergy 33:1586–1594CrossRefPubMedGoogle Scholar
  13. 13.
    Draize JH, Woodard G, Calvery HD (1944) Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Exp Ther 83:377–390Google Scholar
  14. 14.
    Gell PGH, Coombs RRA (1963) Clinical aspects of immunology, 1st edn. Oxford, BlackwellGoogle Scholar
  15. 15.
    Ishizaka K, Ishizaka T (1967) Identification of gamma-E-antibodies as a carrier of reaginic activity. J Immunol 99:1187–1198PubMedGoogle Scholar
  16. 16.
    Lehrer SB, Vaughan JH (1976) Properties of mouse homocytotropic and heterocytotropic antibodies. J Allergy Clin Immunol 57:422–429CrossRefPubMedGoogle Scholar
  17. 17.
    Nydegger UE, Lambert PH, Gerber H, Miescher PA (1974) Circulating immune complexes in the serum in systemic lupus erythematosus and in carriers of hepatitis B antigen. Quantitation by binding to radiolabeled C1q. J Clin Invest 54:297–309CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Vos JC (1977) Immune suppression as related to toxicology. Crit Rev Toxicol 5:67–101CrossRefGoogle Scholar
  19. 19.
    Auerbach C (1958) Mutagenic effects of alkylating agents. Ann N Y Acad Sci 68:731–748CrossRefPubMedGoogle Scholar
  20. 20.
    Luster MI, Blank JA, Dean JH (1987) Molecular and cellular basis of chemically induced immunotoxicity. Annu Rev Pharmacol Toxicol 27:23–49CrossRefPubMedGoogle Scholar
  21. 21.
    Wara WM (1977) Immunosuppression associated with radiation therapy. Int J Radiat Oncol Biol Phys 2:593–596CrossRefPubMedGoogle Scholar
  22. 22.
    Biagini RE (1998) Epidemiology studies in immunotoxicity evaluations. Toxicology 129:37–54CrossRefPubMedGoogle Scholar
  23. 23.
    Levitt SH, O’Foghludha FT, Royster RL, Wolf JS, Lower RR, De Giorgi LS (1971) Radiation for immunosuppression in human organ transplantation. I. Experimental data. Acta Radiol Ther Phys Biol 10:248–256CrossRefPubMedGoogle Scholar
  24. 24.
    Starzl TE, Halgrimson CG, Penn I, Martineau G, Schroter G, Amemiya H, Putnam CW, Groth CG (1971) Cyclophosphamide and human organ transplantation. Lancet 2:70–74CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Murray JE, Merrill JP, Harrison JH, Wilson RE, Dammin GJ (1963) Prolonged survival of human-kidney homografts by immunosuppressive drug therapy. N Engl J Med 268:1315–1323CrossRefPubMedGoogle Scholar
  26. 26.
    Squifflet J-P (2011) The history of kidney transplantation: past, present, and future. In: Understanding the complexities of kidney transplantation. Intech, Croatia, pp 3–40Google Scholar
  27. 27.
    Shubin H, Lambert RE, Ca H, Sokmensuer A, Glaskin A (1959) Steroid therapy and tuberculosis. J Am Med Assoc 170:1885–1890CrossRefPubMedGoogle Scholar
  28. 28.
    Bekesi JG, Holland JF, Anderson HA, Fischbein AS, Rom W, Wolff MS, Selikoff IJ (1978) Lymphocyte function of Michigan dairy farmers exposed to polybrominated biphenyls. Science 1999:1207–1209CrossRefGoogle Scholar
  29. 29.
    Thaxton JP, Tung HT, Hamilton PB (1974) Immunosuppression in chickens by aflatoxin. Poult Sci 53:721–725CrossRefPubMedGoogle Scholar
  30. 30.
    Nakata H, Sakakibrar A, Kanoh M, Kudo S, Watanabe H, Nagai N, Miyazaki N, Asano Y, Tanabe S (2002) Evaluation of mitogen-induced responses in marine mammal and human lymphocytes by in-vitro exposure of butyltins and non-ortho coplanar PCBs. Eviron Pollut 120:245–253CrossRefGoogle Scholar
  31. 31.
    House RV, Luebke RW (2007) Immunotoxicology: thirty years and counting. In: Luebke R, House R, Kimber I (eds) Immunotoxicology and immunopharmacology, 3rd edn. CRC Press, Taylor & Francis Group, Boca Raton, FL, pp 3–20Google Scholar
  32. 32.
    Irey NS (1978) Drug adverse reaction reports related to immunotoxicity. In: Asher IM (ed) Inadvertent modification of the immune response: the effects of foods, drugs, and environmental contaminants. US Food and Drug Administration, Washington, DC, pp 140–143Google Scholar
  33. 33.
    Berlin A, Dean J, Draper M, Smith EMB, Spreafico F (1987) Synopsis, conclusions, and recommendations. In: Berlin A, Dean J, Draper M, Smith EMB, Spreafico F (eds) Immunotoxicology. Martinus Nijhoff, Dordrecht, pp xi–xxviiGoogle Scholar
  34. 34.
    Jerne NK, Nordin AA (1963) Plaque formation in agar by single antibody-producing cells. Science 140:405CrossRefPubMedGoogle Scholar
  35. 35.
    Burleson GR, Burleson FG (2008) Testing human biologicals in animal host resistance models. J Immunotoxicol 5:23–31CrossRefPubMedGoogle Scholar
  36. 36.
    Luster MI, Munson AE, Thomas PT, Holsapple MP, Fenters JD, White KL Jr, Lauer LD, Germolec DR, Rosenthal GJ, Dean JH (1988) Development of a testing battery to assess chemical-induced immunotoxicity: National Toxicology Program’s guidelines for immunotoxicity evaluation in mice. Fundam Appl Toxicol 10:2–19CrossRefPubMedGoogle Scholar
  37. 37.
    Luster MI, Portier C, Pait DC, Rosenthal GJ, Germolec DR, Corsini E, Blaylock BL, Pollock P, Kouchi Y, Craig W et al (1993) Risk assessment in immunotoxicology. II Relationships between immune and host resistance tests. Fundam Appl Toxicol 21:71–82CrossRefPubMedGoogle Scholar
  38. 38.
    Luster MI, Portier C, Pait DG, White KL Jr, Gennings C, Munson AE, Rosenthal GJ (1992) Risk assessment in immunotoxicology. I. Sensitivity and predictability of immune tests. Fundam Appl Toxicol 18:200–210CrossRefPubMedGoogle Scholar
  39. 39.
    van der Laan JW, van Loveren H, Vos JG, Dean JH, Hastings KL (1997) Immunotoxicity of pharmaceuticals: current knowledge, testing strategies, risk evaluation, and consequences for human health. Drug Inf J 31:1301–1305CrossRefGoogle Scholar
  40. 40.
    Hastings KL, Nakamura K (2007) Immunotoxicity hazard identification and testing guidelines. In: Luebke R, House R, Kimber I (eds) Immunotoxicology and immunopharmacology, 3rd edn. CRC Press, Taylor & Francis Group, Boca Raton, FL, pp 21–34Google Scholar
  41. 41.
    US EPA (1996) Health effects test guidelines. OPPTS 870.7800 Immunotoxicity. EPA 712-C-96-351Google Scholar
  42. 42.
    US EPA (2003) Health effects test guidelines. OPPS 870.2600 Skin sensitization. EPA-712-03-351Google Scholar
  43. 43.
    ICH (2005) International conference on harmonization of technical requirements for registration of pharmaceuticals for human use. Immunotoxicity studies for human pharmaceuticals. p. S8Google Scholar
  44. 44.
    Hinton DM (2000) US FDA “Redbook II” immunotoxicity testing guidelines and research in immunotoxicity evaluations of food chemicals and new food proteins. Toxicol Pathol 28:467–478CrossRefPubMedGoogle Scholar
  45. 45.
    US FDA (1999) Guidance for industry and FDA reviewers. Immunotoxicity testing guidance (for medical devices and constituent materials)Google Scholar
  46. 46.
    Basketter DA, Gilmour NJ, Briggs D, Ullmann LG, Gerberick GF, Ryan CA, Dearman RJ, Kimber I (1993) Utility of historic vehicle-control data in the interpretation of the local lymph node assay. Contact Dermatitis 49:37–41CrossRefGoogle Scholar
  47. 47.
    Anderson SE, Siegel PD, Meade BJ (2011) The LLNA: a brief review of recent advances and limitations. J Allergy (Cairo) 2011:424203Google Scholar
  48. 48.
    Descotes J (1992) The popliteal lymph node assay: a tool for studying the mechanisms of drug-induced autoimmune disorders. Toxicol Lett 64–65.(Spec No:101–107CrossRefGoogle Scholar
  49. 49.
    Galbiati V, Papale A, Kummer E, Corsini E (2016) In vitro models to evaluate drug-induced hypersensitivity: potential test based on activation of dendritic cells. Front Pharmacol 7:204CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Descotes J (1985) Pseudoallergic reactions of drug origin. Therapie 40:59–65PubMedGoogle Scholar
  51. 51.
    Szebeni J, Muggia F, Gabizon A, Barenholz Y (2011) Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention. Adv Drug Deliv Rev 63:1020–1030CrossRefPubMedGoogle Scholar
  52. 52.
    Kishimoto TK, Viswanathan K, Ganguly T, Elankumaran S, Smith S, Pelzer K et al (2008) Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med 358:2457–2467CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J, Ustianowski A et al (2010) Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology biologics register (BSRBR). Ann Rheum Dis 69:522–528CrossRefPubMedGoogle Scholar
  54. 54.
    Bloomgren G, Richman S, Hotemans C, Subramanyam M, Goelz S, Natarajan A et al (2012) Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 366:1870–1880CrossRefPubMedGoogle Scholar
  55. 55.
    Hastings KL (2000) Assessment of immunosuppressant drug carcinogenicity: standard and alternative animal models. Hum Exp Toxicol 19:261–265CrossRefPubMedGoogle Scholar
  56. 56.
    Stebbings R, Findlay L, Edwards C, Eastwood D, Bird C, North D et al (2007) “Cytokine storm” in the phase I trial of monoclonal antibody TGN1412: better understanding the causes to improve preclinical testing of immunotherapeutics. J Immunol 179:3325–3331CrossRefPubMedGoogle Scholar
  57. 57.
    Hastings KL (2007) Drug allergy. In: Luebke R, House R, Kimber I (eds) Immunotoxicology and immunopharmacology, 3rd edn. CRC Press, Taylor & Francis Group, Boca Raton, FL, pp 623–632Google Scholar
  58. 58.
    Azzi JR, Sayegh MH, Mallat SG (2013) Calcineurin inhibitors: 40 years later, can’t live without. J Immunol 191:5785–5791CrossRefPubMedGoogle Scholar
  59. 59.
    Yanagida N, Sato S, Asaumi T, Ebisawa M (2016) Comparisons of outcomes with food immunotherapy strategies: efficacy, dosing, adverse effects, and tolerance. Curr Opin Allergy Clin Immunol 16:396–403CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Kenneth L. Hastings
    • 1
  1. 1.Hastings Toxicology Consulting LLCMount AiryUSA

Personalised recommendations