Cellular and Molecular Life Sciences

, Volume 67, Issue 24, pp 4171–4184 | Cite as

T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays

  • Stefan F. Martin
  • Philipp R. Esser
  • Sonja Schmucker
  • Lisa Dietz
  • Dean J. Naisbitt
  • B. Kevin Park
  • Marc Vocanson
  • Jean-Francois Nicolas
  • Monika Keller
  • Werner J. Pichler
  • Matthias Peiser
  • Andreas Luch
  • Reinhard Wanner
  • Enrico Maggi
  • Andrea Cavani
  • Thomas Rustemeyer
  • Anne Richter
  • Hermann-Josef Thierse
  • Federica Sallusto


Chemicals can elicit T-cell-mediated diseases such as allergic contact dermatitis and adverse drug reactions. Therefore, testing of chemicals, drugs and protein allergens for hazard identification and risk assessment is essential in regulatory toxicology. The seventh amendment of the EU Cosmetics Directive now prohibits the testing of cosmetic ingredients in mice, guinea pigs and other animal species to assess their sensitizing potential. In addition, the EU Chemicals Directive REACh requires the retesting of more than 30,000 chemicals for different toxicological endpoints, including sensitization, requiring vast numbers of animals. Therefore, alternative methods are urgently needed to eventually replace animal testing. Here, we summarize the outcome of an expert meeting in Rome on 7 November 2009 on the development of T-cell-based in vitro assays as tools in immunotoxicology to identify hazardous chemicals and drugs. In addition, we provide an overview of the development of the field over the last two decades.


Allergy Contact dermatitis Drug hypersensitivity T cell Immunotoxicology In vitro alternatives Non-animal testing Bioassay 



Allergic contact dermatitis


Adverse drug reaction


Antigen presenting cell


Bandrowski’s base


Dendritic cell




Fluorescein isothiocyanate


Human serum albumin


Intracellular cytokine staining


Langerhans cell


Local lymph node assay


Lymphocyte transformation test


Monocyte-derived dendritic cell


Peripheral blood mononuclear cells




2,4,6-Trinitrobenzene sulphonic acid


Regulatory T cell



We acknowledge the support for the Expert Meeting by the European Commission as part of the project “Novel Testing Strategies for In Vitro Assessment of Allergens (Sens-it-iv)”, LSHB-CT-2005-018681.

Conflict of interest

The authors declare that there are no conflicts of interest.


  1. 1.
    European Commission (2003) Directive 2003/15/EC of the European parliament and of the council of 27 February 2003 amending council directive 76/768/EEC on the approximation of the laws of the member states relating to cosmetic products (7th Amendment to the European cosmetics directive). Official J Eur Union, L 66:26–35Google Scholar
  2. 2.
    Basketter DA, Kimber I (2009) Updating the skin sensitization in vitro data assessment paradigm in 2009. J Appl Toxicol 29:545–550CrossRefPubMedGoogle Scholar
  3. 3.
    Basketter DA, McFadden JF, Gerberick F, Cockshott A, Kimber I (2009) Nothing is perfect, not even the local lymph node assay: a commentary and the implications for REACH. Contact Dermatitis 60:65–69CrossRefPubMedGoogle Scholar
  4. 4.
    European Commission (2006) Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC. Official J Eur Union L 396:1–849Google Scholar
  5. 5.
    Hartung T, Rovida C (2009) Chemical regulators have overreached. Nature 460:1080–1081CrossRefPubMedGoogle Scholar
  6. 6.
    Rovida C, Hartung T (2009) Re-evaluation of animal numbers and costs for in vivo tests to accomplish REACH legislation requirements for chemicals – a report by the transatlantic think tank for toxicology. ALTEX 26:187–208PubMedGoogle Scholar
  7. 7.
    Gilbert N (2010) Streamlined chemical tests rebuffed. Nature 463:142–143CrossRefPubMedGoogle Scholar
  8. 8.
    Collins FS, Gray GM, Bucher JR (2008) Transforming environmental health protection. Science 319:906–907CrossRefPubMedGoogle Scholar
  9. 9.
    National Institute of Environmental Health Sciences (2008) Memorandum of Understanding on High Throughput Screening, Toxicity Pathway Profiling, and Biological Interpretation of Findings. Accessed 11 August 2010
  10. 10.
    National Academy of Sciences (2007) Toxicity Testing in the 21st Century: A Vision and a Strategy. The National Academies Press, Washington, DCGoogle Scholar
  11. 11.
    European Commission (2007) Fifth Report from the Commission to the Council and the European Parliament on the Statistics on the number of animals used for experimental and other scientific purposes in the member states of the European Union.
  12. 12.
    Höfer T, Gerner I, Gundert-Remy U, Liebsch M, Schulte A, Spielmann H, Vogel R, Wettig K (2004) Animal testing and alternative approaches for the human health risk assessment under the proposed new European Chemicals Regulation. Arch Toxicol 78:549–564CrossRefPubMedGoogle Scholar
  13. 13.
    Van der Jagt K, Munn S, Torslov J, de Bruijn J (2004) Alternative approaches can reduce the use of test animals under REACH. European Commission, Joint Research Centre.
  14. 14.
  15. 15.
    European Commission (2007) REACH – Registration, Evaluation, Authorisation and Restriction of Chemicals. Accessed 1 June 2007
  16. 16.
    Jowsey IR, Basketter DA, Westmoreland C, Kimber I (2006) A future approach to measuring relative skin sensitising potency: a proposal. J Appl Toxicol 26:341–350CrossRefPubMedGoogle Scholar
  17. 17.
    dos Santos GG, Reinders J, Ouwehand K, Rustemeyer T, Scheper RJ, Gibbs S (2009) Progress on the development of human in vitro dendritic cell based assays for assessment of the sensitizing potential of a compound. Toxicol Appl Pharmacol 236:372–382CrossRefPubMedGoogle Scholar
  18. 18.
    Martin SF (2010) The role of the innate immune system in allergic contact dermatitis. Allergologie 33:66–70Google Scholar
  19. 19.
    Freudenberg MA, Esser PR, Jakob T, Galanos C, Martin SF (2009) Innate and adaptive immune responses in contact dermatitis: analogy with infections. G Ital Dermatol Venereol 144:173–185PubMedGoogle Scholar
  20. 20.
    Martin SF, Jakob T (2008) From innate to adaptive immune responses in contact hypersensitivity. Curr Opin Allergy Clin Immunol 8:289–293CrossRefPubMedGoogle Scholar
  21. 21.
    Natsch A, Emter R (2008) Skin sensitizers induce antioxidant response element dependent genes: application to the in vitro testing of the sensitization potential of chemicals. Toxicol Sci 102:110–119CrossRefPubMedGoogle Scholar
  22. 22.
    Emter R, Ellis G, Natsch A (2010) Performance of a novel keratinocyte-based reporter cell line to screen skin sensitizers in vitro. Toxicol Appl Pharmacol 245:281–290CrossRefPubMedGoogle Scholar
  23. 23.
    Corsini E, Mitjans M, Galbiati V, Lucchi L, Galli CL, Marinovich M (2009) Use of IL-18 production in a human keratinocyte cell line to discriminate contact sensitizers from irritants and low molecular weight respiratory allergens. Toxicol In Vitro 23:789–796CrossRefPubMedGoogle Scholar
  24. 24.
    Martin SF (2004) T lymphocyte-mediated immune responses to chemical haptens and metal ions: implications for allergic and autoimmune disease. Int Arch Allergy Immunol 134:186–198CrossRefPubMedGoogle Scholar
  25. 25.
    Thierse HJ, Gamerdinger K, Junkes C, Guerreiro N, Weltzien HU (2005) T cell receptor (TCR) interaction with haptens: metal ions as non-classical haptens. Toxicology 209:101–107CrossRefPubMedGoogle Scholar
  26. 26.
    Posadas SJ, Pichler WJ (2007) Delayed drug hypersensitivity reactions – new concepts. Clin Exp Allergy 37:989–999CrossRefPubMedGoogle Scholar
  27. 27.
    Ortmann B, Martin S, von Bonin A, Schiltz E, Hoschutzky H, Weltzien HU (1992) Synthetic peptides anchor T cell-specific TNP epitopes to MHC antigens. J Immunol 148:1445–1450PubMedGoogle Scholar
  28. 28.
    Martin S, Ortmann B, Pflugfelder U, Birsner U, Weltzien HU (1992) Role of hapten-anchoring peptides in defining hapten-epitopes for MHC-restricted cytotoxic T cells. Cross-reactive TNP-determinants on different peptides. J Immunol 149:2569–2575PubMedGoogle Scholar
  29. 29.
    Martin S, von Bonin A, Fessler C, Pflugfelder U, Weltzien HU (1993) Structural complexity of antigenic determinants for class I MHC-restricted, hapten-specific T cells. Two qualitatively differing types of H-2 Kb-restricted TNP epitopes. J Immunol 151:678–687PubMedGoogle Scholar
  30. 30.
    von Bonin A, Ortmann B, Martin S, Weltzien HU (1992) Peptide-conjugated hapten groups are the major antigenic determinants for trinitrophenyl-specific cytotoxic T cells. Int Immunol 4:869–874CrossRefGoogle Scholar
  31. 31.
    Kohler J, Martin S, Pflugfelder U, Ruh H, Vollmer J, Weltzien HU (1995) Cross-reactive trinitrophenylated peptides as antigens for class II major histocompatibility complex-restricted T cells and inducers of contact sensitivity in mice. Limited T cell receptor repertoire. Eur J Immunol 25:92–101CrossRefPubMedGoogle Scholar
  32. 32.
    Padovan E, Bauer T, Tongio MM, Kalbacher H, Weltzien HU (1997) Penicilloyl peptides are recognized as T cell antigenic determinants in penicillin allergy. Eur J Immunol 27:1303–1307CrossRefPubMedGoogle Scholar
  33. 33.
    Lu L, Vollmer J, Moulon C, Weltzien HU, Marrack P, Kappler J (2003) Components of the ligand for a Ni(++) reactive human T cell clone. J Exp Med 197:567–574CrossRefPubMedGoogle Scholar
  34. 34.
    Gamerdinger K, Moulon C, Karp DR, Van Bergen J, Koning F, Wild D, Pflugfelder U, Weltzien HU (2003) A new type of metal recognition by human T cells: contact residues for peptide-independent bridging of T cell receptor and major histocompatibility complex by nickel. J Exp Med 197:1345–1353CrossRefPubMedGoogle Scholar
  35. 35.
    Schnyder B, Mauri-Hellweg D, Zanni M, Bettens F, Pichler WJ (1997) Direct, MHC-dependent presentation of the drug sulfamethoxazole to human alphabeta T cell clones. J Clin Invest 100:136–141CrossRefPubMedGoogle Scholar
  36. 36.
    Zanni MP, von Greyerz S, Schnyder B, Wendland T, Pichler WJ (1998) Allele-unrestricted presentation of lidocaine by HLA-DR molecules to specific alphabeta+ T cell clones. Int Immunol 10:507–515CrossRefPubMedGoogle Scholar
  37. 37.
    Zanni MP, von Greyerz S, Schnyder B, Brander KA, Frutig K, Hari Y, Valitutti S, Pichler WJ (1998) HLA-restricted, processing- and metabolism-independent pathway of drug recognition by human alpha beta T lymphocytes. J Clin Invest 102:1591–1598CrossRefPubMedGoogle Scholar
  38. 38.
    von Greyerz S, Zanni MP, Frutig K, Schnyder B, Burkhart C, Pichler WJ (1999) Interaction of sulfonamide derivatives with the TCR of sulfamethoxazole-specific human alpha beta+ T cell clones. J Immunol 162:595–602Google Scholar
  39. 39.
    Castrejon JL, Berry N, El Ghaiesh S, Gerber PichlerWJ, Park BK, Naisbitt DJ (2010) Stimulation of human T cells with sulfonamides and sulfonamide metabolites. J Allergy Clin Immunol 125:411–418CrossRefPubMedGoogle Scholar
  40. 40.
    Gerberick GF, Vassallo JD, Foertsch LM, Price BB, Chaney JG, Lepoittevin JP (2007) Quantification of chemical peptide reactivity for screening contact allergens: a classification tree model approach. Toxicol Sci 97:417–427CrossRefPubMedGoogle Scholar
  41. 41.
    Gerberick GF, Aleksic M, Basketter D, Casati S, Karlberg AT, Kern P, Kimber I, Lepoittevin JP, Natsch A, Ovigne JM, Rovida C, Sakaguchi H, Schultz T (2008) Chemical reactivity measurement and the predictive identification of skin sensitisers. The report and recommendations of ECVAM Workshop 64. Altern Lab Anim 36:215–242PubMedGoogle Scholar
  42. 42.
    Moulon C, Peguet-Navarro J, Courtellemont P, Redziniak G, Schmitt D (1993) In vitro primary sensitization and restimulation of hapten-specific T cells by fresh and cultured human epidermal Langerhans’ cells. Immunology 80:373–379PubMedGoogle Scholar
  43. 43.
    Krasteva M, Peguet-Navarro J, Moulon C, Courtellemont P, Redziniak G, Schmitt D (1996) In vitro primary sensitization of hapten-specific T cells by cultured human epidermal Langerhans cells – a screening predictive assay for contact sensitizers. Clin Exp Allergy 26:563–570CrossRefPubMedGoogle Scholar
  44. 44.
    Dai R, Streilein JW (1998) Naive, hapten-specific human T lymphocytes are primed in vitro with derivatized blood mononuclear cells. J Invest Dermatol 110:29–33CrossRefPubMedGoogle Scholar
  45. 45.
    Rougier N, Redziniak G, Schmitt D, Vincent C (1998) Evaluation of the capacity of dendritic cells derived from cord blood CD34+ precursors to present haptens to unsensitized autologous T cells in vitro. J Invest Dermatol 110:348–352CrossRefPubMedGoogle Scholar
  46. 46.
    Rougier N, Redziniak G, Mougin D, Schmitt D, Vincent C (2000) In vitro evaluation of the sensitization potential of weak contact allergens using Langerhans-like dendritic cells and autologous T cells. Toxicology 145:73–82CrossRefPubMedGoogle Scholar
  47. 47.
    Rustemeyer T, De Ligter S, von Blomberg BM, Frosch PJ, Scheper RJ (1999) Human T lymphocyte priming in vitro by haptenated autologous dendritic cells. Clin Exp Immunol 117:209–216CrossRefPubMedGoogle Scholar
  48. 48.
    Guironnet G, Dalbiez-Gauthier C, Rousset F, Schmitt D, Peguet-Navarro J (2000) In vitro human T cell sensitization to haptens by monocyte-derived dendritic cells. Toxicol In Vitro 14:517–522CrossRefPubMedGoogle Scholar
  49. 49.
    Moed H, von Blomberg M, Bruynzeel DP, Scheper R, Gibbs S, Rustemeyer T (2005) Improved detection of allergen-specific T-cell responses in allergic contact dermatitis through the addition of ‘cytokine cocktails’. Exp Dermatol 14:634–640CrossRefPubMedGoogle Scholar
  50. 50.
    Vocanson M, Cluzel-Tailhardat M, Poyet G, Valeyrie M, Chavagnac C, Levarlet B, Courtellemont P, Rozieres A, Hennino A, Nicolas JF (2008) Depletion of human peripheral blood lymphocytes in CD25+ cells allows for the sensitive in vitro screening of contact allergens. J Invest Dermatol 128:2119–2122CrossRefPubMedGoogle Scholar
  51. 51.
    Dietz L, Esser PR, Schmucker, S, Goette I, Richter A, Schnöelzer M, Martin SF, Thierse HJ (2010) Tracking human contact allergens: from mass spectrometric identification of peptide-bound reactive small chemicals to chemical-specific naive human T cell priming. Toxicol Sci. DOI:  10.1093/toxsci/kfq209
  52. 52.
    Brander C, Mauri-Hellweg D, Bettens F, Rolli H, Goldman M, Pichler WJ (1995) Heterogeneous T cell responses to beta-lactam-modified self-structures are observed in penicillin-allergic individuals. J Immunol 155:2670–2678PubMedGoogle Scholar
  53. 53.
    Thierse HJ, Moulon C, Allespach Y, Zimmermann B, Doetze A, Kuppig S, Wild D, Herberg F, Weltzien HU (2004) Metal-protein complex-mediated transport and delivery of Ni2+ to TCR/MHC contact sites in nickel-specific human T cell activation. J Immunol 172:1926–1934PubMedGoogle Scholar
  54. 54.
    Jenkinson C, Jenkins RE, Aleksic M, Pirmohamed M, Naisbitt DJ, Park BK (2010) Characterization of p-phenylenediamine-albumin binding sites and T-cell responses to hapten-modified protein. J Invest Dermatol 130:732–742CrossRefPubMedGoogle Scholar
  55. 55.
    Curotto de Lafaille MA, Lafaille JJ (2009) Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 30:626–635CrossRefPubMedGoogle Scholar
  56. 56.
    Frentsch M, Arbach O, Kirchhoff D, Moewes B, Worm M, Rothe M, Scheffold A, Thiel A (2005) Direct access to CD4+ T cells specific for defined antigens according to CD154 expression. Nat Med 11:1118–1124CrossRefPubMedGoogle Scholar
  57. 57.
    Wolfl M, Kuball J, Ho WY, Nguyen H, Manley TJ, Bleakley M, Greenberg PD (2007) Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities. Blood 110:201–210CrossRefPubMedGoogle Scholar
  58. 58.
    Wehler TC, Karg M, Distler E, Konur A, Nonn M, Meyer RG, Huber C, Hartwig UF, Herr W (2008) Rapid identification and sorting of viable virus-reactive CD4(+) and CD8(+) T cells based on antigen-triggered CD137 expression. J Immunol Methods 339:23–37CrossRefPubMedGoogle Scholar
  59. 59.
    Burgdorf S, Kurts C (2008) Endocytosis mechanisms and the cell biology of antigen presentation. Curr Opin Immunol 20:89–95CrossRefPubMedGoogle Scholar
  60. 60.
    Aleksic M, Thain E, Roger D, Saib O, Davies M, Li J, Aptula A, Zazzeroni R (2009) Reactivity profiling: covalent modification of single nucleophile peptides for skin sensitization risk assessment. Toxicol Sci 108:401–411CrossRefPubMedGoogle Scholar
  61. 61.
    Aleksic M, Pease CK, Basketter DA, Panico M, Morris HR, Dell A (2007) Investigating protein haptenation mechanisms of skin sensitisers using human serum albumin as a model protein. Toxicol In Vitro 21:723–733CrossRefPubMedGoogle Scholar
  62. 62.
    Martin SF, Dudda JC, Bachtanian E, Lembo A, Liller S, Durr C, Heimesaat MM, Bereswill S, Fejer G, Vassileva R, Jakob T, Freudenberg N, Termeer CC, Johner C, Galanos C, Freudenberg MA (2008) Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity. J Exp Med 205:2151–2162CrossRefPubMedGoogle Scholar
  63. 63.
    Geiger R, Duhen D, Lanzavecchia A, Sallusto F (2009) Human naive and memory CD4+ T cell repertoires specific for naturally processed antigens analyzed using libraries of amplified T cells. J Exp Med 206:1525–1534CrossRefPubMedGoogle Scholar
  64. 64.
    Heiss K, Junkes C, Guerreiro N, Swamy M, Camacho-Carvajal MM, Schamel WW, Haidl ID, Wild D, Weltzien HU, Thierse HJ (2005) Subproteomic analysis of metal-interacting proteins in human B cells. Proteomics 5:3614–3622CrossRefPubMedGoogle Scholar
  65. 65.
    Martin SF, Merfort I, Thierse H-J (2006) Interactions of chemicals and metal ions with proteins and role for immune responses. Mini Rev Med Chem 6:247–255CrossRefPubMedGoogle Scholar
  66. 66.
    Dietz L, Bosque A, Pankert P, Ohnesorge S, Merz P, Anel A, Schnölzer M, Thierse HJ (2009) Quantitative DY-maleimide-based proteomic 2-DE-labeling strategies using human skin proteins. Proteomics 9:4298–4308CrossRefPubMedGoogle Scholar
  67. 67.
    Schreiner M, Peiser M, Briechle D, Stahlmann R, Zuberbier T, Wanner R (2007) A loose-fit coculture of activated keratinocytes and dendritic cell-related cells for prediction of sensitizing potential. Allergy 62:1419–1428CrossRefPubMedGoogle Scholar
  68. 68.
    Schreiner M, Peiser M, Briechle D, Stahlmann R, Zuberbier T, Wanner R (2008) A new dendritic cell type suitable as sentinel of contact allergens. Toxicology 249:146–152CrossRefPubMedGoogle Scholar
  69. 69.
    Wanner R, Sonnenburg A, Quatchadze M, Schreiner M, Peiser M, Zuberbier T, Stahlmann R (2010) Classification of sensitizing and irritative potential in a combined in vitro assay. Toxicol Appl Pharmacol 245:211–218CrossRefPubMedGoogle Scholar
  70. 70.
    Jenkins RE, Meng X, Elliott VL, Kitteringham NR, Pirmohamed M, Park K (2009) Characterisation of flucloxacillin and 5-hydroxymethyl flucloxacillin haptenated HSA in vitro and in vivo. Proteomics Clin Appl 3:720–729CrossRefGoogle Scholar
  71. 71.
    Callan HE, Jenkins RE, Maggs JL, Lavergne SN, Clarke SE, Naisbitt DJ, Park BK (2009) Multiple adduction reactions of nitroso sulfamethoxazole with cysteinyl residues of peptides and proteins: implications for hapten formation. Chem Res Toxicol 22:1172–1180CrossRefGoogle Scholar
  72. 72.
    Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I, Christiansen FT (2002) Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359:727–732CrossRefPubMedGoogle Scholar
  73. 73.
    Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe’er I, Floratos A, Daly MJ, Goldstein DB, John S, Nelson MR, Graham J, Park BK, Dillon JF, Bernal W, Cordell HJ, Pirmohamed M, Aithal GP, Day CP (2009) HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 41:816–819CrossRefPubMedGoogle Scholar
  74. 74.
    Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, Wu JY, Chen YT (2004) Medical genetics: a marker for Stevens-Johnson syndrome. Nature 428:486CrossRefPubMedGoogle Scholar
  75. 75.
    Chessman D, Kostenko L, Lethborg T, Purcell AW, Williamson NA, Chen Z, Kjer-Nielsen L, Mifsud NA, Tait BD, Holdsworth R, Almeida CA, Nolan D, Macdonald WA, Archbold JK, Kellerher AD, Marriott D, Mallal S, Bharadwaj M, Rossjohn J, McCluskey J (2008) Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity 28:822–832CrossRefPubMedGoogle Scholar
  76. 76.
    Beeler A, Zaccaria L, Kawabata T, Gerber BO, Pichler WJ (2008) CD69 upregulation on T cells as an in vitro marker for delayed-type drug hypersensitivity. Allergy 63:181–188PubMedGoogle Scholar
  77. 77.
    Sachs B, Erdmann S, Baron JM, Neis M, Al Masaoudi T, Merk HF (2002) Determination of interleukin-5 secretion from drug-specific activated ex vivo peripheral blood mononuclear cells as a test system for the in vitro detection of drug sensitization. Clin Exp Allergy 32:736–744CrossRefPubMedGoogle Scholar
  78. 78.
    Halevy S, Cohen AD, Grossman N (2005) Clinical implications of in vitro drug-induced interferon gamma release from peripheral blood lymphocytes in cutaneous adverse drug reactions. J Am Acad Dermatol 52:254–261CrossRefPubMedGoogle Scholar
  79. 79.
    Lochmatter P, Beeler A, Kawabata TT, Gerber BO, Pichler WJ (2009) Drug-specific in vitro release of IL-2, IL-5, IL-13 and IFN-gamma in patients with delayed-type drug hypersensitivity. Allergy 64:1269–1278CrossRefPubMedGoogle Scholar
  80. 80.
    Ryan CA, Gildea LA, Hulette BC, Dearman RJ, Kimber I, Gerberick GF (2004) Gene expression changes in peripheral blood-derived dendritic cells following exposure to a contact allergen. Toxicol Lett 150:301–316CrossRefPubMedGoogle Scholar
  81. 81.
    Gildea LA, Ryan CA, Foertsch LM, Kennedy LM, Dearman RJ, Kimber I, Gerberick GF (2006) Identification of gene expression changes induced by chemical allergens in dendritic cells: opportunities for skin sensitization testing. J Invest Dermatol 126:1813–1822CrossRefPubMedGoogle Scholar
  82. 82.
    Gerberick GF, Ryan CA, Kern PS, Schlatter H, Dearman RJ, Kimber I, Patlewicz GY, Basketter DA (2005) Compilation of historical local lymph node data for evaluation of skin sensitization alternative methods. Dermatitis 16:157–202PubMedGoogle Scholar
  83. 83.
    Kern PS, Gerberick GF, Ryan CA, Kimber I, Aptula A, Basketter DA (2010) Local lymph node data for the evaluation of skin sensitization alternatives: a second compilation. Dermatitis 21:8–32PubMedGoogle Scholar
  84. 84.
    Janetzki S, Britten CM, Kalos M, Levitsky HI, Maecker HT, Melief CJ, Old LJ, Romero P, Hoos A, Davis MM (2009) “MIATA” – minimal information about T cell assays. Immunity 31:527–528CrossRefPubMedGoogle Scholar
  85. 85.
    O’Shea JJ, Paul WE (2010) Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327:1098–1102CrossRefPubMedGoogle Scholar
  86. 86.
    Merk HF, Baron J, Neis MM, Obrigkeit DH, Karlberg AT (2007) Skin: major target organ of allergic reactions to small molecular weight compounds. Toxicol Appl Pharmacol 224:313–317CrossRefPubMedGoogle Scholar
  87. 87.
    Karlberg AT, Bergstrom MA, Borje A, Luthman K, Nilsson JL (2008) Allergic contact dermatitis – formation, structural requirements, and reactivity of skin sensitizers. Chem Res Toxicol 21:53–69CrossRefPubMedGoogle Scholar
  88. 88.
    Vocanson M, Hennino A, Cluzel-Tailhardat M, Saint-Mezard P, Benetiere J, Chavagnac C, Berard F, Kaiserlian D, Nicolas JF (2006) CD8+ T cells are effector cells of contact dermatitis to common skin allergens in mice. J Invest Dermatol 126:815–820CrossRefPubMedGoogle Scholar
  89. 89.
    Lass C, Vocanson M, Wagner S, Schempp CM, Nicolas JF, Merfort I, Martin SF (2008) Anti-inflammatory and immune regulatory mechanisms prevent contact hypersensitivity to Arnica montana L. Exp Dermatol 17:849–857CrossRefPubMedGoogle Scholar
  90. 90.
    Vocanson M, Hennino A, Rozieres A, Cluzel-Tailhardat M, Poyet G, Valeyrie M, Benetiere J, Tedone R, Kaiserlian D, Nicolas JF (2009) Skin exposure to weak and moderate contact allergens induces IFNgamma production by lymph node cells of CD4+ T-cell-depleted mice. J Invest Dermatol 129:1185–1191CrossRefPubMedGoogle Scholar
  91. 91.
    Weltzien HU, Corsini E, Gibbs S, Borrebaeck C, Budde P, Thierse HJ, Martin SF, Roggen EL (2009) Safe cosmetics without animal testing? Contributions of the EU Project Sens-it-iv. J Verbr Lebensm 4(Suppl. II):S41–S48CrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • Stefan F. Martin
    • 1
  • Philipp R. Esser
    • 1
    • 2
  • Sonja Schmucker
    • 3
  • Lisa Dietz
    • 4
  • Dean J. Naisbitt
    • 5
  • B. Kevin Park
    • 5
  • Marc Vocanson
    • 6
  • Jean-Francois Nicolas
    • 6
  • Monika Keller
    • 7
  • Werner J. Pichler
    • 7
  • Matthias Peiser
    • 8
  • Andreas Luch
    • 8
  • Reinhard Wanner
    • 9
  • Enrico Maggi
    • 10
  • Andrea Cavani
    • 11
  • Thomas Rustemeyer
    • 12
  • Anne Richter
    • 3
  • Hermann-Josef Thierse
    • 4
  • Federica Sallusto
    • 13
  1. 1.Allergy Research Group, Department of DermatologyUniversity Medical Center FreiburgFreiburgGermany
  2. 2.Faculty of BiologyUniversity of FreiburgFreiburgGermany
  3. 3.Miltenyi Biotec GmbHBergisch GladbachGermany
  4. 4.Research Group for Immunology and Proteomics, Department of Dermatology and University Medical Center MannheimUniversity of HeidelbergMannheimGermany
  5. 5.Department of Pharmacology, MRC Centre for Drug Safety ScienceUniversity of LiverpoolLiverpoolUK
  6. 6.Faculté de Médecine Lyon-Sud, INSERM U851Université de Lyon1LyonFrance
  7. 7.Division of Allergology, Clinic of Rheumatology and Clinical Immunology/Allergology, InselspitalUniversity Hospital and University of BernBernSwitzerland
  8. 8.BfR-Federal Institute for Risk AssessmentBerlinGermany
  9. 9.Institute of Molecular Biology and BioinformaticsCharitéBerlinGermany
  10. 10.Immunoallergology Unit, Policlinico di Careggi, Department of Internal MedicineUniversity of FlorenceFlorenceItaly
  11. 11.Laboratory of ImmunologyIstituto Dermopatico dell’Immacolata-Istituto di Ricovero e Cura a Carattere ScientificoRomeItaly
  12. 12.Department of DermatologyVU Medical CenterAmsterdamThe Netherlands
  13. 13.Institute for Research in BiomedicineBellinzonaSwitzerland

Personalised recommendations