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T Lymphocytes as Tools in Diagnostics and Immunotoxicology pp 137–163Cite as

T Cell Responses to Drugs and Drug Metabolites

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Part of the book series: Experientia Supplementum ((EXS,volume 104))

Abstract

Understanding the chemical mechanisms by which drugs and drug metabolites interact with cells of the immune system is pivotal to our knowledge of drug hypersensitivity as a whole.

In this chapter, we will discuss the currently accepted mechanisms where there is scientific and clinical evidence to support the ways in which drugs and their metabolites interact with T cells. We will also discuss bioanalytical platforms, such as mass spectrometry, and in vitro test assays such as the lymphocyte transformation test that can be used to study drug hypersensitivity; the combination of such techniques can be used to relate the chemistry of drug antigen formation to immune function. Ab initio T cell priming assays are also discussed with respect to predicting the potential of a drug to cause hypersensitivity reactions in humans in relation to the chemistry of the drug and its ability to form haptens, antigens and immunogens in patients.

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Abbreviations

ADH:

Alcohol dehydrogenase

ADR:

Adverse drug reaction

APC:

Antigen-presenting cell

CFSE:

Carboxyfluorescein succinimidyl ester

DC:

Dendritic cell

DHR:

Delayed hypersensitivity reaction

DNA:

Deoxyribonucleic acid

EBV:

Epstein-Barr virus

ELISA:

Enzyme-linked immunosorbent assay

ELISpot:

Enzyme-linked immunosorbent spot

FACS:

Fluorescence-activated cell sorting

HHV-6:

Human herpes virus-6

HIV:

Human immunodeficiency virus

HLA:

Human leukocyte antigen

HSA:

Human serum albumin

IFN:

Interferon

IL:

Interleukin

LC-MS/MS:

Liquid chromatography coupled with tandem mass spectrometry

LTT:

Lymphocyte transformation test

MHC:

Major histocompatibility complex

MRM:

Multiple reaction monitoring

PBMC:

Peripheral blood mononuclear cell

RCM:

Radiocontrast media

REDOX:

Reduction-oxidation

SI:

Stimulation Index

SJS:

Stevens–Johnson syndrome

TCR:

T cell receptor

TEN:

Toxic epidermal necrolysis

TH :

T helper

TNF:

Tumour necrosis factor

β-lactam:

Beta-lactam

References

  • Aberer W, Bircher A, Romano A, Blanca M, Campi P, Fernandez J, Brockow K, Pichler WJ, Demoly P, European Network for Drug Allergy (ENDA), EAACI interest group on drug hypersensitivity (2003) Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy 58:854–863

    Article  CAS  PubMed  Google Scholar 

  • Adam J, Pichler WJ, Yerly D (2011) Delayed drug hypersensitivity: models of T-cell stimulation. Br J Clin Pharmacol 71:701–707

    Article  CAS  PubMed  Google Scholar 

  • Amacher DE (2010) The discovery and development of proteomic safety biomarkers for the detection of drug-induced liver toxicity. Toxicol Appl Pharmacol 245:134–142

    Article  CAS  PubMed  Google Scholar 

  • Ariza A, Garzon D, Abánades DR, de los Ríos V, Vistoli G, Torres MJ, Carini M, Aldini G, Pérez-Sala D (2012) Protein haptenation by amoxicillin: high resolution mass spectrometry analysis and identification of target proteins in serum. J Proteom 77:504–520

    Article  CAS  Google Scholar 

  • Batchelor FR, Dewdney JM, Gazzard D (1965) Penicillin allergy—the formation of the penicilloyl determinant. Nature 206:362–364

    Article  CAS  PubMed  Google Scholar 

  • Beeler A, Engler O, Gerber BO, Pichler WJ (2006) Long-lasting reactivity and high frequency of drug specific T cells after severe systemic drug hypersensitivity reactions. J Allergy Clin Immunol 117:455–462

    Article  CAS  PubMed  Google Scholar 

  • 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 63:181–188

    CAS  PubMed  Google Scholar 

  • Bigby M, Jick S, Jick H, Arndt K (1986) Drug-induced cutaneous reactions—a report from the Boston Collaborative Drug Surveillance Program on 15438 consecutive inpatients, 1975 to 1982. JAMA 256:3358–3363

    Article  CAS  PubMed  Google Scholar 

  • Brander C, Maurihellweg 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 155:2670–2678

    CAS  PubMed  Google Scholar 

  • Britschgi M, Steiner UC, Schmid S, Depta JPH, Senti G, Bircher A, Burkhart C, Yawalkar N, Pichler WJ (2001) T-cell involvement in drug-induced acute generalized exanthematous pustulosis. J Clin Invest 107:1433–1441

    Article  CAS  PubMed  Google Scholar 

  • Burkhart C, Britschgi M, Strasser I, Depta JPH, von Greyerz S, Barnaba V, Pichler WJ (2002) Non covalent presentation of sulfamethoxazole to human CD4+ T cells is independent of distinct human leucocyte antigen-bound peptides. Clin Exp Allergy 32:1635–1643

    Article  CAS  PubMed  Google Scholar 

  • Burrows JA, Nissen LM, Kirkpatrick CMJ, Bell SC (2007) Beta-lactam allergy in adults with cystic fibrosis. J Cyst Fibros 6:297–303

    Article  CAS  PubMed  Google Scholar 

  • Caruso A, Licenziati S, Corulli M, Canaris AD, DeFrancesco MA, Fiorentini S, Peroni L, Fallacara F, Dima F, Balsari A, Turano A (1997) Flow cytometric analysis of activation markers on stimulated T cells and their correlation with cell proliferation. Cytometry 27:71–76

    Article  CAS  PubMed  Google Scholar 

  • Castell JV, Castell M (2006) Allergic hepatitis induced by drugs. Curr Opin Allergy Clin Immunol 6:258–265

    CAS  PubMed  Google Scholar 

  • Castrejon JL, Berry N, El-Ghaiesh S, Gerber B, Pichler WJ, Park BK, Naisbitt DJ (2010) Stimulation of human T cells with sulfonamides and sulfonamide metabolites. J Allergy Clin Immunol 125:411–418

    Article  CAS  PubMed  Google Scholar 

  • Chakraborty AK (2002) Lighting up TCR takes advantage of serial triggering. Nat Immunol 3:895–896

    Article  CAS  PubMed  Google Scholar 

  • 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, Macdonalds 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 28:822–832

    Article  CAS  PubMed  Google Scholar 

  • Christiansen C, Pichler WJ, Skotland T (2000) Delayed allergy-like reactions to X-ray contrast media: mechanistic considerations. Eur Radiol 10:1965–1975

    Article  CAS  PubMed  Google Scholar 

  • Clay PG, Rathbun RC, Slater LN (2000) Management protocol for abacavir-related hypersensitivity reaction. Ann Pharmacother 34:247–249

    Article  CAS  PubMed  Google Scholar 

  • Coombs PR, Gell PG (1968) Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: Gell RR (ed) Clinical aspects of immunology. Oxford University Press, Oxford, pp 575–596

    Google Scholar 

  • Cribb AE, Spielberg SP (1992) Sulfamethoxazole is metabolized to the hydroxylamine in humans. Clin Pharmacol Ther 51:522–526

    Article  CAS  PubMed  Google Scholar 

  • Cribb AE, Miller M, Leeder JS, Hill J, Spielberg SP (1991) Reactions of the nitroso and hydroxylamine metabolites of sulfamethoxazole with reduced glutathione—implications for idiosyncratic toxicity. Drug Metab Dispos 19:900–906

    CAS  PubMed  Google Scholar 

  • Cribb AE, Spielberg SP, Griffin GP (1995) N4-hydroxylation of sulfamethoxazole by cytochrome P450 of the cytochrome P4502C subfamily and reduction of sulfamethoxazole hydroxylamine in human and rat hepatic microsomes. Drug Metab Dispos 23:406–414

    CAS  PubMed  Google Scholar 

  • Curtsinger JM, Mescher MF (2010) Inflammatory cytokines as a third signal for T cell activation. Curr Opin Immunol 22:333–340

    Article  CAS  PubMed  Google Scholar 

  • Curtsinger JM, Schmidt CS, Mondino A, Lins DC, Kedl RM, Jenkins MK, Mescher MF (1999) Inflammatory cytokines provide a third signal for activation of naive CD4+ and CD8+ T cells. J Immunol 162:3256–3262

    CAS  PubMed  Google Scholar 

  • 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, DILIGEN Study, International SAE Consortium (2009) HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 41:816–819

    Article  CAS  PubMed  Google Scholar 

  • Depta JPH, Altznauer F, Gamerdinger K, Burkhart C, Weltzien HU, Pichler WJ (2004) Drug interaction with T-cell receptors: T-cell receptor density determines degree of cross-reactivity. J Allergy Clin Immunol 113:519–527

    Article  CAS  PubMed  Google Scholar 

  • Dietz L, Esser PR, Schmucker SS, Goette I, Richter A, Schnoelzer M, Martin SF, Thierse H-J (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 117:336–347

    Article  CAS  PubMed  Google Scholar 

  • Dodd CC, Naisbitt DJ, Vilar FJ, Gordon SF, Maggs JL, Park BK, Pirmohamed M (2003) Abacavir hypersensitivity in human immunodeficiency virus-positive patients: demonstration of the presence of drug-specific lymphocyte proliferation in vitro. Br J Clin Pharmacol 55:421

    Google Scholar 

  • Elsheikh A, Lavergne SN, Castrejon JL, Farrell J, Wang H, Sathish J, Pichler WJ, Park BK, Naisbitt DJ (2010) Drug antigenicity, immunogenicity, and costimulatory signaling: evidence for formation of a functional antigen through immune cell metabolism. J Immunol 185:6448–6460

    Article  CAS  PubMed  Google Scholar 

  • Elsheikh A, Castrejon L, Lavergne SN, Whitaker P, Monshi M, Callan H, El-Ghaiesh S, Farrell J, Pichler WJ, Peckham D, Park BK, Naisbitt DJ (2011) Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis. J Allergy Clin Immunol 127:1543–1551

    Article  CAS  PubMed  Google Scholar 

  • Engler OB, Strasser I, Naisbitt DJ, Cerny A, Pichler WJ (2004) A chemically inert drug can stimulate T cells in vitro by their T cell receptor in non-sensitised individuals. Toxicology 197:47–56

    Article  CAS  PubMed  Google Scholar 

  • Esser S, Jablonka R, Heinemann FM, Reuter S, Jaeger H, von Krosigk A, Schenk-Westkamp P, Schadendorf D, Horn PA, Lindemann M (2012) Detection of Abacavir hypersensitivity by ELISpot method. Inflamm Allergy Drug Targets 11:227–234

    Article  CAS  PubMed  Google Scholar 

  • Ferrell PB Jr, McLeod HL (2008) Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics 9:1543–1546

    Article  CAS  PubMed  Google Scholar 

  • Hetherington S, McGuirk S, Powell G, Cutrell A, Naderer O, Spreen B, Lafon S, Pearce G, Steel H (2001) Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin Ther 23:1603–1614

    Article  CAS  PubMed  Google Scholar 

  • Hunziker T, Kunzi UP, Braunschweig S, Zehnder D, Hoigne R (1997) Comprehensive hospital drug monitoring (CHDM): adverse skin reactions, a 20-year survey. Allergy 52:388–393

    Article  CAS  PubMed  Google Scholar 

  • Jenkins RE, Meng X, Elliott VL, Kitteringham NR, Pirmohamed M, Park BK (2009) Characterisation of flucloxacillin and 5-hydroxymethyl flucloxacillin haptenated HSA in vitro and in vivo. Proteomics Clin Appl 3:720–729

    Article  CAS  PubMed  Google Scholar 

  • Kano Y, Hirahara K, Mitsuyama Y, Takahashi R, Shiohara T (2007) Utility of the lymphocyte transformation test in the diagnosis of drug sensitivity: dependence on its timing and the type of drug eruption. Allergy 62:1439–1444

    Article  CAS  PubMed  Google Scholar 

  • Kitteringham NR, Jenkins RE, Lane CS, Elliott VL, Park BK (2009) Multiple reaction monitoring for quantitative biomarker analysis in proteomics and metabolomics. J Chromatogr B Analyt Technol Biomed Life Sci 877:1229–1239

    Article  CAS  PubMed  Google Scholar 

  • Ko T-M, Chung W-H, Wei C-Y, Shih H-Y, Chen J-K, Lin C-H, Chen Y-T, Hung S-I (2011) Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome. J Allergy Clin Immunol 128:1266–1276

    Article  CAS  PubMed  Google Scholar 

  • Koch C, Hjelt K, Pedersen SS, Jensen ET, Jensen T, Lanng S, Valerius NH, Pedersen M, Hoiby N (1991) Retrospective clinical study of hypersensitivity reactions to aztreonam and 6 other beta-lactam antibiotics in cystic fibrosis patients receiving multiple treatment courses. Rev Infect Dis 13:S608–S611

    Article  PubMed  Google Scholar 

  • Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3:711–715

    Article  CAS  PubMed  Google Scholar 

  • Lafaye P, Lapresle C (1988) Fixation of penicilloyl groups to albumin and appearance of anti-penicilloyl antibodies in penicillin-treated patients. J Clin Invest 82:7–12

    Article  CAS  PubMed  Google Scholar 

  • Landsteiner K, Jacobs J (1935) Studies on the sensitization of animals with simple chemical compounds. J Exp Med 61:643–656

    Article  CAS  PubMed  Google Scholar 

  • Landsteiner K, Jacobs J (1936) Studies on the sensitization of animals with simple chemical compounds. II. J Exp Med 64:625–639

    Article  CAS  PubMed  Google Scholar 

  • Lazarou J, Pomeranz BH, Corey PN (1998) Incidence of adverse drug reactions in hospitalized patients—A meta-analysis of prospective studies. JAMA 279:1200–1205

    Article  CAS  PubMed  Google Scholar 

  • Lertratanangkoon K, Horning MG (1982) Metabolism of carbamazepine. Drug Metab Dispos 10:1–10

    CAS  PubMed  Google Scholar 

  • Levine BB (1960) Studies on the mechanism of the formation of the penicillin antigen. I. Delayed allergic cross-reactions among penicillin-g and its degradation products. J Exp Med 112:1131–1156

    Article  CAS  PubMed  Google Scholar 

  • Levine BB, Ovary Z (1961) Studies on mechanism of formation of the penicillin antigen. III. The N-(D α-benzylpenicilloyl) group as an antigenic determinant responsible for hypersensitivity to penicillin g. J Exp Med 114:875–904

    Article  CAS  PubMed  Google Scholar 

  • Lochmatter P, Beeler A, Kawabata TT, Gerber BO, Pichler WJ (2009a) Drug-specific in vitro release of IL-2, IL-5, IL-13 and IFN-gamma in patients with delayed-type drug hypersensitivity. Allergy 64:1269–1278

    Article  CAS  PubMed  Google Scholar 

  • Lochmatter P, Zawodniak A, Pichler WJ (2009b) In vitro tests in drug hypersensitivity diagnosis. Immunol Allergy Clin North Am 29:537–554

    Article  PubMed  Google Scholar 

  • Luque I, Leyva L, Torres MJ, Rosal M, Mayorga C, Segura JM, Blanca M, Juarez C (2001) In vitro T-cell responses to beta-lactam drugs in immediate and nonimmediate allergic reactions. Allergy 56:611–618

    Article  CAS  PubMed  Google Scholar 

  • 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 359:727–732

    Article  CAS  PubMed  Google Scholar 

  • Martin M, Wurpts G, Ott H, Baron JM, Erdmann S, Merk HF, Sachs B (2010a) In vitro detection and characterization of drug hypersensitivity using flow cytometry. Allergy 65:32–39

    Article  CAS  PubMed  Google Scholar 

  • Martin SF, Esser PR, Schmucker S, Dietz L, Naisbitt DJ, Park BK, Vocanson M, Nicolas J-F, Keller M, Pichler WJ, Peiser M, Luch A, Wanner R, Maggi E, Cavani A, Rustemeyer T, Richter A, Thierse H-J, Sallusto F (2010b) T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays. Cell Mol Life Sci 67:4171–4184

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Meng X, Jenkins RE, Berry NG, Maggs JL, Farrell J, Lane CS, Stachulski AV, French NS, Naisbitt DJ, Pirmohamed M, Park BK (2011) Direct evidence for the formation of diastereoisomeric benzylpenicilloyl haptens from benzylpenicillin and benzylpenicillenic acid in patients. J Pharmacol Exp Therap 338:841–849

    Article  CAS  Google Scholar 

  • Messaad D, Sahla H, Benahmed S, Godard P, Bousquet J, Demoly P (2004) Drug provocation tests in patients with a history suggesting an immediate drug hypersensitivity reaction. Ann Intern Med 140:1001–1006

    Article  PubMed  Google Scholar 

  • Mitra AK, Thummel KE, Kalhorn TF, Kharasch ED, Unadkat JD, Slattery JT (1996) Inhibition of sulfamethoxazole hydroxylamine formation by fluconazole in human liver microsomes and healthy volunteers. Clin Pharmacol Ther 59:332–340

    Article  CAS  PubMed  Google Scholar 

  • Moreno E, Macias E, Davila I, Laffond E, Ruiz A, Lorente F (2008) Hypersensitivity reactions to cephalosporins. Expert Opin Drug Saf 7:295–304

    Article  CAS  PubMed  Google Scholar 

  • Naisbitt DJ (2004) Drug hypersensitivity reactions in skin: understanding mechanisms and the development of diagnostic and predictive tests. Toxicology 194:179–196

    Article  CAS  PubMed  Google Scholar 

  • Naisbitt DJ, Oneill PM, Pirmohamed M, Park BK (1996) Synthesis and reactions of nitroso sulphamethoxazole with biological nucleophiles: implications for immune mediated toxicity. Bioorg Med Chem Lett 6:1511–1516

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Naisbitt DJ, Vilar FJ, Stalford AC, Wilkins EGL, Pirmohamed M, Park BK (2000b) Plasma cysteine deficiency and decreased reduction of nitrososulfamethoxazole with HIV infection. AIDS Res Hum Retrovirus 16:1929–1938

    Article  CAS  Google Scholar 

  • Naisbitt DJ, Gordon SF, Pirmohamed M, Burkhart C, Cribb AE, Pichler WJ, Park BK (2001) Antigenicity and immunogenicity of sulphamethoxazole: demonstration of metabolism-dependent haptenation and T-cell proliferation in vivo. Br J Pharmacol 133:295–305

    Article  CAS  PubMed  Google Scholar 

  • Naisbitt DJ, Farrell J, Gordon SF, Maggs JL, Burkhart C, Pichler WJ, Pirmohamed M, Park BK (2002) Covalent binding of the nitroso metabolite of sulfamethoxazole leads to toxicity and major histocompatibility complex-restricted antigen presentation. Mol Pharmacol 62:628–637

    Article  CAS  PubMed  Google Scholar 

  • Naisbitt DJ, Britschgi M, Wong G, Farrell J, Depta JPH, Chadwick DW, Pichler WJ, Pirmohamed M, Park BK (2003) Hypersensitivity reactions to carbamazepine: characterization of the specificity, phenotype, and cytokine profile of drug-specific T cell clones. Mol Pharmacol 63:732–741

    Article  CAS  PubMed  Google Scholar 

  • Nassif A, Bensussan A, Dorothee G, Mani-Chouaib F, Bachot N, Bagot M, Boumsell L, Roujeau JC (2002) Drug specific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis. J Invest Dermatol 118:728–733

    Article  CAS  PubMed  Google Scholar 

  • Nassif A, Bensussan A, Boumsell L, Deniaud A, Moslehi H, Wolkenstein P, Bagot M, Roujeau JC (2004) Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells. J Allergy Clin Immunol 114:1209–1215

    Article  CAS  PubMed  Google Scholar 

  • Nishio D, Izu K, Kabashima K, Tokura Y (2007) T cell populations propagating in the peripheral blood of patients with drug eruptions. J Dermatol Sci 48:25–33

    Article  CAS  PubMed  Google Scholar 

  • Norrby SR (1987) Side-effects of cephalosporins. Drugs 34:105–120

    Article  PubMed  Google Scholar 

  • Padial A, Antunez C, Blanca-Lopez N, Fernandez TD, Cornejo-Garcia JA, Mayorga C, Torres MJ, Blanca M (2008) Non-immediate reactions to beta-lactams: diagnostic value of skin testing and drug provocation test. Clin Exp Allergy 38:822–828

    Article  CAS  PubMed  Google Scholar 

  • 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 27:1303–1307

    Article  CAS  PubMed  Google Scholar 

  • Paul C, Wolkenstein P, Adle H, Wechsler J, Garchon HJ, Revuz J, Roujeau JC (1996) Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis. Br J Dermatol 134:710–714

    Article  CAS  PubMed  Google Scholar 

  • Perez-Inestrosa E, Suau R, Montanez MI, Rodriguez R, Mayorga C, Torres MJ, Blanca M (2005) Cephalosporin chemical reactivity and its immunological implications. Curr Opin Allergy Clin Immunol 5:323–330

    Article  CAS  PubMed  Google Scholar 

  • Phillips EJ, Wong GA, Kaul R, Shahabi K, Nolan DA, Knowles SR, Martin AM, Mallal SA, Shear NH (2005) Clinical and immunogenetic correlates of abacavir hypersensitivity. AIDS 19:979–981

    Article  CAS  PubMed  Google Scholar 

  • Phillips EJ, Chung W-H, Mockenhaupt M, Roujeau J-C, Mallal SA (2011) Drug hypersensitivity: pharmacogenetics and clinical syndromes. J Allergy Clin Immunol 127:S60–S66

    Article  CAS  PubMed  Google Scholar 

  • Pichler WJ (2003) Delayed drug hypersensitivity reactions. Ann Intern Med 139:683–693

    Article  CAS  PubMed  Google Scholar 

  • Pichler WJ, Yawalkar N, Britschgi M, Depta J, Strasser I, Schmid S, Kuechler P, Naisbitt D (2002) Cellular and molecular pathophysiology of cutaneous drug reactions. Am J Clin Dermatol 3:229–238

    Article  PubMed  Google Scholar 

  • Pichler WJ, Adam J, Daubner B, Gentinetta T, Keller M, Yerly D (2010) Drug hypersensitivity reactions: pathomechanism and clinical symptoms. Med Clin N Am 94:645–664

    Article  CAS  PubMed  Google Scholar 

  • Pichler WJ, Naisbitt DJ, Park BK (2011) Immune pathomechanism of drug hypersensitivity reactions. J Allergy Clin Immunol 127:S74–S81

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Pirmohamed M, Naisbitt DJ, Gordon F, Park BK (2002) The danger hypothesis—potential role in idiosyncratic drug reactions. Toxicology 181:55–63

    Article  PubMed  Google Scholar 

  • Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, Farrar K, Park BK, Breckenridge AM (2004) Adverse drug reactions as cause of admission to hospital: prospective analysis of 18,820 patients. Br Med J 329:15–19

    Article  Google Scholar 

  • Pleasants RA, Walker TR, Samuelson WM (1994) Allergic reactions to parenteral beta-lactam antibiotics in patients with cystic fibrosis. Chest 106:1124–1128

    Article  CAS  PubMed  Google Scholar 

  • Porebski G, Gschwend-Zawodniak A, Pichler WJ (2011) In vitro diagnosis of T cell-mediated drug allergy. Clin Exp Allergy 41:461–470

    Article  CAS  PubMed  Google Scholar 

  • Romano A, Blanca M, Torres MJ, Bircher A, Aberer W, Brockow K, Pichler WJ, Demoly P, ENDA; EAACI (2004) Diagnosis of nonimmediate reactions to beta-lactam antibiotics. Allergy 59:1153–1160

    Article  CAS  PubMed  Google Scholar 

  • Romano A, Gueant-Rodriguez RM, Viola M, Amoghly F, Gaeta F, Nicolas JP, Gueant JL (2005) Diagnosing immediate reactions to cephalosporins. Clin Exp Allergy 35:1234–1242

    Article  CAS  PubMed  Google Scholar 

  • Roujeau JC (2005) Clinical heterogeneity of drug hypersensitivity. Toxicology 209:123–129

    Article  CAS  PubMed  Google Scholar 

  • Rozieres A, Hennino A, Rodet K, Gutowski MC, Gunera-Saad N, Berard F, Cozon G, Bienvenu J, Nicolas JF (2009a) Detection and quantification of drug-specific T cells in penicillin allergy. Allergy 64:534–542

    Article  CAS  PubMed  Google Scholar 

  • Rozieres A, Vocanson M, Ben Said B, Nosbaum A, Nicolas J-F (2009b) Role of T cells in nonimmediate allergic drug reactions. Curr Opin Allergy Clin Immunol 9:305–310

    Article  CAS  PubMed  Google Scholar 

  • Schmittel A, Keilholz U, Bauer S, Kuhne U, Stevanovic S, Thiel E, Scheibenbogen C (2001) Application of the IFN-gamma ELISPOT assay to quantify T cell responses against proteins. J Immunol Methods 247:17–24

    Article  CAS  PubMed  Google Scholar 

  • Schnyder B, Pichler WJ (1997) T cell activation in drug allergies. Allergologie 20:58–62

    Google Scholar 

  • Schnyder B, Pichler WJ (2000) Skin and laboratory tests in amoxicillin- and penicillin-induced morbilliform skin eruption. Clin Exp Allergy 30:590–595

    Article  CAS  PubMed  Google Scholar 

  • Schnyder B, Mauri-Hellweg D, Zanni M, Bettens F, Pichler WJ (1997) Direct, MHC-dependent presentation of the drug sulfamethoxazole to human alpha beta T cell clones. J Clin Invest 100:136–141

    Article  CAS  PubMed  Google Scholar 

  • Schnyder B, Frutig K, Mauri-Hellweg D, Limat A, Yawalkar N, Pichler WJ (1998) T-cell-mediated cytotoxicity against keratinocytes in sulfamethoxazole-induced skin reaction. Clin Exp Allergy 28:1412–1417

    Article  CAS  PubMed  Google Scholar 

  • Schnyder B, Burkhart C, Schnyder-Frutig K, von Greyerz S, Naisbitt DJ, Pirmohamed M, Park BK, Pichler WJ (2000) Recognition of sulfamethoxazole and its reactive metabolites by drug-specific CD4(+) T cells from allergic individuals. J Immunol 164:6647–6654

    CAS  PubMed  Google Scholar 

  • Schodin BA, Tsomides TJ, Kranz DM (1996) Correlation between the number of T cell receptors required for T cell activation and TCR-ligand affinity. Immunity 5:137–146

    Article  CAS  PubMed  Google Scholar 

  • Sieben S, Kawakubo Y, Al Masaoudi T, Merk HF, Blomeke B (2002) Delayed-type hypersensitivity reaction to paraphenylenediamine is mediated by 2 different pathways of antigen recognition by specific alpha beta(+) human T-cell clones. J Allergy Clin Immunol 109:1005–1011

    Article  CAS  PubMed  Google Scholar 

  • Sullivan JR, Shear NH (2001) The drug hypersensitivity syndrome—what is the pathogenesis? Arch Dermatol 137:357–364

    CAS  PubMed  Google Scholar 

  • Takahashi R, Kano Y, Yamazaki Y, Kimishima M, Mizukawa Y, Shiohara T (2009) Defective regulatory T cells in patients with severe drug eruptions: timing of the dysfunction is associated with the pathological phenotype and outcome. J Immunol 182:8071–8079

    Article  CAS  PubMed  Google Scholar 

  • Tang YH, Mockenhaupt M, Henry A, Bounoua M, Naldi L, Le Gouvello S, Bensussan A, Roujeau JC (2012) Poor relevance of a lymphocyte proliferation assay in lamotrigine-induced Stevens-Johnson syndrome or toxic epidermal necrolysis. Clin Exp Allergy 42:248–254

    Article  CAS  PubMed  Google Scholar 

  • Torres MJ, Blanca M, Fernandez J, Romano A, de Weck A, Aberer W, Brockow K, Pichler WJ, Demoly P, Enda E (2003) Diagnosis of immediate allergic reactions to beta-lactam antibiotics. Allergy 58:961–972

    Article  CAS  PubMed  Google Scholar 

  • Trepanier LA, Yoder AR, Bajad S, Beckwith MD, Bellehumeur JL, Graziano FM (2004) Plasma ascorbate deficiency is associated with impaired reduction of sulfamethoxazole-nitroso in HIV infection. J Acquir Immune Defic Syndr 36:1041–1050

    Article  CAS  PubMed  Google Scholar 

  • van der Linden PD, van der Lei J, Vlug AE, Stricker BHC (1998) Skin reactions to antibacterial agents in general practice. J Clin Epidemiol 51:703–708

    Article  PubMed  Google Scholar 

  • Vanderven A, Mantel MA, Vree TB, Koopmans PP, Vandermeer JWM (1994) Formation and elimination of sulfamethoxazole hydroxylamine after oral administration of sulfamethoxazole. Br J Clin Pharmacol 38:147–150

    Article  CAS  Google Scholar 

  • Walmsley SL, Winn LM, Harrison ML, Uetrecht JP, Wells PG (1997) Oxidative stress and thiol depletion in plasma and peripheral blood lymphocytes from HIV-infected patients: toxicological and pathological implications. AIDS 11:1689–1697

    Article  CAS  PubMed  Google Scholar 

  • Walsh JS, Reese MJ, Thurmond LM (2002) The metabolic activation of abacavir by human liver cytosol and expressed human alcohol dehydrogenase isozymes. Chem Biol Interact 142:135–154

    Article  CAS  PubMed  Google Scholar 

  • Whitaker P, Meng X, Lavergne SN, El-Ghaiesh S, Monshi M, Earnshaw C, Peckham D, Gooi J, Conway S, Pirmohamed M, Jenkins RE, Naisbitt DJ, Park BK (2011) Mass spectrometric characterization of circulating and functional antigens derived from piperacillin in patients with cystic fibrosis. J Immunol 187:200–211

    Article  CAS  PubMed  Google Scholar 

  • Wu Y, Sanderson JP, Farrell J, Drummond NS, Hanson A, Bowkett E, Berry N, Stachulski AV, Clarke SE, Pichler WJ, Pirmohamed M, Park BK, Naisbitt DJ (2006) Activation of T cells by carbamazepine and carbamazepine metabolites. J Allergy Clin Immunol 118:233–241

    Article  CAS  PubMed  Google Scholar 

  • Yang C-WO, Hung S-I, Juo C-G, Lin Y-P, Fang W-H, Lu IH, Chen S-T, Chen Y-T (2007) HLA-B*1502 bound peptides: implications for the pathogenesis of carbamazepine-induced Stevens-Johnson syndrome. J Allergy Clin Immunol 120:870–877

    Article  CAS  PubMed  Google Scholar 

  • Yawalkar N, Egli F, Hari Y, Nievergelt H, Braathen LR, Pichler WJ (2000) Infiltration of cytotoxic T cells in drug-induced cutaneous eruptions. Clin Exp Allergy 30:847–855

    Article  CAS  PubMed  Google Scholar 

  • Zanni MP, MauriHellweg D, Brander C, Wendland T, Schnyder B, Frei E, vonGreyerz S, Bircher A, Pichler WJ (1997) Characterization of lidocaine-specific T cells. J Immunol 158:1139–1148

    CAS  PubMed  Google Scholar 

  • Zanni MP, von Greyerz S, Schnyder B, Wendland T, Pichler WJ (1998a) Allele-unrestricted presentation of lidocaine by HLA-DR molecules to specific alpha beta(+) T cell clones. Int Immunol 10:507–515

    Article  CAS  PubMed  Google Scholar 

  • Zanni MP, von Greyerz S, Schnyder B, Brander KA, Frutig K, Hari Y, Valitutti S, Pichler WJ (1998b) HLA restricted, processing- and metabolism-independent pathway of drug recognition by human alpha beta T lymphocytes. J Clin Invest 102:1591–1598

    Article  CAS  PubMed  Google Scholar 

  • Zawodniak A, Lochmatter P, Yerly D, Kawabata T, Lerch M, Yawalkar N, Pichler WJ (2010) In vitro detection of cytotoxic T and NK cells in peripheral blood of patients with various drug-induced skin diseases. Allergy 65:376–384

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular and Clinical Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Building, Ahston Street, Liverpool, L69 3GE, UK

    C. J. Earnshaw, B. K. Park & D. J. Naisbitt

  2. ADR-AC GmbH, Bern, Switzerland

    T. Pecaric-Petkovic

  3. Division of Allergology, Department of Rheumatology, Clinical Immunology and Allergology, Inselspital, University of Bern, Bern, Switzerland

    T. Pecaric-Petkovic

Authors
  1. C. J. Earnshaw
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  2. T. Pecaric-Petkovic
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  3. B. K. Park
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  4. D. J. Naisbitt
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Correspondence to C. J. Earnshaw .

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  1. Department of Dermatology and Venereology, University Medical Center Freiburg, Freiburg, Germany

    Stefan F. Martin

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Earnshaw, C.J., Pecaric-Petkovic, T., Park, B.K., Naisbitt, D.J. (2014). T Cell Responses to Drugs and Drug Metabolites. In: Martin, S. (eds) T Lymphocytes as Tools in Diagnostics and Immunotoxicology. Experientia Supplementum, vol 104. Springer, Basel. https://doi.org/10.1007/978-3-0348-0726-5_10

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