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• W2044141570 abstract "Exposure to carbamazepine (CBZ) is associated with rare, but severe immunologically mediated hypersensitivity reactions. CBZ-responsive CD4+ and CD8+ T lymphocytes have been isolated from patients presenting with reactions of varying severity and characterized in terms of immunologic function and drug cross-reactivity. Genome-wide association studies have shown linkage predisposition of severe CBZ-associated reactions with specific HLA alleles. For instance, HLA-B*15:02 predisposes to CBZ-induced Stevens-Johnson syndrome in Han Chinese and Asian subjects. In this patient group, CBZ-specific T-cell responses are HLA-B*15:02-restricted, providing evidence of the functional role of this HLA protein in determining disease pathogenesis. Furthermore, pre-prescription genotyping for HLA-B*15:02 is associated with a decrease in the incidence of CBZ-induced Stevens-Johnson syndrome.1Wei C.Y. Chung W.H. Huang H.W. Chen Y.T. Hung S.I. Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome.J Allergy Clin Immunol. 2012; 129: 1562-1569.e5Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 2Chen P. Lin J.J. Lu C.S. Ong C.T. Hsieh P.F. Yang C.C. et al.Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan.N Engl J Med. 2011; 364: 1126-1133Crossref PubMed Scopus (536) Google Scholar HLA-A*31:01 has recently been shown to be associated with a wider spectrum of CBZ hypersensitivity reactions in subjects of European/Japanese origin3McCormack M. Alfirevic A. Bourgeois S. Farrell J.J. Kasperaviciute D. Carrington M. et al.HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.N Engl J Med. 2011; 364: 1134-1143Crossref PubMed Scopus (713) Google Scholar; however, an interaction between CBZ and the HLA protein is yet to be characterized.The nature of the drug-derived antigenic determinants that interact with immunologic receptors remains an area of debate. The hapten theory stipulates that peptides irreversibly modified with drugs are antigenic determinants. In support of this theory, β-lactam albumin conjugates stimulate lymphocytes from hypersensitive subjects.4Whitaker P. Meng X. Lavergne S.N. El-Ghaiesh S. Monshi M. Earnshaw C. et al.Mass spectrometric characterization of circulating and functional antigens derived from piperacillin in patients with cystic fibrosis.J Immunol. 2011; 187: 200-211Crossref PubMed Scopus (95) Google Scholar The pharmacologic interaction hypothesis states that drug molecules interact directly with HLA molecules to activate T cells. Functional studies showing the rapid, processing independent activation of T cells by certain drugs supports this hypothesis.5Adam J. Eriksson K.K. Schnyder B. Fontana S. Pichler W.J. Yerly D. Avidity determines T-cell reactivity in abacavir hypersensitivity.Eur J Immunol. 2012; 42: 1706-1716Crossref PubMed Scopus (77) Google Scholar Recently, direct binding of the drugs abacavir and CBZ to specific HLA molecules has been shown to alter the peptide repertoire displayed on the surface of antigen-presenting cells,6Illing P.T. Vivian J.P. Dudek N.L. Kostenko L. Chen Z. Bharadwaj M. et al.Immune self-reactivity triggered by drug-modified HLA-peptide repertoire.Nature. 2012; 486: 554-558PubMed Google Scholar leading the authors to propose that endogenous peptides activate “drug”-specific T cells.CBZ is metabolized to more than 30 metabolites in human liver.7Pearce R.E. Vakkalagadda G.R. Leeder J.S. Pathways of carbamazepine bioactivation in vitro, I: characterization of human cytochromes P450 responsible for the formation of 2- and 3-hydroxylated metabolites.Drug Metab Dispos. 2002; 30: 1170-1179Crossref PubMed Scopus (109) Google Scholar Several cysteine reactive metabolites including a 2,3-substituted arene oxide, o-quinones, a carbonium ion, a carboxaldehyde, and an iminoquinone have been identified, each of which has the potential to modify protein and generate antigenic determinants for T cells. A recent attempt to elute and characterize CBZ-modified HLA-B*15:02 binding peptides by mass spectrometry proved unsuccessful,8Yang C.W. Hung S.I. Juo C.G. Lin Y.P. Fang W.H. Lu I.H. et al.HLA-B*1502-bound peptides: implications for the pathogenesis of carbamazepine-induced Stevens-Johnson syndrome.J Allergy Clin Immunol. 2007; 120: 870-877Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar prompting the authors to conclude that CBZ must interact directly with HLA-binding peptides to activate T cells. However, CBZ metabolite–derived protein adducts were not studied and the levels of CBZ metabolites formed in lymphocyte test systems is known to be extremely low and almost certainly below the limit of detection by conventional mass spectrometers. Thus, we have developed an alternative strategy to explore whether CBZ-responsive T cells are activated via a metabolism-independent pathway. Two series of derivatives of CBZ, namely, 2-monohalo and 2,8-dihalo compounds, were prepared and their ability to activate CBZ-responsive T-cell clones was explored. We have recently reported the routes of synthesis from benzohalogenated iminostilbenes and the effects of halogen substitution on the metabolism of CBZ in freshly isolated rat hepatocytes.9Elliott E.C. Regan S. Maggs J. Bowkett E. Parry L. Williams D. et al.Haloarene derivatives of carbamazepine with reduced bioactivation liabilities: 2-monohalo and 2,8-dihalo derivatives.J Med Chem. 2012; 55: 9773-9784Crossref PubMed Scopus (13) Google Scholar Importantly, none of the derivatives underwent dehalogenation and with the exception of 2-fluoro CBZ, aromatic hydroxylation via putative arene oxide intermediates was inhibited.CBZ-responsive T-cell clones were generated from a 74-year-old subject carrying the HLA risk allele A*31:01 who developed drug rash with eosinophilia and systemic symptoms (DRESS) 6 days after commencing drug treatment and a CBZ-naive subject carrying HLA-B*1502. Blood samples were obtained under ethics approval with specific consent. The serial dilution procedure used to generate clones was the same for both subjects.4Whitaker P. Meng X. Lavergne S.N. El-Ghaiesh S. Monshi M. Earnshaw C. et al.Mass spectrometric characterization of circulating and functional antigens derived from piperacillin in patients with cystic fibrosis.J Immunol. 2011; 187: 200-211Crossref PubMed Scopus (95) Google Scholar EBV-transformed B-cell lines were used as autologous antigen-presenting cells. To test the specificity of the clones, T cells (0.5 × 105) were incubated with antigen-presenting cells (0.1 × 105) and CBZ. After 48 hours, [3H]thymidine (0.5 μCi) was added and proliferation was measured by scintillation counting.CBZ-stimulated PBMCs from the CBZ-associated DRESS and HLA-B*15:02 positive CBZ-naive subject were serially diluted into 96-well plates at 0.1 to 1 cell per well and stimulated with PHA. Two hundred forty well-growing clones were tested for CBZ specificity. Of these, 75 were designated CBZ-responsive on the basis of their proliferative response profiles (CBZ-associated DRESS subject [n = 31]: 0, 6,668 ± 7,854 cpm; CBZ 100 μM, 29,609 ± 27,345 cpm; HLA-B*1502 positive subject [n = 44]: 0, 4,488 ± 5,077 cpm; CBZ 100 μM, 18,695 ± 14,280 cpm). In agreement with Wei et al,1Wei C.Y. Chung W.H. Huang H.W. Chen Y.T. Hung S.I. Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome.J Allergy Clin Immunol. 2012; 129: 1562-1569.e5Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar all CBZ-responsive clones from the drug-naive subject carrying HLA-B*15:02 were CD8+, while CBZ-responsive CD4+ and CD8+ clones were detected from the HLA-A31:01 positive patient with DRESS. Six CD4+ and 11 CD8+ well-growing clones were expanded to explore cross-reactivity with the halogenated derivatives in proliferation and cytokine release assays. IFN-γ ELIspot was selected to measure secreted cytokines as IFN-γ is the predominant cytokine released from CBZ-stimulated clones.The CBZ-specific proliferative response of clones from the CBZ-associated DRESS and HLA-B*1502 positive subject and cytokine release were concentration-dependent. Subsequent experiments were performed with equivalent molar concentrations of CBZ and the halogenated derivatives. Clones from the CBZ-associated DRESS patient displayed a range of cross-reactivity patterns with the halogenated derivatives. Fig 1, A, depicts the proliferative response profile of a panel of clones highlighting the various patterns observed. Fig 1, B, shows a representative clone secreting IFN-γ following drug stimulation. The pattern of cross-reactivity with the different CBZ derivatives was similar when the 2 readouts were compared. A similar pattern of cross-reactivity was observed with clones generated from the CBZ-naive HLA-B*1502 positive subject (Fig 2). Collectively, these data show that CBZ can activate clones without first needing to be metabolized.Fig 2Activation of T-cell clones (all CD8+) from a CBZ-naive subject with halogenated CBZ derivatives. Proliferation was measured by the addition of [3H]thymidine. Results show the maximum response seen with each CBZ derivative (2-bromo CBZ was not available for studies with the naive subject). Data as mean ± SD. The Mann-Whitney test was used to compare proliferation in the presence and absence of antigen.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Although the maximal response was lower with the halogenated derivatives, 11 of 17 clones were clearly activated by at least 2 of the monohalogenated CBZ derivatives. The dihalogenated derivatives displayed more limited cross-reactivity; only 3 clones were activated to proliferate with 2,8-dibromo CBZ. To interpret these data, one needs to appreciate the effects of halogen substitution on drug disposition. Fluorine and hydrogen have only slight differences in their size (van der Walls radius: fluorine, 1.47 Å; hydrogen, 1.57 Å); however, they have very different electronic properties, resulting in a change in the electron distribution in a molecule. Furthermore, fluorine forms an extremely strong bond with carbon, which is usually resistant to hydroxylation. As such, fluorine substitution is an effective strategy to block metabolic activation. The carbon halogen bond length increases dramatically with the larger halogens, and as such chlorine and bromine introduce a significant steric effect at specific HLA molecules, which likely explains why only a small number of clones are activated with 2,8-dibromo CBZ. Based on this brief discussion and our recent findings discussed above, our data show that drug metabolism is not required for the activation of T cells with CBZ. Further work is however still needed to characterize the different pathways of drug-specific T-cell activation in patients exposed simultaneously to varying concentrations of drug, drug metabolites, and drug metabolite protein adducts. Exposure to carbamazepine (CBZ) is associated with rare, but severe immunologically mediated hypersensitivity reactions. CBZ-responsive CD4+ and CD8+ T lymphocytes have been isolated from patients presenting with reactions of varying severity and characterized in terms of immunologic function and drug cross-reactivity. Genome-wide association studies have shown linkage predisposition of severe CBZ-associated reactions with specific HLA alleles. For instance, HLA-B*15:02 predisposes to CBZ-induced Stevens-Johnson syndrome in Han Chinese and Asian subjects. In this patient group, CBZ-specific T-cell responses are HLA-B*15:02-restricted, providing evidence of the functional role of this HLA protein in determining disease pathogenesis. Furthermore, pre-prescription genotyping for HLA-B*15:02 is associated with a decrease in the incidence of CBZ-induced Stevens-Johnson syndrome.1Wei C.Y. Chung W.H. Huang H.W. Chen Y.T. Hung S.I. Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome.J Allergy Clin Immunol. 2012; 129: 1562-1569.e5Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 2Chen P. Lin J.J. Lu C.S. Ong C.T. Hsieh P.F. Yang C.C. et al.Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan.N Engl J Med. 2011; 364: 1126-1133Crossref PubMed Scopus (536) Google Scholar HLA-A*31:01 has recently been shown to be associated with a wider spectrum of CBZ hypersensitivity reactions in subjects of European/Japanese origin3McCormack M. Alfirevic A. Bourgeois S. Farrell J.J. Kasperaviciute D. Carrington M. et al.HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.N Engl J Med. 2011; 364: 1134-1143Crossref PubMed Scopus (713) Google Scholar; however, an interaction between CBZ and the HLA protein is yet to be characterized. The nature of the drug-derived antigenic determinants that interact with immunologic receptors remains an area of debate. The hapten theory stipulates that peptides irreversibly modified with drugs are antigenic determinants. In support of this theory, β-lactam albumin conjugates stimulate lymphocytes from hypersensitive subjects.4Whitaker P. Meng X. Lavergne S.N. El-Ghaiesh S. Monshi M. Earnshaw C. et al.Mass spectrometric characterization of circulating and functional antigens derived from piperacillin in patients with cystic fibrosis.J Immunol. 2011; 187: 200-211Crossref PubMed Scopus (95) Google Scholar The pharmacologic interaction hypothesis states that drug molecules interact directly with HLA molecules to activate T cells. Functional studies showing the rapid, processing independent activation of T cells by certain drugs supports this hypothesis.5Adam J. Eriksson K.K. Schnyder B. Fontana S. Pichler W.J. Yerly D. Avidity determines T-cell reactivity in abacavir hypersensitivity.Eur J Immunol. 2012; 42: 1706-1716Crossref PubMed Scopus (77) Google Scholar Recently, direct binding of the drugs abacavir and CBZ to specific HLA molecules has been shown to alter the peptide repertoire displayed on the surface of antigen-presenting cells,6Illing P.T. Vivian J.P. Dudek N.L. Kostenko L. Chen Z. Bharadwaj M. et al.Immune self-reactivity triggered by drug-modified HLA-peptide repertoire.Nature. 2012; 486: 554-558PubMed Google Scholar leading the authors to propose that endogenous peptides activate “drug”-specific T cells. CBZ is metabolized to more than 30 metabolites in human liver.7Pearce R.E. Vakkalagadda G.R. Leeder J.S. Pathways of carbamazepine bioactivation in vitro, I: characterization of human cytochromes P450 responsible for the formation of 2- and 3-hydroxylated metabolites.Drug Metab Dispos. 2002; 30: 1170-1179Crossref PubMed Scopus (109) Google Scholar Several cysteine reactive metabolites including a 2,3-substituted arene oxide, o-quinones, a carbonium ion, a carboxaldehyde, and an iminoquinone have been identified, each of which has the potential to modify protein and generate antigenic determinants for T cells. A recent attempt to elute and characterize CBZ-modified HLA-B*15:02 binding peptides by mass spectrometry proved unsuccessful,8Yang C.W. Hung S.I. Juo C.G. Lin Y.P. Fang W.H. Lu I.H. et al.HLA-B*1502-bound peptides: implications for the pathogenesis of carbamazepine-induced Stevens-Johnson syndrome.J Allergy Clin Immunol. 2007; 120: 870-877Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar prompting the authors to conclude that CBZ must interact directly with HLA-binding peptides to activate T cells. However, CBZ metabolite–derived protein adducts were not studied and the levels of CBZ metabolites formed in lymphocyte test systems is known to be extremely low and almost certainly below the limit of detection by conventional mass spectrometers. Thus, we have developed an alternative strategy to explore whether CBZ-responsive T cells are activated via a metabolism-independent pathway. Two series of derivatives of CBZ, namely, 2-monohalo and 2,8-dihalo compounds, were prepared and their ability to activate CBZ-responsive T-cell clones was explored. We have recently reported the routes of synthesis from benzohalogenated iminostilbenes and the effects of halogen substitution on the metabolism of CBZ in freshly isolated rat hepatocytes.9Elliott E.C. Regan S. Maggs J. Bowkett E. Parry L. Williams D. et al.Haloarene derivatives of carbamazepine with reduced bioactivation liabilities: 2-monohalo and 2,8-dihalo derivatives.J Med Chem. 2012; 55: 9773-9784Crossref PubMed Scopus (13) Google Scholar Importantly, none of the derivatives underwent dehalogenation and with the exception of 2-fluoro CBZ, aromatic hydroxylation via putative arene oxide intermediates was inhibited. CBZ-responsive T-cell clones were generated from a 74-year-old subject carrying the HLA risk allele A*31:01 who developed drug rash with eosinophilia and systemic symptoms (DRESS) 6 days after commencing drug treatment and a CBZ-naive subject carrying HLA-B*1502. Blood samples were obtained under ethics approval with specific consent. The serial dilution procedure used to generate clones was the same for both subjects.4Whitaker P. Meng X. Lavergne S.N. El-Ghaiesh S. Monshi M. Earnshaw C. et al.Mass spectrometric characterization of circulating and functional antigens derived from piperacillin in patients with cystic fibrosis.J Immunol. 2011; 187: 200-211Crossref PubMed Scopus (95) Google Scholar EBV-transformed B-cell lines were used as autologous antigen-presenting cells. To test the specificity of the clones, T cells (0.5 × 105) were incubated with antigen-presenting cells (0.1 × 105) and CBZ. After 48 hours, [3H]thymidine (0.5 μCi) was added and proliferation was measured by scintillation counting. CBZ-stimulated PBMCs from the CBZ-associated DRESS and HLA-B*15:02 positive CBZ-naive subject were serially diluted into 96-well plates at 0.1 to 1 cell per well and stimulated with PHA. Two hundred forty well-growing clones were tested for CBZ specificity. Of these, 75 were designated CBZ-responsive on the basis of their proliferative response profiles (CBZ-associated DRESS subject [n = 31]: 0, 6,668 ± 7,854 cpm; CBZ 100 μM, 29,609 ± 27,345 cpm; HLA-B*1502 positive subject [n = 44]: 0, 4,488 ± 5,077 cpm; CBZ 100 μM, 18,695 ± 14,280 cpm). In agreement with Wei et al,1Wei C.Y. Chung W.H. Huang H.W. Chen Y.T. Hung S.I. Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome.J Allergy Clin Immunol. 2012; 129: 1562-1569.e5Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar all CBZ-responsive clones from the drug-naive subject carrying HLA-B*15:02 were CD8+, while CBZ-responsive CD4+ and CD8+ clones were detected from the HLA-A31:01 positive patient with DRESS. Six CD4+ and 11 CD8+ well-growing clones were expanded to explore cross-reactivity with the halogenated derivatives in proliferation and cytokine release assays. IFN-γ ELIspot was selected to measure secreted cytokines as IFN-γ is the predominant cytokine released from CBZ-stimulated clones. The CBZ-specific proliferative response of clones from the CBZ-associated DRESS and HLA-B*1502 positive subject and cytokine release were concentration-dependent. Subsequent experiments were performed with equivalent molar concentrations of CBZ and the halogenated derivatives. Clones from the CBZ-associated DRESS patient displayed a range of cross-reactivity patterns with the halogenated derivatives. Fig 1, A, depicts the proliferative response profile of a panel of clones highlighting the various patterns observed. Fig 1, B, shows a representative clone secreting IFN-γ following drug stimulation. The pattern of cross-reactivity with the different CBZ derivatives was similar when the 2 readouts were compared. A similar pattern of cross-reactivity was observed with clones generated from the CBZ-naive HLA-B*1502 positive subject (Fig 2). Collectively, these data show that CBZ can activate clones without first needing to be metabolized. Although the maximal response was lower with the halogenated derivatives, 11 of 17 clones were clearly activated by at least 2 of the monohalogenated CBZ derivatives. The dihalogenated derivatives displayed more limited cross-reactivity; only 3 clones were activated to proliferate with 2,8-dibromo CBZ. To interpret these data, one needs to appreciate the effects of halogen substitution on drug disposition. Fluorine and hydrogen have only slight differences in their size (van der Walls radius: fluorine, 1.47 Å; hydrogen, 1.57 Å); however, they have very different electronic properties, resulting in a change in the electron distribution in a molecule. Furthermore, fluorine forms an extremely strong bond with carbon, which is usually resistant to hydroxylation. As such, fluorine substitution is an effective strategy to block metabolic activation. The carbon halogen bond length increases dramatically with the larger halogens, and as such chlorine and bromine introduce a significant steric effect at specific HLA molecules, which likely explains why only a small number of clones are activated with 2,8-dibromo CBZ. Based on this brief discussion and our recent findings discussed above, our data show that drug metabolism is not required for the activation of T cells with CBZ. Further work is however still needed to characterize the different pathways of drug-specific T-cell activation in patients exposed simultaneously to varying concentrations of drug, drug metabolites, and drug metabolite protein adducts. We thank the CDSS nurses who helped to collect samples, as well as the patient who participated in the project." @default.
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• W2044141570 title "Activation of carbamazepine-responsive T-cell clones with metabolically inert halogenated derivatives" @default.
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