Burkhart, Christoph;
Von Greyerz, Salome;
Depta, Jan P H;
Naisbitt, Dean J;
Britschgi, Markus;
Park, Kevin B;
Pichler, Werner J
Influence of reduced glutathione on the proliferative response of sulfamethoxazole‐specific and sulfamethoxazole‐metabolite‐specific human CD4+ T‐cells
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Media type:
E-Article
Title:
Influence of reduced glutathione on the proliferative response of sulfamethoxazole‐specific and sulfamethoxazole‐metabolite‐specific human CD4+ T‐cells
Contributor:
Burkhart, Christoph;
Von Greyerz, Salome;
Depta, Jan P H;
Naisbitt, Dean J;
Britschgi, Markus;
Park, Kevin B;
Pichler, Werner J
imprint:
Wiley, 2001
Published in:British Journal of Pharmacology
Language:
English
DOI:
10.1038/sj.bjp.0703845
ISSN:
0007-1188;
1476-5381
Origination:
Footnote:
Description:
<jats:p>
<jats:list list-type="explicit-label">
<jats:list-item><jats:p>Hypersensitivity to the drug sulfamethoxazole (SMX) is thought to be a consequence of bioactivation to the hydroxylamine metabolite (SMX‐NHOH) and further oxidation to the ultimate reactive metabolite, nitroso‐sulfamethoxazole (SMX‐NO). SMX‐NO covalently modifies self proteins which in turn might be recognized as neo‐antigens by T‐cells. The antioxidant glutathione (GSH) is known to protect cells from reactive metabolites by conjugation and subsequent dissociation to SMX‐NHOH and/or SMX.</jats:p></jats:list-item>
<jats:list-item><jats:p>To study the reactivity of T‐cells to SMX metabolites and their respective role in the generation of drug‐specific T‐cells, we analysed the effect of GSH on the response of PBMC to SMX and its metabolites SMX‐NHOH and SMX‐NO. Furthermore, we monitored the proliferative response of drug‐specific T‐cell clones in the presence or absence of GSH.</jats:p></jats:list-item>
<jats:list-item><jats:p>We found that addition of GSH to peripheral blood mononuclear cells had no effect on the SMX‐specific response but enhanced the proliferation to SMX‐metabolites. The response of SMX‐NO‐specific T‐cell clones was abrogated when GSH was present during the covalent haptenation of antigen presenting cells (APC). Conversely, SMX‐specific T‐cell clones gained reactivity through the conversion of SMX‐NO to the parent drug by GSH. While GSH had no effect on the initial activation of T‐cell clones, it prevented covalent binding to APCs, reduced toxicity and thereby led to proliferation of drug‐specific T‐cells to non‐reactive drug metabolites.</jats:p></jats:list-item>
<jats:list-item><jats:p>Our data support the concept that in allergic individuals T‐cells recognize the non‐covalently bound parent drug rather than APC covalently modified by SMX‐NO.</jats:p></jats:list-item>
</jats:list>
</jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2001) <jats:bold>132</jats:bold>, 623–630; doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0703845">10.1038/sj.bjp.0703845</jats:ext-link></jats:p>