QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.107.043273v1 73/6/1769    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cheng, L. Articles by Ju, C. Search for Related Content PubMed PubMed Citation Articles by Cheng, L. Articles by Ju, C.

Covalent Binding of the Nitroso Metabolite of Sulfamethoxazole Is Important in Induction of Drug-Specific T-Cell Responses in Vivo

Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado (L.C., B.J.S., Q.Y., D.R.P., C.J.); Pfizer Global Research and Development, Groton, Connecticut (J.A.W., J.R.P., T.T.K.)

Immune-mediated drug hypersensitivity reactions (IDHRs) represent a significant problem due to their unpredictable and severe nature, as well as the lack of understanding of the pathogenesis. Sulfamethoxazole (SMX), a widely used antibiotic, has been used as a model compound to investigate the underlying mechanism of IDHRs because it has been associated with a relatively high incidence of hypersensitivity. Previous studies by others showed that administration of 4-(nitroso)-N-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide (SMX-NO), the reactive metabolite of SMX, to rats resulted in the generation of SMX-specific antibodies and ex vivo splenocyte proliferative responses, as well as haptenation of skin keratinocytes, circulating peripheral blood mononuclear cells, and splenocytes. The objective of the present study was to further investigate SMX-NO-protein binding in relationship to its immunogenicity. In female DBA/1 mice treated with SMX-NO, varying degrees of SMX-NO-dependent T-cell responses and SMX-NO-protein adduct formation were observed in the spleen and in inguinal, brachial, and axillary lymph nodes. The data suggested a tissue-specific threshold of SMX-NO dosage that triggers the detection of adducts and immune response. Furthermore, serum albumin and immunoglobulin were identified as protein targets for SMX-NO modification. It seemed that these adducts were formed in the blood, circulated to lymphoid tissues, and initiated SMX-NO-dependent immune responses. Collectively, these data revealed a causal link between the deposition of SMX-NO-protein adducts in a lymphoid tissue and the induction of immune response in that tissue. Our findings also suggest that the immunogenicity of SMX-NO is determined by the immunogenic nature of the hapten, rather than special characteristics of the adducted protein.

Address correspondence to: Dr. Cynthia Ju, Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, 4200 East 9th Ave., Denver, CO 80262. E-mail: cynthia.ju{at}uchsc.edu

This article has been cited by other articles:

				M. E. Falagas, P.-E. Valkimadi, Y.-T. Huang, D. K. Matthaiou, and P.-R. Hsueh Therapeutic options for Stenotrophomonas maltophilia infections beyond co-trimoxazole: a systematic review J. Antimicrob. Chemother., November 1, 2008; 62(5): 889 - 894. [Abstract] [Full Text] [PDF]