Characterization of T-Cell Responses to SMX and SMX-NO in Co-Trimoxazole Hypersensitivity Patients Expressing HLA-B*13:01.

Abstract

HLA-B*13:01-positive patients in Thailand can develop frequent co-trimoxazole hypersensitivity reactions. This study aimed to characterize drug-specific T cells from three co-trimoxazole hypersensitive patients presenting with either Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms. Two of the patients carried the HLA allele of interest, namely HLA-B*13:01. Sulfamethoxazole and nitroso sulfamethoxazole specific T cell clones were generated from T cell lines of co-trimoxazole hypersensitive HLA-B*13:01-positive patients. Clones were characterized for antigen specificity and cross-reactivity with structurally related compounds by measuring proliferation and cytokine release. Surface marker expression was characterized via flow cytometry. Mechanistic studies were conducted to assess pathways of T cell activation in response to antigen stimulation. Peripheral blood mononuclear cells from all patients were stimulated to proliferate and secrete IFN-γ with nitroso sulfamethoxazole. All sulfamethoxazole and nitroso sulfamethoxazole specific T cell clones expressed the CD4+ phenotype and strongly secreted IL-13 as well as IFN-γ, granzyme B and IL-22. No secretion of IL-17 was observed. A number of nitroso sulfamethoxazole-specific clones cross-reacted with nitroso dapsone but not sulfamethoxazole whereas sulfamethoxazole specific clones cross-reacted with nitroso sulfamethoxazole only. The nitroso sulfamethoxazole specific clones were activated in both antigen processing-dependent and -independent manner, while sulfamethoxazole activated T cell responses via direct HLA binding. Furthermore, activation of nitroso sulfamethoxazole-specific, but not sulfamethoxazole-specific, clones was blocked with glutathione. Sulfamethoxazole and nitroso sulfamethoxazole specific T cell clones from hypersensitive patients were CD4+ which suggests that HLA-B*13:01 is not directly involved in the iatrogenic disease observed in co-trimoxazole hypersensitivity patients.

• Authors: Jirawat Pratoomwun, Paul Thomson, Kanoot Jaruthamsophon, Rawiporn Tiyasirichokchai, Pimonpan Jinda, Ticha Rerkpattanapipat, Wichittra Tassaneeyakul, Nontaya Nakkam, Pawinee Rerknimitr, Jettanong Klaewsongkram, Yuttana Srinoulprasert, Munir Pirmohamed, Dean J Naisbitt, Chonlaphat Sukasem
• Journal: Frontiers in immunology (Front Immunol) Vol. 12 Pg. 658593 ( 2021) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 33995375 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Pratoomwun, Thomson, Jaruthamsophon, Tiyasirichokchai, Jinda, Rerkpattanapipat, Tassaneeyakul, Nakkam, Rerknimitr, Klaewsongkram, Srinoulprasert, Pirmohamed, Naisbitt and Sukasem.

Chemical References

• HLA-B13 Antigen
• Histocompatibility Antigens Class II
• Trimethoprim, Sulfamethoxazole Drug Combination

Topics

• Adult
• Antigen Presentation (immunology)
• Antigen-Presenting Cells (immunology, metabolism)
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• Cells, Cultured
• Drug Hypersensitivity (etiology, metabolism)
• Female
• Gene Expression
• HLA-B13 Antigen (genetics, immunology)
• Histocompatibility Antigens Class II (genetics, immunology)
• Humans
• Leukocytes, Mononuclear (immunology, metabolism)
• Lymphocyte Activation (genetics, immunology)
• Male
• T-Cell Antigen Receptor Specificity
• T-Lymphocytes (immunology, metabolism)
• Trimethoprim, Sulfamethoxazole Drug Combination (adverse effects)