T‐cell‐mediated cytotoxicity against keratinocytes in sulfamethoxazol‐induced skin reaction

Schnyder, Benno; Frutig, Karin; Mauri-Hellweg, D; Limat, Alain; Yawalkar, Nikhil; Pichler, Werner J.

doi:10.1046/j.1365-2222.1998.00419.x

Cited by 145 publications

(131 citation statements)

References 19 publications

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“…This ability was not dependent on pretreatment of the keratinocytes with IFN-c and was only partially inhibited by blockage of LFA-1/ICAM-1 interactions by an anti-LFA-1 antibody, suggesting that ICAM-1 co-stimulation by keratinocytes is less important for CD8 + T cell cytokine secretion than for CD4 + T cells. Previous studies have suggested that keratinocytes are susceptible to perforin and Fas-mediated cell lysis by drug and hapten-specific T cells [28,29]. We tested the susceptibility of adhered keratinocytes to lysis by CD8 + T cells specific for a known viral epitope.…”

Section: Discussionmentioning

confidence: 99%

Human keratinocyte induction of rapid effector function in antigen‐specific memory CD4⁺ and CD8⁺ T cells

et al. 2007

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The ability of human keratinocytes to present antigen to T cells is controversial and, indeed, it has been suggested that keratinocytes may promote T cell hyporesponsiveness. Furthermore, it is unclear whether keratinocytes can process antigen prior to MHC class I and class II presentation. We tested the ability of keratinocytes to induce functional responses in epitope-specific CD4 + and CD8 + memory T cells using peptides, protein and recombinant expression vectors as sources of antigen. Keratinocytes were able to efficiently process and present protein antigen to CD4 + T cells, resulting in cytokine secretion (Th1 and Th2). This interaction was dependent on keratinocyte expression of HLA class II and ICAM-1, which could be induced by IFN-c. In addition, keratinocytes could present virally encoded or exogenous peptide to CD8 + T cells, resulting in T cell cytokine production and target cell lysis. Finally, T cell lines grown using keratinocytes as stimulators showed no loss of function. These findings demonstrate that keratinocytes are able to efficiently process and present antigen to CD4 + and CD8 + memory T cells and induce functional responses. The findings have broad implications for the pathogenesis of cutaneous disease and for transcutaneous drug or vaccine delivery.

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Section: Discussionmentioning

confidence: 99%

Human keratinocyte induction of rapid effector function in antigen‐specific memory CD4⁺ and CD8⁺ T cells

et al. 2007

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“…The function of the drug-specific T cells from patients with AGEP seem to be heterogeneous: As in other drug-induced reactions, the degree of either CD4 or CD8 cell involvement, as well as the degree of activating CD4 + T cells with distinct functions (cytokine production), might determine the clinical picture (37,38). In AGEP, immunohistology as well as the characterization of TCCs revealed evidence for production of the potent PMN-attractive chemokine IL-8 by keratinocytes and drug-specific CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

T-cell involvement in drug-induced acute generalized exanthematous pustulosis

Britschgi¹,

Steiner²,

Schmid³

et al. 2001

J. Clin. Invest.

331

287

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Acute generalized exanthematous pustulosis (AGEP) is an uncommon eruption most often provoked by drugs, by acute infections with enteroviruses, or by mercury. It is characterized by acute, extensive formation of nonfollicular sterile pustules on erythematous background, fever, and peripheral blood leukocytosis. We present clinical and immunological data on four patients with this disease, which is caused by different drugs. An involvement of T cells could be implied by positive skin patch tests and lymphocyte transformation tests. Immunohistochemistry revealed a massive cell infiltrate consisting of neutrophils in pustules and T cells in the dermis and epidermis. Expression of the potent neutrophil-attracting chemokine IL-8 was elevated in keratinocytes and infiltrating mononuclear cells. Drug-specific T cells were generated from the blood and skin of three patients, and phenotypic characterization showed a heterogeneous distribution of CD4/CD8 phenotype and of T-cell receptor Vβ-expression. Analysis of cytokine/chemokine profiles revealed that IL-8 is produced significantly more by drug-specific T cells from patients with AGEP compared with drug-specific T cells from patients that had non-AGEP exanthemas. In conclusion, our data demonstrate the involvement of drug-specific T cells in the pathomechanism of this rather rare and peculiar form of drug allergy. In addition, they indicate that even in some neutrophil-rich inflammatory responses specific T cells are engaged and might orchestrate the immune reaction. T cells from the circulation (19,20) and an enhanced eotaxin production by endothelial cells and infiltrating T cells (19). Interestingly, previous studies in patients with AGEP have revealed a high rate of strongly positive patch tests to drugs compared with patients with other drug eruptions (21)(22)(23)(24). This suggests that T cells are involved in AGEP as well. They may contribute to the accumulation of polymorphonuclear neutrophils (PMN) at the site of the lesions by the preferential release of PMN-attractive chemokines, mainly CXC chemokines such as 26).To understand the function of T cells in AGEP patients we generated drug-specific TCLs and TCCs from the circulation and skin biopsy specimens and analyzed their phenotypes, specificities, and cytokine and chemokine profiles in vitro. Immunohistochemical analysis of the acute and patch-test lesions ex vivo was performed to determine the nature of the inflammatory cell infiltrate in vivo and to supplement the in vitro studies. The data point to an important role of drug-specific T cells in AGEP, which clearly exert distinct functions compared with other cutaneous drug eruptions. MethodsPatients. A summary of the patients' clinical characteristics is given in Table 1. Patient AP developed a generalized erythema after oral administration of Augmentin (amoxicillin and clavulanic acid; SmithKline Beecham Pharmaceuticals, Irvine, United Kingdom), which was given to treat an otitis media. She had fever (40°C) and developed pustules on the back, arms, and f...

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“…Immunohistological findings (4) as well as drug-specific T cell proliferation and T cell cytotoxicity in vitro (5,6) suggest that T lymphocytes are directly involved in these allergic reactions.…”

Section: Recognition Of Sulfamethoxazole and Its Reactive Metabolitesmentioning

confidence: 99%

“…Two years later, he suffered a generalized exanthem within 1 day of re-exposure to co-trimoxazole that persisted for several days. No specific IgE and IgG Abs against SMX or trimethoprim were detected, but the lymphocyte transformation test demonstrated strong T cell proliferation to SMX (6,11). The second allergic donor (KG) was a young pharmacist who developed allergic symptoms (exanthem) after being treated for a urinary tract infection with an unknown sulfonamide.…”

Section: Donor Characteristicsmentioning

confidence: 99%

Recognition of Sulfamethoxazole and Its Reactive Metabolites by Drug-Specific CD4+ T Cells from Allergic Individuals

Schnyder

Burkhart

Schnyder-Frutig

et al. 2000

The Journal of Immunology

201

204

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The recognition of the antibiotic sulfamethoxazole (SMX) by T cells is usually explained with the hapten-carrier model. However, recent investigations have revealed a MHC-restricted but processing- and metabolism-independent pathway of drug presentation. This suggested a labile, low-affinity binding of SMX to MHC-peptide complexes on APC. To study the role of covalent vs noncovalent drug presentation in SMX allergy, we analyzed the proliferative response of PBMC and T cell clones from patients with SMX allergy to SMX and its reactive oxidative metabolites SMX-hydroxylamine and nitroso-SMX. Although the great majority of T cell clones were specific for noncovalently bound SMX, PBMC and a small fraction of clones responded to nitroso-SMX-modified cells or were cross-reactive. Rapid down-regulation of TCR expression in T cell clones upon stimulation indicated a processing-independent activation irrespective of specificity for covalently or noncovalently presented Ag. In conclusion, our data show that recognition of SMX presented in covalent and noncovalent bound form is possible by the same TCR but that the former is the exception rather than the rule. The scarcity of cross-reactivity between covalently and noncovalently bound SMX suggests that the primary stimulation may be directed to the noncovalently bound SMX.

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T‐cell‐mediated cytotoxicity against keratinocytes in sulfamethoxazol‐induced skin reaction

Cited by 145 publications

References 19 publications

Human keratinocyte induction of rapid effector function in antigen‐specific memory CD4⁺ and CD8⁺ T cells

Human keratinocyte induction of rapid effector function in antigen‐specific memory CD4⁺ and CD8⁺ T cells

T-cell involvement in drug-induced acute generalized exanthematous pustulosis

Recognition of Sulfamethoxazole and Its Reactive Metabolites by Drug-Specific CD4+ T Cells from Allergic Individuals

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T‐cell‐mediated cytotoxicity against keratinocytes in sulfamethoxazol‐induced skin reaction

Cited by 145 publications

References 19 publications

Human keratinocyte induction of rapid effector function in antigen‐specific memory CD4+ and CD8+ T cells

Human keratinocyte induction of rapid effector function in antigen‐specific memory CD4+ and CD8+ T cells

T-cell involvement in drug-induced acute generalized exanthematous pustulosis

Recognition of Sulfamethoxazole and Its Reactive Metabolites by Drug-Specific CD4+ T Cells from Allergic Individuals

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Human keratinocyte induction of rapid effector function in antigen‐specific memory CD4⁺ and CD8⁺ T cells

Human keratinocyte induction of rapid effector function in antigen‐specific memory CD4⁺ and CD8⁺ T cells