T Cells Isolated from Positive Epicutaneous Test Reactions to Amoxicillin and Ceftriaxone are Drug Specific and Cytotoxic

Yawalkar, Nikhil; Hari, Yvonne; Frutig, Karin; Egli, F; Wendland, Thomas; Braathen, Lasse R.; Pichler, Werner J.

doi:10.1046/j.1523-1747.2000.00105.x

Cited by 87 publications

(55 citation statements)

References 23 publications

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“…Identification of drug-specific T cells in the peripheral circulation and skin, at the time of the reaction, provides evidence that the immune system is involved in the development of clinical symptoms (Mauri-Hellweg et al, 1995;Schnyder et al, 1997;Yawalkar et al, 2000). Despite this, the nature of the drug antigen that stimulates hypersensitivity reactions is a matter of debate.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Sulfamethoxazole and Sulfamethoxazole Metabolite-Specific T-Cell Responses in Animals and Humans

Farrell

Naisbitt²,

Drummond³

et al. 2003

J Pharmacol Exp Ther

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Sulfamethoxazole (SMX) is associated with hypersensitivity reactions. Identification of drug-specific lymphocytes from hypersensitive patients suggests involvement of the immune system. Lymphocytes from humans recognize SMX and nitroso-SMX (SMX-NO), whereas cells from sensitized rats recognize only SMX-NO. In this investigation, we study the nature of SMXspecific T cells in four species. Male rats, mice, and rabbits were immunized with SMX (50 mg kg Ϫ1 ) or SMX-NO (1 mg kg Ϫ1 ). Lymphocytes and/or splenocytes were isolated and incubated with SMX, SMX-hydroxylamine or SMX-NO and proliferation were measured. Lymphocytes were also isolated from SMX-hypersensitive patients (n ϭ 3) and drug-specific proliferation was measured. In addition, rabbits were bled fortnightly for 4 months to determine whether SMX-NO-specific T cells cross-react with SMX. To confirm that SMX-NO responses were due to covalent binding and not cross-reactivity, cells were pulsed with SMX-NO and/or coincubated with glutathione. Splenocytes from mice, rats, and rabbits proliferated when stimulated with SMX-NO, but not SMX. A 2-h pulse with SMX-NO was sufficient for proliferation, whereas cells coincubated with SMX-NO and glutathione did not proliferate. Rabbit lymphocytes proliferated in the presence of SMX-NO and SMX-hydroxylamine, but not SMX. SMX-hydroxylamine was converted to SMX-NO in culture. The SMX-NO-specific response of rabbit lymphocytes was maintained for at least 4 months and the cells did not cross-react with SMX. Human lymphocytes from hypersensitive patients proliferated in the presence of SMX and both metabolites. These results highlight important differences in T-cell recognition of drug (metabolite) antigens in animals that have been sensitized against a drug metabolite and patients with hypersensitivity to the drug.

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Section: Discussionmentioning

confidence: 99%

Characterization of Sulfamethoxazole and Sulfamethoxazole Metabolite-Specific T-Cell Responses in Animals and Humans

Farrell

Naisbitt²,

Drummond³

et al. 2003

J Pharmacol Exp Ther

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“…Some 5-mm punch-biopsy specimens were obtained after 48 hours from the positive epicutaneous test reactions of patients AP, JS, and EB (Table 1). Drugspecific T cells were isolated and cloned as described previously in detail (31). The isolated cells were cultured in U-bottom 96-well plates in a final volume of 100 µl/well with 2.5 × 10 4 allogeneic irradiated PBMCs in CM enriched with 1 µg/ml PHA and 20 U/ml rIL-2 and expanded as described above.…”

Section: Methodsmentioning

confidence: 99%

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

Britschgi¹,

Steiner²,

Schmid³

et al. 2001

J. Clin. Invest.

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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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“…Of particular importance is the finding that elution of T cells from patch test lesions from two patients with bullous reactions to b-lactams revealed that about onethird of the infiltrating T cells were drug specific (52).…”

Section: Skin Testsmentioning

confidence: 96%

Diagnosis of nonimmediate reactions to β‐lactam antibiotics

Romano

Blanca

Torres

et al. 2004

Allergy

320

368

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Nonimmediate manifestations (i.e. occurring more than 1 h after drug administration), particularly maculopapular and urticarial eruptions, are common during β‐lactam treatment. The mechanisms involved in most nonimmediate reactions seem to be heterogeneous and are not yet completely understood. However, clinical and immunohistological studies, as well as analysis of drug‐specific T‐cell clones obtained from the circulating blood and the skin, suggest that a type‐IV (cell‐mediated) pathogenic mechanism may be involved in some nonimmediate reactions such as maculopapular or bullous rashes and acute generalized exanthematous pustulosis. In the diagnostic work‐up, the patient's history is fundamental; patch testing is useful, together with delayed‐reading intradermal testing. The latter appears to be somewhat more sensitive than patch testing, but also less specific. In case of negative allergologic tests, consideration should be given to provocation tests, and the careful administration of the suspect agents. With regard to in vitro tests, the lymphocyte transformation test may contribute to the identification of the responsible drug.Under the aegis of the European Academy of Allergology and Clinical Immunology (EAACI) interest group on drug hypersensitivity and the European Network for Drug Allergy (ENDA), in this review we describe the general guidelines for evaluating subjects with nonimmediate reactions to β‐lactams.

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T Cells Isolated from Positive Epicutaneous Test Reactions to Amoxicillin and Ceftriaxone are Drug Specific and Cytotoxic

Cited by 87 publications

References 23 publications

Characterization of Sulfamethoxazole and Sulfamethoxazole Metabolite-Specific T-Cell Responses in Animals and Humans

Characterization of Sulfamethoxazole and Sulfamethoxazole Metabolite-Specific T-Cell Responses in Animals and Humans

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

Diagnosis of nonimmediate reactions to β‐lactam antibiotics

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