Evidence for a role for IL-5 and eotaxin in activating and recruiting eosinophils in drug-induced cutaneous eruptions

Yawalkar, Nikhil; Shrikhande, M.; Hari, Yvonne; Nievergelt, Helga; Braathen, Lasse R.; Pichler, Werner J.

doi:10.1067/mai.2000.110922

Cited by 122 publications

(109 citation statements)

References 25 publications

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“…The cytokine profile associated with a particular reaction determines the nature of the induced immune response (1, 38-42). Ag (43,44), was not seen in piperacillin-hypersensitive patients, and this may relate to the absence of eosinophilia as a clinical feature. The detection of IL-1b, TNF-a, and IL-6 in culture supernatant containing piperacillin-stimulated PBMCs from hypersensitive patients and tolerant controls (albeit to a lesser extent) are suggestive of a dendritic cell response against piperacillin, as has recently been described with amoxicillin (45,46).…”

Section: Discussionmentioning

confidence: 99%

Mass Spectrometric Characterization of Circulating and Functional Antigens Derived from Piperacillin in Patients with Cystic Fibrosis

Whitaker

Meng

Lavergne

et al. 2011

The Journal of Immunology

100

142

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A mechanistic understanding of the relationship between the chemistry of drug antigen formation and immune function is lacking. Thus, mass spectrometric methods were employed to detect and fully characterize circulating antigens derived from piperacillin in patients undergoing therapy and the nature of the drug derived-epitopes on protein which can function as an antigen to stimulate T-cells. Albumin modification with piperacillin in vitro resulted in the formation of two distinct haptens, one formed directly from piperacillin and a second in which the dioxopiperazine ring had undergone hydrolysis. Modification was time- and concentration-dependent, with selective modification of Lys541 observed at low concentrations, whereas at higher concentrations up to 13/59 lysine residues were modified, four of which (Lys190, 195, 432 and 541) were detected in patients’ plasma. Piperacillin-specific T-lymphocyte responses (proliferation, cytokines and granzyme-B release) were detected ex vivo with cells from hypersensitive patients, and analysis of incubation medium showed that modification of the same lysine residues in albumin occurred in situ. The antigenicity of piperacillin-modified albumin was confirmed by stimulation of T-cells with characterized synthetic conjugates. Analysis of minimally-modified T-cell stimulatory albumin conjugates revealed peptide sequences incorporating Lys190, 432 and 541 as principal functional epitopes for T-cells. This study has characterized the multiple haptenic structures on albumin in patients, and showed that they constitute functional antigenic determinants for T-cells.

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Section: Discussionmentioning

confidence: 99%

Mass Spectrometric Characterization of Circulating and Functional Antigens Derived from Piperacillin in Patients with Cystic Fibrosis

Whitaker

Meng

Lavergne

et al. 2011

The Journal of Immunology

100

142

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“…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).…”

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confidence: 99%

“…In addition, immunohistochemistry was performed of skin biopsy specimens from the acute lesions as well as from the positive epicutaneous test reactions at 48 hours (patients AP and JS). The biopsy specimens were snapfrozen in tissue-embedding medium using isopentane precooled in liquid nitrogen and stored at -80°C.Immunostaining for IL-5 and RANTES was performed using the alkaline phosphatase anti-alkaline phosphatase (APAAP) method (D0651; Diagnostics AG, Zug, Switzerland) and for CD4, CD8, CD25, human leukocyte antigen-DR (HLA-DR), neutrophil elastase, EG2, eotaxin, and IL-8 using the avidin-biotin complex/alkaline phosphatase method (K0376; Diagnostics AG), as described previously in detail (8,19). Finally, all sections were developed in fuchsin substrate-chromogen (K0624; Diagnostics AG) and counterstained with hematoxylin (Haemalaun; Dr. Grogg Chemie AG, Stettlen, Switzerland).…”

mentioning

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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“…In MPE or DRESS an increase has also been found in IL-5 and chemokines such as RANTES and eotaxins, which explains the involvement of eosinophils expressing CCR3 (Hertl et al, 1993). In AGEP, another severe delayed drug-induced reaction, lymphocytes have a dual role as cytotoxic agents and inducing migration of neutrophils to the skin by producing IL-8 (Britschgi & Pichler, 2002;Hertl et al, 1993;Padial et al, 2004;Yawalkar et al, 2000). At the acute phase of TEN, T cells are recruited to the skin, producing cytotoxic markers such as perforin and granzyme B (Fernandez et al, 2010;Mayorga et al, 2003;Pichler, 2003;Posadas et al, 2002;Torres et al, 2006;Zawodniak et al, 2010), and they express high levels of CCR10 and their chemokine CCL27 .…”

Section: Monitoring Delayed Reaction To Drugsmentioning

confidence: 99%

“…Different studies have shown the good sensitivity and specificity of the LTT, with heterogeneity in the drugs and clinical entities (Luque et al, 2001;Naisbitt et al, 2003aNaisbitt et al, , 2003bNyfeler & Pichler, 1997;. The most frequent drugs studied are beta-lactam antibiotics and anti-epileptics, particularly carbamazepine (Hertl et al, 1993;Luque et al, 2001;Mauri-Hellweg et al, 1995;Nyfeler & Pichler, 1997;Tapia et al, 2004;Yawalkar et al, 2000). These studies have shown an overall sensitivity of 60-70% for LTT (Lerch et al, 2007;Luque et al, 2001;Mauri-Hellweg et al, 1995;Pichler & Tilch, 2004).…”

Section: Lymphocyte Transformation Testmentioning

confidence: 99%