T cell recognition of penicillin G: Structural features determining antigenic specificity

Padovan, Elisabetta; Mauri-Hellweg, D; Pichler, Werner J.; Weltzien, Hans Ulrich

doi:10.1002/eji.1830260107

Cited by 114 publications

(76 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In delayed allergy to aminopenicillins, both the b-lactam core structure and the whole molecule (core structure and the amino-benzyl group of the side chain) are recognized by T cells (54,55). However, the amino-benzyl group plays a predominant role: more than 70% of patients with such hypersensitivity display negative responses to BP in intradermal and/or patch tests (32,33,37,42,46).…”

Section: Patch Testingmentioning

confidence: 99%

Diagnosis of nonimmediate reactions to β‐lactam antibiotics

Romano

Blanca

Torres

et al. 2004

Allergy

324

368

View full text Add to dashboard Cite

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.

show abstract

Section: Patch Testingmentioning

confidence: 99%

Diagnosis of nonimmediate reactions to β‐lactam antibiotics

Romano

Blanca

Torres

et al. 2004

Allergy

324

368

View full text Add to dashboard Cite

show abstract

“…Such T cell-mediated sensitization to certain drugs has been detected by epicutaneous testing, lymphocytetransformation tests (LTTs), and generation of T-cell lines (TCLs) and clones (TCCs) (9)(10)(11)(12)(13). They are due to drugs such as aminopenicillins, which represent typical haptens able to covalently modify peptides and proteins (13,14). However, cutaneous T-cell reactions might also be elicited by a direct recognition of drugs that bind to the MHC-peptide complex in a noncovalent way (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

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

Britschgi¹,

Steiner²,

Schmid³

et al. 2001

J. Clin. Invest.

Self Cite

331

287

View full text Add to dashboard Cite

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...

show abstract

“…It is thought that drugs activate T cells by covalent modification of protein generating novel antigenic determinants (2,3,(7)(8)(9). However, the paucity of studies that define the chemistry of drug-protein binding in patients has severely restricted mechanistic studies that relate the chemistry of Ag formation to immune function.…”

mentioning

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

View full text Add to dashboard Cite

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.

show abstract

T cell recognition of penicillin G: Structural features determining antigenic specificity

Cited by 114 publications

References 25 publications

Diagnosis of nonimmediate reactions to β‐lactam antibiotics

Diagnosis of nonimmediate reactions to β‐lactam antibiotics

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

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

Contact Info

Product

Resources

About