1 research outputs found
β‑Lactam Antibiotics Form Distinct Haptenic Structures on Albumin and Activate Drug-Specific T‑Lymphocyte Responses in Multiallergic Patients with Cystic Fibrosis
β-Lactam
antibiotics provide the cornerstone of treatment
for respiratory exacerbations in patients with cystic fibrosis. Unfortunately,
approximately 20% of patients develop multiple nonimmediate allergic
reactions that restrict therapeutic options. The purpose of this study
was to explore the chemical and immunological basis of multiple β-lactam
allergy through the analysis of human serum albumin (HSA) covalent
binding profiles and T-cell responses against 3 commonly prescribed
drugs; piperacillin, meropenem, and aztreonam. The chemical structures
of the drug haptens were defined by mass spectrometry. Peripheral
blood mononuclear cells (PBMC) were isolated from 4 patients with
multiple allergic reactions and cultured with piperacillin, meropenem,
and aztreonam. PBMC responses were characterized using the lymphocyte
transformation test and IFN-γ /IL-13 ELIspot. T-cell clones
were generated from drug-stimulated T-cell lines and characterized
in terms of phenotype, function, and cross-reactivity. Piperacillin,
meropenem, and aztreonam formed complex and structurally distinct
haptenic structures with lysine residues on HSA. Each drug modified
Lys190 and at least 6 additional lysine residues in a time- and concentration-dependent
manner. PBMC proliferative responses and cytokine release were detected
with cells from the allergic patients, but not tolerant controls,
following exposure to the drugs. 122 CD4+, CD8+, or CD4+CD8+ T-cell
clones isolated from the allergic patients were found to proliferate
and release cytokines following stimulation with piperacillin, meropenem,
or aztreonam. Cross-reactivity with the different drugs was not observed.
In conclusion, our data show that piperacillin-, meropenem-, and aztreonam-specific
T-cell responses are readily detectable in allergic patients with
cystic fibrosis, which indicates that multiple β-lactam allergies
are instigated through priming of naïve T-cells against the
different drug antigens. Characterization of complex haptenic structures
on distinct HSA lysine residues provides a chemical basis for the
drug-specific T-cell response