What’s “hapten”-ing in β-lactam hypersensitivity?

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Science Translational Medicine  03 May 2017:
Vol. 9, Issue 388, eaan3774
DOI: 10.1126/scitranslmed.aan3774


Piperacillin binding to proteins can but does not always induce a hypersensitivity reaction.

β-lactam antibiotics are a first-line therapy for many bacterial infections. Hypersensitivity reactions, characterized by rash and fever, develop in certain people while they are receiving β-lactam antibiotics, such as piperacillin. Hypersensitivity to β-lactams is an immune response to β-lactam (hapten) irreversibly bound to protein (carrier). After it is processed, the β-lactam-protein complex can activate T cells.

In a recent paper from Meng et al. investigated the dynamics of T cell proliferation in response to natural and engineered piperacillin-protein complexes. These studies focused on human serum albumin as a protein carrier. The hapten piperacillin binds to albumin at lysine residues, in particular, Lys541. Initial studies examined piperacillin-albumin complexes isolated from the blood of 10 people before and after 14 days of piperacillin treatment, and from 3 people at the time they developed piperacillin hypersensitivity reactions. Interestingly, the fraction of albumin with piperacillin-bound Lys541 was not significantly different between people with or without hypersensitivity. This suggests that piperacillin-albumin complexes alone are not sufficient to induce a hypersensitivity reaction to piperacillin.

T cell clones generated from patients with piperacillin hypersensitivity expressed chemokine receptors CCR4, CCR9, CCR10, and CXCR3 and could be activated by piperacillin. Increasing concentrations of piperacillin resulted in increased frequency of piperacillin-bound Lys541, and this modification was detectable sooner with higher concentrations of piperacillin. A separate population of T cell clones was generated by activating peripheral blood mononuclear cells with engineered piperacillin-albumin complexes. Proliferation of these clones increased as the degree of piperacillin-albumin modification increased and was increased when compared with piperacillin alone. These T cell clones responsive to piperacillin-albumin complexes did not activate in response to amoxicillin or penicillin bound to albumin, even though the β-lactam-albumin modifications occur at similar lysine residues. It is unclear why the piperacillin-albumin complexes generated a hypersensitivity reaction in only a subset of patients in this study. Further research is needed to understand the steps in developing piperacillin hypersensitivity, particularly how the hapten-carrier complex is processed and presented to T cells in people at risk for hypersensitivity.

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