Potent NLRP3 inflammasome activation by the HIV reverse-transcriptase inhibitor abacavir

What is it about?

Problem: Drug administration can lead to unpredictable hypersensitivity responses that in the worst case scenario can result in life-threatening adverse events. Frequently a T cell-mediated delayed-type response directed against the culprit drug is responsible for elicitation of drug-hypersensitivity. Yet, it is currently unclear which factors drive the formation of reactive T cells in delayed-type drug allergy. In particular, it is unknown if a directly drug-associated activation of the innate immune system is involved. Results: Using the well-characterized HIV-1 reverse transcriptase inhibitor abacavir as exemplary stimulus we show here that a drug inducing T-cell mediated delayed-type hypersensitivity can potently trigger activation of the inflammasome, an innate immune receptor complex responsible for proteolytic cleavage and release of the key proinflammatory cytokine interleukin-1ß. We demonstrate that abacavir-induced inflammasome activation is associated with drug-induced cytotoxicity and generation of mitochondrial reactive oxygen species that together with IL-1ß release may be interpreted by the immune system as danger signal to which it responds by generation of drug-responsive T cells and mounting of an adaptive immune response.

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Why is it important?

Our data suggest that drug administration may result in direct or indirect innate immune activation, which might contribute to sensitization for medication-associated hypersensitivity and be of predicative value to judge the allergenic potential of new drugs. Our results warrant routine testing of new substances for the induction of innate immune activation in cell-based assays as standard procedure in pre-clinical development to identify potentially allergenic substances at an early stage.