Abstract
Type B adverse drug reactions (ADRs) are unpredictable based on the drug’s pharmacology and represent a key challenge in pharmacovigilance. For human leukocyte antigen (HLA)-mediated type B ADRs, it is assumed that the protein/small-molecule interaction alters the biophysical and mechanistic properties of the antigen presenting cells. Sophisticated methods enabled the molecular appreciation of HLA-mediated ADRs; in several instances, the drug molecule occupies part of the HLA peptide binding groove and modifies the recruited peptide repertoire thereby causing a strong T-cell-mediated immune response that is resolved upon withdrawal of medication. The severe ADR in HLA-B*57:01+ patients treated with the antiretroviral drug abacavir (ABC) in anti-HIV therapy is an example of HLA-drug-T cell cooperation. However, the long-term damages of the HLA-B*57:01-expressing immune cells following ABC treatment remain unexplained. Utilizing full proteome sequencing following ABC treatment of HLA-B*57:01+ cells, we demonstrate stringent proteomic alteration of the HLA/drug presenting cells. The proteomic content indisputably reflects the cellular condition; this knowledge directs towards individual pharmacovigilance for the development of personalized and safe medication.
Highlights
Adverse drug reactions (ADRs) are harmful and unintended reactions triggered by a drug used in the prevention, diagnosis or therapy of diseases at suitable pharmacological dosage [1]
For human leukocyte antigen (HLA)-mediated type B adverse drug reactions (ADRs), it is assumed that the protein/small-molecule interaction alters the biophysical and mechanistic properties of the antigen presenting cells
Sophisticated methods enabled the molecular appreciation of HLA-mediated ADRs; in several instances, the drug molecule occupies part of the HLA peptide binding groove and modifies the recruited peptide repertoire thereby causing a strong T-cell-mediated immune response that is resolved upon withdrawal of medication
Summary
Adverse drug reactions (ADRs) are harmful and unintended reactions triggered by a drug used in the prevention, diagnosis or therapy of diseases at suitable pharmacological dosage [1]. They occur despite proper application of the respective drug and are classified as type A and type B reactions based on their pharmacological predictability [2]. Type B reactions are not predictable based on the drug’s pharmacology and seem to be idiosyncratic Both the innate and the adaptive immune system can be involved in the development of an idiosyncratic ADR; they occur especially in patients with a certain predisposition and result in high mortalities [5,6]. Manifestations comprise cutaneous symptoms ranging from milder exanthema to life-threatening Stevens–Johnson Syndrome (SJS) or toxic epidermal necrolysis (TEN), yet liver, kidney and blood cells might be affected as well [7]
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