Immune-mediated toxicity - Immune-mediated drug toxicity (HLA, hapten, p-i en altered repetoir)
14 important questions on Immune-mediated toxicity - Immune-mediated drug toxicity (HLA, hapten, p-i en altered repetoir)
What kind of adverse drug reactions belong under type B reactions?
- Idiosyncratic drug reactions.
- Unpredictable
- not related to its known pharmacological properties and occur in a small number of susceptible individuals.
What causes idiosyncratic drug reactions? (2) give examples
Biology - P450, UGT = patient specific.
What types of immune mediated drug toxicities do we have?
- Type I (immediate, IgE-mediated like anaphylaxis)
- Type II (cytotoxic, antibody-coated cells)
- Type III (immune complex-mediated, like serum sickness)
- Type IV (delayed, T-cell mediated, like rashes)
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Why does type IV take such a long time?
- Hapten concept involved.
- P-I concept can be involved
- Danger singals
Name an example of an HLA dependent immune-mediated drug allergy.
- Abacavir.
- Anti HIV drug
- Rash
- Infiltrating CD8 en CD4 in the skin => immune mediated
Welk concept is important in HLA dependent immune-mediated drug allergies?
Abacavir verandert het peptide-repertoire van HLA-B*57:01 door binding in de F-pocket, maar klinische hypersensitiviteit hangt ook af van TCR-repertoire, inflammatie, tolerantie, en biologische variatie. Daarom reageert 100% in vitro, maar slechts 55% klinisch. => iemand moet een reactive T-cel hebben die daar dan weer op reageert.
What is a danger signal?
- Endogenous molecules with altered expression or location due to tissue damage (DAMPs-Damage-Associated Molecular Patterns)
What are examples of Danger signals? (4). Where do these signals bind to?
- mtDNA
- Heat shock proteins
- S100 proteins
- Il-1
- High mobility group box 1 (HMGB1) chromosomal protein
Bind to TOLL LIKE receptors!
What kind of drugs are sensitive to hapten?
Flucloxacillin:
What is the difference between hapten and PI model?
- hapten= binding aan eiwit en dan opname door apc
- pi = direct binding aan HLA molecuul, no COVALENT binding met peptide. No processing with apc cell. Bind zowel aan de t-cel als aan het hla molecuul.
- Difference metabolism-dependent and independent antigenicity.
- To what belongs hapten?
- Sommige geneesmiddelen veroorzaken immuunreacties alleen na metabolische activatie → metabolism-dependent antigenicity
- Andere geneesmiddelen zijn direct reactief → metabolism-independent antigenicity
- HAPTEN = metabolism independent.
Negative regulation and tolerance mechanism.
- Negative regulation: cancer cells => inhibition of the immune system by the cancer cell. => Als PD-L1 bindt aan PD-1, krijgt de T‑cel een “stop”-signaal → T‑cel valt de kankercel niet aan. (dit is ook om je eigen cellen te beschermen)
- Dit hierboven is eigenlijk ook immune tolerance mechanisms
What is the pathway of carbamazepine?-
Which factors are involved in drug hypersensitivity? (3)
- Geno
- Pheno
- Drug
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