Pembrolizumab, an anti-PD-1 monoclonal antibody, causes immune-related adverse events (irAEs) because:
- A PD-1 blockade activates NK cells that destroy self-antigen-expressing cells in thyroid, gut, and skin
- B Anti-PD-1 antibodies cross-react with PDL-1 on endothelial cells, causing complement-mediated vasculitis
- C PD-1 normally maintains peripheral immune tolerance by suppressing autoreactive T-cells; its blockade allows pre-existing autoreactive T-cell clones to attack normal tissues ✓
- D Pembrolizumab activates Treg cells that paradoxically release IL-17, causing autoimmune tissue damage
Explanation
The PD-1/PD-L1 checkpoint normally dampens T-cell activation in peripheral tissues to prevent autoimmunity — it is the 'immune brake.' Autoreactive T-cell clones exist in every individual but are kept in check by this and other regulatory mechanisms. Pembrolizumab (anti-PD-1) removes this brake, unleashing both anti-tumor T-cells AND pre-existing autoreactive T-cell clones that attack self-tissues. irAEs include: pneumonitis, colitis, hepatitis, thyroiditis, hypophysitis, dermatitis, nephritis, myocarditis (rarest but most lethal). Management involves systemic corticosteroids for grade 2+, and high-dose steroids ± steroid-sparing agents for severe irAEs.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.