Pharmacology for Immunity – Drug Classes That Target T-Cell Activation

week 1, pt. 2

Drug Classes That Target T-Cell Activation

• Calcineurin Inhibitors

• Co-Stimulation Blockers

• IL-2 Receptor Blockers

Co-Stimulation Blockers – Mechanism of Action – Abatacept

T-cell activation requires 2 signals: antigen recognition & co-stimulation. Abatacept binds CD80/86 on antigen-presenting cells. Prevention interaction with CD28 on T-cells.

= prevents full T-cell activation & reduces cytokine production

Co-Stimulation Blockers – Indications – Abatacept

Rheumatoid arthritis (moderate-severe)

Juvenile idiopathic arthritis

Psoriatic arthritis

Co-Stimulation Blockers – Adverse Effects – Abatacept

• Increased risk of infection (serious, respiratory, TB reactivation)

• Infusion/hypersensitivity reactions

• Headache

• Possible malignancy risk

Co-Stimulation Blockers – Safety – Abatacept

• Avoid combination with other biologic immunosuppressants → increase infection risk

• Caution with other immunosuppressants

• Decreased vaccine response

Co-Stimulation Blockers – Contraindications – Abatacept

• Active serious infection

• Screen for latent TB before starting

• Live vaccines

Calcineurin Inhibitors (e.g., Cyclosporine, Tacrolimus) – Mechanism of Action

• Inhibits calcineurin = decreased IL-2 production

→ Prevents T-cell activation & proliferation

Calcineurin Inhibitors – Indications

• Organ transplant rejection prevention

• Treatment of autoimmune disease (e.g., rheumatoid arthritis, lupus, psoriasis).

Calcineurin Inhibitors – Adverse Effects

• Nephrotoxicity

• Hypertension

• Hyperkalemia

• Neurotoxicity (tremor, headache)

• Increased infection risk

Calcineurin Inhibitors – Drug Interactions

• CYP3A4 inhibitors (e.g., grapefruit juice) → increase drug levels = toxicity

• CYP3A4 inducers (e.g., phenytoin, rifampin) → decrease drug levels = decreased efficacy

• Nephrotoxic drugs (e.g., NSAIDs) → increase kidney injury

Calcineurin Inhibitors – Contraindications

• Uncontrolled HTN

• Significant renal impairment

• Active serious infection

• Live vaccines

IL-2 Receptor Blockers (e.g., basiliximab) – Mechanism of Action

• Binds IL-2 receptor (CD25) on activated T cells

• → Blocks IL-2 signalling

• → Inhibits T-cell proliferation & expansion

IL-2 Receptor Blockers – Indications

• Prevention of acute transplant rejection

IL-2 Receptor Blockers – Adverse Effects

• Increased risk of infection

• Hypersensitivity reactions

• Possible increased risk of malignancy

IL-2 Receptor Blockers – Drug Interactions

• Additive immunosuppression with other immunosuppressants → increase infection risk

• Decrease vaccine response (especially inactivated vaccines)

IL-2 Receptor Blockers – Contraindications

• Active serious infection

• Live vaccines