Learning Objective
Differentiate immunosuppressant drugs used in transplant medicine based on their molecular target, mechanism of action, and major side effects.
Immunosuppressants Overview
These drugs block lymphocyte activation and proliferation, reducing acute transplant rejection by suppressing T-cell–mediated immunity. Often used in combinations to increase efficacy and reduce individual drug toxicity. Chronic use increases the risk of infection and malignancy.
Major Agents by Sites of Action
Calcineurin Inhibitors
Block IL-2 transcription → ↓ T-cell activation
Cyclosporine
Mechanism
- Binds cyclophilin
- Inhibits calcineurin
- ↓ IL-2 transcription
Major Toxicity
- Nephrotoxicity (dose-limiting)
- Hypertension
- Gingival hyperplasia
- Hirsutism
Tacrolimus (FK506)
Mechanism
- Binds FKBP
- Inhibits calcineurin
- ↓ IL-2 transcription
Major Toxicity
- Nephrotoxicity
- Neurotoxicity
(No gingival hyperplasia or hirsutism—unlike cyclosporine)
IL-2 Receptor Blocker
Basiliximab
Mechanism
- Monoclonal antibody against CD25 (IL-2R)
Major Toxicity
- Edema
- Hypertension
- Tremor
Used especially during transplantation induction.
mTOR Inhibitor
Sirolimus (Rapamycin)
Mechanism
- Binds FKBP
- Inhibits mTOR
- Blocks response to IL-2 → ↓ T-cell proliferation
Major Toxicity
- Pancytopenia
- Hyperlipidemia
- NOT nephrotoxic
Unique point
- Often used for renal transplants because the kidneys are already at risk.
Antimetabolites
Azathioprine
Mechanism
- Converted to 6-MP
- Inhibits purine synthesis
Major Toxicity
- Bone marrow suppression
- GI upset
- Worse toxicity with allopurinol
→ allopurinol inhibits XO → ↑ active metabolite levels
Mycophenolate mofetil
Mechanism
- Inhibits IMP dehydrogenase
- Blocks de novo purine synthesis in lymphocytes
Major Toxicity
- GI upset (diarrhea)
- Pancytopenia
- Hypertension
- Associated with CMV infection risk
Glucocorticoids
Mechanism
- Inhibit NF-κB signaling
- ↓ cytokine transcription
- Induce apoptosis of lymphocytes
Major Toxicity
- Cushingoid changes
- Osteoporosis
- Diabetes
- Hypertension
- Avascular necrosis
Summary
| Drug | Mechanism | Clinical Indications | Key Toxicities / Notes |
|---|---|---|---|
| Cyclosporine | Calcineurin inhibitor; binds cyclophilin, prevents IL-2 transcription → blocks T-cell activation | Solid organ transplant, psoriasis, RA | Nephrotoxicity, hypertension, hyperlipidemia, neurotoxicity, gingival hyperplasia, hirsutism |
| Tacrolimus (FK506) | Calcineurin inhibitor; binds FKBP, prevents IL-2 transcription → blocks T-cell activation | Immunosuppression after solid organ transplant | Nephrotoxicity, ↑ risk of diabetes, neurotoxicity; no gingival hyperplasia or hirsutism |
| Sirolimus (Rapamycin) | mTOR inhibitor; binds FKBP → blocks response to IL-2 → inhibits T- and B-cell proliferation | Kidney transplant prophylaxis, drug-eluting stents | Pancytopenia, insulin resistance, hyperlipidemia; not nephrotoxic; synergistic with cyclosporine |
| Basiliximab | Monoclonal antibody against CD25 (IL-2 receptor) → blocks T-cell activation | Kidney transplant prophylaxis | Edema, hypertension, tremor |
| Azathioprine | Antimetabolite; prodrug of 6-MP → inhibits de novo purine synthesis → blocks lymphocyte proliferation | RA, Crohn disease, autoimmune glomerulonephritis | Pancytopenia; ↑ toxicity with allopurinol |
| Mycophenolate mofetil | Reversibly inhibits IMP dehydrogenase → prevents de novo purine synthesis in T and B cells | Glucocorticoid-sparing agent in rheumatic disease, transplant prophylaxis | GI upset, pancytopenia, hypertension, ↑ risk of CMV infection |
| Glucocorticoids | Inhibit NF-κB → ↓ cytokine transcription; induce T-cell apoptosis; suppress B- and T-cell function | Autoimmune disorders, adrenal insufficiency, CLL, non-Hodgkin lymphoma, asthma | Cushingoid appearance, osteoporosis, hyperglycemia, diabetes, adrenal suppression, psychosis, cataracts, avascular necrosis |
