8.6 Immunosuppressant Drugs
Immunosuppressants prevent organ transplant rejection and treat autoimmune diseases by inhibiting T-cell activation, proliferation, or cytokine production. Careful monitoring is essential to balance efficacy against infection risk and toxicity.
Principles of Immunosuppression
T-Cell Activation
Three signals: TCR-MHC, costimulation (CD28-B7), IL-2 signaling
Combination Therapy
Use multiple agents with different mechanisms to reduce toxicity and resistance
Monitoring
Therapeutic drug monitoring (TDM) for calcineurin inhibitors and mTOR inhibitors
Calcineurin Inhibitors
Cyclosporine
Mechanism of Action:
Binds to cyclophilin, forming complex that inhibits calcineurin. Prevents dephosphorylation of NFAT, blocking IL-2 transcription and T-cell activation.
Clinical Uses:
- • Organ transplant (kidney, liver, heart)
- • Severe psoriasis, rheumatoid arthritis
- • Aplastic anemia
⚠️ Major Toxicities:
- • Nephrotoxicity: Dose-limiting; vasoconstriction of afferent arteriole
- • Hypertension (↑ endothelin, ↓ NO)
- • Neurotoxicity (tremor, seizures)
- • Gingival hyperplasia, hirsutism
- • Hyperlipidemia, hyperglycemia
- • Increased infection risk (opportunistic)
Drug Interactions:
Metabolized by CYP3A4. Levels ↑ by azoles, macrolides, grapefruit juice; ↓ by rifampin, phenytoin
Tacrolimus (FK506)
Mechanism:
Binds to FKBP-12, forming complex that inhibits calcineurin (same downstream effect as cyclosporine). More potent than cyclosporine (10-100x).
Clinical Uses:
- • First-line for liver transplant
- • Kidney, heart, lung transplants
- • Often preferred over cyclosporine (more potent, no hirsutism/gingival hyperplasia)
Toxicities (similar to cyclosporine):
- • Nephrotoxicity, neurotoxicity
- • Diabetes (more than cyclosporine)
- • Hypertension (less than cyclosporine)
- • GI disturbances
- • No gingival hyperplasia or hirsutism
- Monitor trough levels; CYP3A4 substrate
mTOR Inhibitors
Sirolimus (Rapamycin) & Everolimus
Mechanism of Action:
Binds FKBP-12, but the complex inhibits mTOR (mammalian target of rapamycin) instead of calcineurin. Blocks IL-2 receptor signaling, preventing T-cell proliferation (G1 → S phase arrest).
Clinical Uses:
- • Kidney transplant (often with calcineurin inhibitor)
- • Drug-eluting stents (prevent restenosis)
- • Lymphangioleiomyomatosis (LAM)
- • Antiproliferative properties
Adverse Effects:
- • Hyperlipidemia (↑ LDL, ↑ TG)
- • Myelosuppression (thrombocytopenia, anemia)
- • Impaired wound healing
- • Proteinuria (but less nephrotoxic than CNIs)
- • Interstitial pneumonitis
- • Mouth ulcers, diarrhea
Advantages:
- ✓ Not nephrotoxic (can spare kidneys)
- ✓ Antiproliferative, antitumor effects
Antimetabolites
Azathioprine
Mechanism:
Prodrug of 6-mercaptopurine (6-MP). Inhibits purine synthesis, blocking DNA/RNA synthesis and lymphocyte proliferation.
Clinical Uses:
- • Transplant rejection prophylaxis
- • Autoimmune diseases (SLE, RA, IBD)
- • Steroid-sparing agent
Toxicities:
- • Bone marrow suppression (dose-limiting)
- • GI disturbances, hepatotoxicity
- ⚠️ Reduce dose 75% if on allopurinol (inhibits xanthine oxidase)
Mycophenolate Mofetil (MMF)
Mechanism:
Inhibits inosine monophosphate dehydrogenase (IMPDH), blocking de novo purine synthesis. Lymphocytes lack salvage pathway, making them particularly sensitive.
Clinical Uses:
- • First-line for kidney transplant (with tacrolimus + steroids)
- • Heart, liver transplants
- • Lupus nephritis
Toxicities:
- • GI disturbances (diarrhea, common)
- • Myelosuppression (leukopenia)
- • Teratogenic (contraception required)
Monoclonal Antibodies & Biologics
Anti-CD3: Muromonab-CD3 (OKT3)
Monoclonal antibody against CD3 on T cells. Blocks T-cell function and depletes T cells (opsonization, complement activation).
Use:
- • Acute transplant rejection (rescue therapy)
- • Largely replaced by newer agents
Adverse Effects:
- • Cytokine release syndrome: First dose (fever, hypotension, pulmonary edema)
- • Increased infection risk (CMV, EBV)
- • Post-transplant lymphoproliferative disorder (PTLD)
Anti-IL-2R: Basiliximab & Daclizumab
Monoclonal antibodies against CD25 (IL-2 receptor α-chain). Block IL-2-mediated T-cell activation and proliferation.
Use:
- • Induction therapy for kidney transplant
- • Reduces acute rejection without severe side effects
Advantages:
- ✓ Well-tolerated
- ✓ No cytokine release syndrome
- ✓ Humanized antibodies
TNF-α Inhibitors
Infliximab
- • Chimeric anti-TNF-α mAb
- • RA, IBD, psoriasis, ankylosing spondylitis
- • IV infusion
Adalimumab
- • Fully human anti-TNF-α mAb
- • RA, IBD, psoriasis
- • SC injection
Etanercept
- • Soluble TNF receptor fusion protein
- • RA, psoriatic arthritis
- • SC injection
⚠️ Major Risks:
- • Reactivation of latent TB: Screen with PPD/IGRA before starting
- • Serious infections (bacterial, viral, fungal)
- • Demyelinating disorders
- • Heart failure exacerbation
- • Lupus-like syndrome
Other Biologics
Rituximab (Anti-CD20)
- • Depletes B cells
- • RA (refractory), lupus, vasculitis
- • Progressive multifocal leukoencephalopathy (PML) risk
Abatacept (CTLA-4-Ig)
- • Blocks CD28-B7 costimulation
- • RA, psoriatic arthritis
- • Generally well-tolerated
Corticosteroids
Mechanism & Uses in Immunosuppression
Inhibit NF-κB, reducing cytokine production (IL-1, IL-2, IL-6, TNF-α). Induce apoptosis of activated T cells. Broad anti-inflammatory effects.
Common Agents:
- • Prednisone: Oral maintenance
- • Methylprednisolone: IV pulse therapy for acute rejection
- • Part of triple therapy (with CNI + MMF)
Long-Term Toxicities:
- • Osteoporosis, avascular necrosis
- • Hyperglycemia, diabetes
- • Hypertension, hyperlipidemia
- • Cushingoid features
- • Cataracts, glaucoma
- • Adrenal suppression
- • Growth retardation (children)
Standard Transplant Regimens
Induction (Perioperative)
- • Basiliximab or antithymocyte globulin (ATG)
- • High-dose methylprednisolone
- • Goal: Prevent acute rejection early
Maintenance (Long-Term)
- • Triple therapy:
- - Tacrolimus or cyclosporine (CNI)
- - Mycophenolate mofetil (MMF)
- - Prednisone (low-dose)
- Alternative: Sirolimus to spare kidneys