Immunomodulators

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Immunomodulators - Comprehensive Exam Review

The 3-Signal Model of Immune Activation

Understanding the three-signal model is fundamental - all immunosuppressant drug classes target one or more of these signals.

Signal	What Happens	Target Receptor	Drugs That Block It
Signal 1	Antigen (on APC via MHC II) binds T-cell receptor (TCR/CD3 complex)	CD3/TCR	Anti-thymocyte globulins, alemtuzumab
Signal 2	CD80/86 on APC binds CD28 on T cell (costimulation)	CD28/CD80/86	Belatacept (CTLA-4 fusion protein)
Signal 3	IL-2 binds IL-2R (CD25) → mTOR activation → T-cell proliferation	IL-2R / mTOR	mTOR inhibitors (sirolimus, everolimus); IL-2R antibodies (basiliximab)

The calcium-calcineurin pathway is activated by Signals 1+2 and drives IL-2 production - this is where calcineurin inhibitors act.

Class 1 - Calcineurin Inhibitors (CNIs)

Mechanism: Block calcineurin → prevent dephosphorylation of NFAT → no IL-2 gene transcription → no T-cell activation.

Drug	Key Points
Cyclosporine (NEORAL, SANDIMMUNE)	Binds cyclophilin → complex inhibits calcineurin. SE: nephrotoxicity, hypertension, hirsutism, gingival hyperplasia, hyperlipidemia, tremor, neurotoxicity. Metabolized by CYP3A4/P-gp - many drug interactions. Uses: transplant rejection prophylaxis, psoriasis, rheumatoid arthritis, dry eye disease
Tacrolimus (PROGRAF)	Binds FKBP-12 → complex inhibits calcineurin. SE: nephrotoxicity, neurotoxicity, GI complaints, hypertension, glucose intolerance/diabetes. Metabolized by CYP3A. More potent than cyclosporine. Uses: transplant rejection prophylaxis
Pimecrolimus / Tacrolimus (topical)	Topical calcineurin inhibitors for atopic dermatitis. Inhibit T-lymphocyte activation and prevent cytokine release. FDA black box warning re: long-term risk of malignancy (animal data). Tacrolimus 0.03% approved for children >2 years

Key exam point: Both CNIs have a narrow therapeutic index - therapeutic drug monitoring (TDM) is mandatory. CYP3A4 inhibitors (azole antifungals, macrolides, grapefruit) increase levels; CYP3A4 inducers (rifampin, phenytoin) decrease levels.

Class 2 - mTOR Inhibitors

Mechanism: Bind FKBP-12 → complex inhibits mTOR → blocks IL-2-driven cell cycle progression (G1 → S phase) → prevents T-cell proliferation (Signal 3 blockade).

Drug	Key Uses	Key Side Effects
Sirolimus (rapamycin, RAPAMUNE)	Transplant rejection prophylaxis, GVHD prevention/treatment, sirolimus-coated coronary stents (prevent restenosis)	Hyperlipidemia, thrombocytopenia, poor wound healing, pulmonary toxicity, mouth ulcers
Everolimus (ZORTRESS)	Transplant rejection prophylaxis, oncology (various cancers)	Similar to sirolimus

Key exam point: mTOR inhibitors are used in combination with CNIs to reduce CNI doses (and CNI nephrotoxicity). They also require TDM due to narrow therapeutic index.

Class 3 - Antiproliferatives (Antimetabolites)

These block lymphocyte proliferation by inhibiting nucleic acid synthesis.

Drug	Mechanism	Key Points
Azathioprine (IMURAN)	Prodrug → 6-mercaptopurine (6-MP) → thioinosinic acid → incorporated into DNA → blocks chain elongation	Dose-limiting SE: bone marrow suppression (leukopenia). Xanthine oxidase metabolizes 6-MP - avoid with allopurinol (reduce dose 75%) and contraindicated with febuxostat.
Mycophenolate mofetil (CELLCEPT)	Prodrug → mycophenolic acid (MPA) → reversible non-competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) → blocks de novo guanosine synthesis → selectively blocks T- and B-cell proliferation (lymphocytes lack salvage pathway)	Has largely replaced azathioprine. SE: GI distress (nausea, vomiting, diarrhea), bone marrow suppression (anemia, leukopenia, thrombocytopenia), increased infections. Enterohepatic recirculation prolongs effect.
Mycophenolate sodium (MYFORTIC)	Active form (MPA); enteric-coated to reduce GI side effects	Equivalent efficacy to MMF
Methotrexate	Inhibits dihydrofolate reductase → blocks purine and pyrimidine synthesis. Also anti-inflammatory (adenosine release)	Used in RA, psoriasis, IBD, prevention of GVHD. SE: hepatotoxicity, pulmonary fibrosis, mucositis, bone marrow suppression. Requires folate supplementation.

Class 4 - Costimulation Blocker

Drug	Mechanism	Key Points
Belatacept (NULOJIX)	CTLA-4-Ig fusion protein - binds CD80/CD86 on APCs → prevents CD28 engagement → blocks Signal 2	IV infusion only. Approved for kidney transplantation (with basiliximab + MMF + corticosteroids). Avoids CNI nephrotoxicity. Contraindicated in EBV-seronegative patients (risk of post-transplant lymphoproliferative disorder, PTLD - especially CNS).

Class 5 - Antibodies (Biologics)

Polyclonal Antibodies (Induction / Anti-rejection)

Drug	Target	Use
Anti-thymocyte globulin (equine) - ATGAM	T lymphocytes	Induction, treatment of acute rejection
Anti-thymocyte globulin (rabbit) - THYMOGLOBULIN	T lymphocytes	More potent than equine; preferred in high-risk patients

Monoclonal Antibodies

Drug	Target	Type	Key Use	Key Side Effects
Basiliximab (SIMULECT)	IL-2R (CD25) - blocks Signal 3	Chimeric (mouse/human)	Induction in renal transplantation	Well tolerated
Rituximab (RITUXAN)	CD20 on B cells	Chimeric	B-cell lymphomas, RA, GVHD, antibody-mediated rejection	Infusion reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation
Alemtuzumab (CAMPATH)	CD52 on T and B cells	Humanized	Induction, CLL, MS	Profound lymphodepletion, infusion reactions, autoimmune cytopenias
Belimumab (BENLYSTA)	BLyS (B-lymphocyte stimulator)	Fully human	Systemic lupus erythematosus (SLE)	Infection, depression, infusion reactions

TNF Inhibitors (used in autoimmune diseases)

Drug	Type	Key Uses	Key Risks
Etanercept (ENBREL)	Soluble TNF receptor fusion protein	RA, psoriasis, psoriatic arthritis, ankylosing spondylitis	Infection, TB reactivation
Infliximab (REMICADE)	Chimeric IgG1 anti-TNF antibody	RA, IBD (Crohn's, UC), psoriasis, AS	TB reactivation (screen before use), hepatotoxicity
Adalimumab (HUMIRA)	Fully human anti-TNF antibody	RA, IBD, psoriasis, AS, uveitis	Infection, TB reactivation

Key exam point on TNF inhibitors: Screen all patients for latent TB (TB test + CXR) before initiating. Contraindicated in active TB, serious infections, and Class III-IV heart failure. Risk of demyelinating disease, lymphoma.

IL Blockers

Drug	Target	Key Use
Tocilizumab (ACTEMRA)	IL-6 receptor	RA, giant cell arteritis, cytokine release syndrome (CRS)
Secukinumab (COSENTYX)	IL-17A	Psoriasis, ankylosing spondylitis, psoriatic arthritis
Ustekinumab (STELARA)	IL-12 and IL-23 (p40 subunit)	Psoriasis, psoriatic arthritis, Crohn's disease
Dupilumab (DUPIXENT)	IL-4 receptor alpha (blocks IL-4 and IL-13)	Atopic dermatitis, asthma, eosinophilic esophagitis
Mepolizumab (NUCALA)	IL-5	Eosinophilic asthma
Canakinumab	IL-1β	Periodic fever syndromes, gout flares

Class 6 - JAK Inhibitors (Small Molecule Targeted Therapy)

Mechanism: Inhibit Janus kinases (JAK1, JAK2, JAK3, TYK2) → block cytokine-driven STAT phosphorylation → reduce immune cell proliferation and cytokine production.

Drug	Selectivity	Key Uses	Key Adverse Effects
Tofacitinib (XELJANZ)	JAK1/JAK3	RA, psoriatic arthritis, ulcerative colitis	Infections, herpes zoster reactivation, thrombosis, ↑ malignancy risk (black box warning); CYP2C19/CYP3A4 interactions
Baricitinib (OLUMIANT)	JAK1/JAK2	RA, COVID-19 (severe)	Similar to tofacitinib + thromboembolism risk
Upadacitinib (RINVOQ)	JAK1 selective	RA, atopic dermatitis	Similar

Class 7 - Corticosteroids (as Immunosuppressants)

Mechanism: Bind glucocorticoid receptor → translocates to nucleus → suppresses NF-κB → ↓ transcription of proinflammatory cytokines (IL-1, IL-6, TNF-α) → broad effects on cellular immunity.

Uses: transplant rejection, autoimmune diseases, GVHD, asthma, IBD, SLE, RA, MS relapses
SE: hyperglycemia, hypertension, Cushingoid habitus, weight gain, osteoporosis, glaucoma, cataracts, adrenal suppression (with long-term use - must taper slowly)
Prednisone is a prodrug converted to prednisolone in the liver (inactive in severe hepatic disease)

Class 8 - Topical Immunomodulators (Dermatology)

Drug	Mechanism	Use
Imiquimod (ALDARA 5%, ZYCLARA 3.75%)	TLR-7/8 agonist → stimulates mononuclear cells to release IFN-α, IL-1, IL-6, IL-8, TNF-α	Genital warts, actinic keratoses, superficial basal cell carcinoma
Crisaborole (EUCRISA)	PDE-4 inhibitor (non-steroidal)	Mild-moderate atopic dermatitis ≥2 years
Apremilast (OTEZLA)	PDE-4 inhibitor (oral)	Psoriasis, psoriatic arthritis, oral ulcers in Behcet's

Summary: Drug Classification by Mechanism

SIGNAL 1 BLOCKERS:    Anti-thymocyte globulins, alemtuzumab
SIGNAL 2 BLOCKERS:    Belatacept (CTLA-4 fusion protein)
CALCINEURIN INH:      Cyclosporine, Tacrolimus → block IL-2 production
IL-2R BLOCKERS:       Basiliximab (Signal 3)
mTOR INHIBITORS:      Sirolimus, Everolimus → block IL-2 driven proliferation
ANTIMETABOLITES:      Azathioprine (purine analog), Mycophenolate (IMPDH inhibitor)
CORTICOSTEROIDS:      Broad cytokine suppression (NF-κB inhibition)
B-CELL DEPLETION:     Rituximab (anti-CD20)
TNF INHIBITORS:       Etanercept, Infliximab, Adalimumab
IL BLOCKERS:          Tocilizumab (IL-6R), Dupilumab (IL-4Ra), Secukinumab (IL-17A)
JAK INHIBITORS:       Tofacitinib, Baricitinib, Upadacitinib

High-Yield Exam Associations

Association	Answer
Nephrotoxicity + hirsutism + gingival hyperplasia	Cyclosporine
Nephrotoxicity + diabetes mellitus + neurotoxicity	Tacrolimus
Blocks de novo guanosine synthesis (IMPDH)	Mycophenolate
Prodrug → 6-MP → inhibits DNA chain elongation	Azathioprine
Contraindicated with allopurinol (or reduce dose)	Azathioprine
Contraindicated in EBV-seronegative transplant patients	Belatacept
Blocks CD80/86 (costimulation signal 2)	Belatacept
Used in SLE (blocks BLyS)	Belimumab
Screen for latent TB before use	All TNF inhibitors
Sirolimus-eluting stent purpose	Prevents restenosis (inhibits endothelial proliferation)
TDM required (narrow therapeutic index)	CNIs + mTOR inhibitors
Fully human monoclonal antibody (ends in -umab)	Adalimumab, belimumab
Chimeric antibody (ends in -ximab)	Rituximab, infliximab, basiliximab

Sources: Lippincott Illustrated Reviews: Pharmacology, Ch. 38; Goodman & Gilman's Pharmacological Basis of Therapeutics; Katzung's Basic and Clinical Pharmacology, 16th Ed.

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