Immunosuppressants are one of those Step topics that feel like “a million drug names”… until you organize them by where they hit the immune response and what toxicities they love to test. This one-page cheat sheet is built for rapid recall on transplant and autoimmune questions—mechanism, key uses, and the classic adverse effects you’re expected to recognize in stems.
The Big Picture: “Stop the T cell”
Most high-yield immunosuppressants work by blocking T-cell activation or T-cell proliferation, because T cells drive rejection and amplify autoimmune inflammation.
A quick mental map:
- Signal 1 (TCR recognizes antigen on MHC) → downstream calcineurin → IL-2 transcription
- Signal 2 (costimulation via CD28–B7)
- Signal 3 (IL-2 binds IL-2 receptor) → clonal expansion (cell cycle/protein synthesis)
If you know which “signal” a drug blocks, you can predict what it’s used for and what side effects show up.
Visual Mnemonic Device (shareable)
“The Transplant Team: CAL & TAC call for IL-2, SIR says ‘stop’, MMF files the paperwork, AZA makes bad copies.”
- Cyclosporine (CAL) & Tacrolimus (TAC): stop IL-2 transcription (calcineurin inhibitors)
- Sirolimus (SIR): stops IL-2 response (mTOR inhibitor)
- Mycophenolate mofetil (MMF): blocks de novo purine synthesis (lymphocytes suffer)
- Azathioprine (AZA): “bad copies” of purines (6-MP prodrug) → impaired DNA synthesis
One-Liner Core Concepts (highest yield)
- Calcineurin inhibitors (cyclosporine, tacrolimus): “No calcineurin → no IL-2 transcription → no T-cell activation.”
- mTOR inhibitor (sirolimus/everolimus): “Blocks IL-2 signaling → arrests T-cell proliferation.”
- Antimetabolites (mycophenolate, azathioprine): “Starve rapidly dividing lymphocytes of purines.”
- Glucocorticoids: “Turn down cytokines and leukocyte trafficking—fast, broad immunosuppression.”
- Biologics: “Target a specific immune ‘node’ (TNF, IL-6, IL-17/23, integrins, B cells, CTLA-4, JAK).”
One-Page Table: Immunosuppressants You Must Know (Step 1/2)
Transplant staples + classic autoimmune meds
| Class/Drug | Mechanism (what it blocks) | High-yield uses | Signature adverse effects / testable pearls |
|---|---|---|---|
| Cyclosporine | Binds cyclophilin → inhibits calcineurin → ↓ IL-2 transcription → ↓ T-cell activation | Transplant rejection prophylaxis, some autoimmune (e.g., RA, psoriasis) | Nephrotoxicity, HTN, neurotoxicity (tremor), gingival hyperplasia, hirsutism |
| Tacrolimus | Binds FKBP → inhibits calcineurin → ↓ IL-2 transcription | Transplant rejection prophylaxis, atopic dermatitis topical | Nephrotoxicity, neurotoxicity, hyperglycemia/diabetes, HTN (no gingival hyperplasia/hirsutism classically) |
| Sirolimus (rapamycin) / Everolimus | Binds FKBP → inhibits mTOR → blocks IL-2 signaling → ↓ T-cell proliferation | Kidney transplant (often when calcineurin toxicity is an issue), drug-eluting stents | Pancytopenia, hyperlipidemia, impaired wound healing; NOT nephrotoxic (classic contrast vs calcineurin inhibitors) |
| Mycophenolate mofetil | Inhibits IMP dehydrogenase → ↓ de novo guanine synthesis (lymphocytes rely on this) | Transplant, lupus nephritis | GI upset/diarrhea, leukopenia; teratogenic risk (high yield counseling) |
| Azathioprine (prodrug of 6-MP) | Inhibits purine synthesis → ↓ DNA/RNA synthesis in rapidly dividing cells | Transplant, autoimmune (IBD, RA, SLE) | Myelosuppression, hepatotoxicity; toxicity ↑ with allopurinol/febuxostat (xanthine oxidase inhibitors) |
| Methotrexate | Inhibits dihydrofolate reductase → ↓ thymidylate/purines; ↑ adenosine (anti-inflammatory) | RA (first-line DMARD), psoriasis, ectopic pregnancy, some cancers | Mucositis, myelosuppression, hepatotoxicity, pneumonitis; give folinic acid (leucovorin) rescue (or folate) |
| Cyclophosphamide | Alkylates DNA (cross-links) → ↓ proliferation | Severe autoimmune (e.g., SLE nephritis/vasculitis), cancers | Hemorrhagic cystitis (acrolein; prevent with mesna), myelosuppression, infertility, secondary malignancy |
| Glucocorticoids (prednisone, methylpred, etc.) | ↓ NF-κB, ↓ cytokines (IL-1/2/6, TNF-α), ↓ adhesion/migration | Acute rejection episodes, autoimmune flares, asthma/COPD, etc. | Osteoporosis, hyperglycemia, HTN, weight gain, mood changes, proximal myopathy; infection risk; adrenal suppression |
| Anti-thymocyte globulin (ATG) | Antibodies against T cells → T-cell depletion | Induction therapy in transplant, steroid-resistant rejection | Infusion reactions, serum sickness; opportunistic infections |
| Basiliximab | Anti-IL-2 receptor (CD25) on activated T cells | Transplant induction | Generally well tolerated; infection risk (still testable conceptually) |
Biologics: The High-Yield “Autoimmune Board Favorites”
TNF-α inhibitors (“-cept” “-mab”)
| Drug | Key use | Big adverse effect pearl |
|---|---|---|
| Infliximab, adalimumab, golimumab (mAbs) ; etanercept (decoy receptor) | RA, IBD (except etanercept), psoriasis, ankylosing spondylitis | Reactivation of TB/histoplasmosis, serious infections; avoid in severe CHF; can cause demyelination |
Mnemonic: “TNF fixes granulomas” → blocking TNF can unmask latent TB.
IL inhibitors (Step-relevant patterns)
- Tocilizumab (anti-IL-6 receptor): RA, giant cell arteritis
- Pearl: infection risk; can raise LFTs/lipids.
- Ustekinumab (anti-IL-12/23): psoriasis, psoriatic arthritis, Crohn disease
- Secukinumab (anti-IL-17): psoriasis, ankylosing spondylitis
- Pearl: mucocutaneous candidiasis can show up with IL-17 blockade.
B-cell targeted
- Rituximab (anti-CD20): RA, certain vasculitides, B-cell lymphomas
- Pearl: PML (JC virus), hepatitis B reactivation.
Costimulation blocker
- Abatacept (CTLA-4-Ig): binds B7 (CD80/86) on APC → prevents CD28 costimulation
- Use: RA
- Pearl: “Signal 2 blocker.”
Integrin blocker (GI-friendly buzzword)
- Natalizumab: blocks α4-integrin (MS, Crohn) → ↓ leukocyte migration
- Pearl: PML risk.
JAK inhibitors (small molecules, big board presence)
- Tofacitinib, baricitinib, upadacitinib: block JAK-STAT signaling (RA, others)
- Pearl: infections (zoster), thrombosis warnings appear in question stems.
Stem-Ready Associations (what to recognize fast)
1) Kidney transplant patient + rising creatinine + tremor + HTN
Think calcineurin inhibitor toxicity (cyclosporine/tacrolimus) → nephrotoxicity.
2) Transplant patient + high lipids + low platelets + poor wound healing
Think sirolimus (mTOR inhibitor).
3) RA patient on biologic + night sweats + apical cavitary lesion
Think anti-TNF → TB reactivation.
4) Autoimmune patient + severe hemorrhagic cystitis
Think cyclophosphamide; prevention = mesna.
5) On azathioprine + started allopurinol → pancytopenia
Think drug interaction: xanthine oxidase inhibitors increase 6-MP/azathioprine toxicity.
Micro-Concepts They Like to Test
- Why lymphocytes are so sensitive to mycophenolate: they rely heavily on de novo purine synthesis (other cells can salvage).
- Why sirolimus isn’t nephrotoxic: it blocks proliferation downstream of IL-2 rather than calcineurin in renal arterioles (classic exam contrast).
- Opportunistic infections are a class effect: any significant immunosuppression → think reactivation (TB, HBV) and atypicals (fungi, JC virus).
- Vaccines: avoid live vaccines in significantly immunosuppressed patients (common Step counseling point).
Ultra-Short “Last-Minute” Recap Box
- Cyclosporine/Tacrolimus: calcineurin ↓ → IL-2 ↓ → nephrotoxic, neurotoxic; cyclosporine = gingival hyperplasia/hirsutism
- Sirolimus: mTOR ↓ → no IL-2 response → pancytopenia, hyperlipidemia, poor wound healing; not nephrotoxic
- MMF/AZA/MTX: “DNA/purine/folate blockers” → marrow + GI toxicity (MTX: mucositis, hepatotox; AZA: allopurinol interaction)
- Anti-TNF: serious infections + TB reactivation
- Rituximab/Natalizumab: watch for PML