STEPTRACKERPHARMACOLOGY + IMMUNOLOGY | IMMUNOMODULATORS | HIGH-YIELD REVIEW

Immunosuppressants & Biologics

Transplant and autoimmune drugs block T-cell activation at defined steps; cytokine-targeted biologics are named by their target, and almost all raise infection risk.

FOCUS ON
Calcineurin inhibitors: cyclosporine (binds cyclophilin), tacrolimus (binds FKBP12) → block NFAT → ↓ IL-2; toxicity — nephrotoxicity, HTN, hyperkalemia, neurotoxicity (tremor, PRES), hyperglycemia (tacrolimus), gingival hyperplasia and hirsutism (cyclosporine); CYP3A4 substrates. mTOR inhibitors: sirolimus, everolimus (FKBP12 → mTOR → block IL-2 response) — not nephrotoxic; hyperlipidemia, poor wound healing, pneumonitis, cytopenias; coated stents. Antimetabolites: mycophenolate (IMP dehydrogenase → ↓ guanine in lymphocytes; GI, marrow, CMV, teratogen), azathioprine (TPMT, allopurinol interaction). Basiliximab (anti-IL-2Rα, CD25), belatacept (CTLA-4-Ig), antithymocyte globulin, alemtuzumab (CD52). Glucocorticoids. Biologics: TNF (infliximab, adalimumab, etanercept), IL-1 (anakinra, canakinumab), IL-6 (tocilizumab), IL-17 (secukinumab, ixekizumab — psoriasis, AS; IBD flare), IL-12/23 (ustekinumab), IL-23 (guselkumab), IL-4Rα (dupilumab), IL-5 (mepolizumab), IgE (omalizumab), C5 (eculizumab — meningococcus), CD20 (rituximab), BAFF (belimumab — SLE), α4 integrin (natalizumab — PML).
DRUG
MECHANISM
USE
SIGNATURE TOXICITY
Cyclosporine
Cyclophilin → calcineurin block → ↓ NFAT, IL-2
Transplant, psoriasis, RA, aplastic anemia
Nephrotoxicity, HTN, ↑ K⁺, gingival hyperplasia, hirsutism, tremor
Tacrolimus
FKBP12 → calcineurin block
Transplant (first-line), topical for eczema
Nephrotoxicity, neurotoxicity, new-onset diabetes, ↑ K⁺; levels ↑ with azoles, macrolides
Sirolimus · everolimus
FKBP12 → mTOR block → no IL-2 response
Kidney transplant, drug-eluting stents, LAM, TSC tumors
Hyperlipidemia, cytopenias, mouth ulcers, poor healing, pneumonitis; spares kidney
Mycophenolate mofetil
IMP dehydrogenase → ↓ de novo guanine synthesis (lymphocytes)
Transplant, lupus nephritis
GI upset, leukopenia, CMV, teratogen
Azathioprine
6-MP prodrug → purine antimetabolite
Transplant, IBD, autoimmune hepatitis
Marrow (TPMT), pancreatitis; allopurinol ↑ toxicity
Basiliximab
Anti-CD25 (IL-2Rα)
Transplant induction
Few; hypersensitivity
Belatacept · abatacept
CTLA-4-Ig → blocks CD80/86–CD28 costimulation
Kidney transplant · RA
PTLD in EBV-seronegative (belatacept)
Antithymocyte globulin · alemtuzumab
Polyclonal anti-T cell · anti-CD52
Induction, acute rejection · CLL, MS
Cytokine release, serum sickness · autoimmunity (alemtuzumab)
IL-17 · IL-23 · IL-12/23 inhibitors
Secukinumab, ixekizumab · guselkumab, risankizumab · ustekinumab
Psoriasis, psoriatic arthritis, AS; IL-23 and IL-12/23 also IBD
IL-17 blockers: candidiasis, IBD flares
IL-1 · IL-6 inhibitors
Anakinra, canakinumab · tocilizumab, sarilumab
Autoinflammatory disease, gout · RA, giant cell arteritis, CRS
Infections; tocilizumab lipids, GI perforation
Eculizumab · ravulizumab
Anti-C5 → no MAC
PNH, atypical HUS, myasthenia, NMO
Neisseria meningitidis — vaccinate before starting
Belimumab · anifrolumab
Anti-BAFF (BLyS) · type I interferon receptor
SLE
Infections, depression (belimumab)
Recombinant cytokines
Aldesleukin (IL-2), interferon-α/β/γ, filgrastim, epoetin, romiplostim
Melanoma/RCC · hepatitis, MS, CGD · cytopenias
IL-2 capillary leak; interferon flu-like, depression

Mechanism — T-cell activation steps

Signal 1: TCR–MHC→ calcineurin → NFAT (cyclosporine, tacrolimus)
→
Signal 2: CD28–B7(belatacept, abatacept)
→
IL-2 → IL-2R (CD25)(basiliximab)
→
mTOR → proliferation(sirolimus) → DNA synthesis (mycophenolate, azathioprine)

Kidney-sparing choices

DRUG
NEPHROTOXIC?
KEY ISSUE
Cyclosporine, tacrolimus
Yes
Level monitoring
Sirolimus
No
Lipids, wound healing
Mycophenolate
No
Marrow, GI, teratogen
Belatacept
No
PTLD risk

How it's tested

COMMON CONFUSIONTacrolimus and sirolimus both bind FKBP12 — but tacrolimus then blocks calcineurin, while sirolimus blocks mTOR.
THE TRAPAdding clarithromycin, fluconazole or diltiazem to a transplant patient on tacrolimus raises levels → AKI, tremor; rifampin or St John's wort lowers them → rejection.
YOUR APPROACHStep blocked → drug → organ toxicity → infections to screen or prevent (TB, HBV, meningococcus, PJP, CMV).

If you see… think…

Rising creatinine, tremor, HTN after kidney transplant → calcineurin inhibitor toxicity
Gum overgrowth and hirsutism → cyclosporine
New diabetes after transplant → tacrolimus (± steroids)
Hyperlipidemia and mouth ulcers on transplant drug → sirolimus
IMP dehydrogenase inhibitor → mycophenolate
Anti-CD25 induction → basiliximab
Meningococcal sepsis on PNH therapy → eculizumab
Mucocutaneous candidiasis on psoriasis biologic → IL-17 inhibitor
Drug-eluting stent coating → sirolimus/everolimus
Capillary leak syndrome on cancer cytokine therapy → aldesleukin (IL-2)