STEPTRACKERIMMUNOLOGY + PHARMACOLOGY | IMMUNOSUPPRESSION | HIGH-YIELD REVIEW

Immunosuppressants

Each immunosuppressant blocks a step in T-cell activation or lymphocyte proliferation — and each has a signature toxicity worth recognizing on sight.

FOCUS ON

Calcineurin inhibitors: cyclosporine (binds cyclophilin) and tacrolimus (binds FKBP12) → block calcineurin → no NFAT → ↓ IL-2; toxicity: nephrotoxicity, hypertension, hyperkalemia, neurotoxicity/tremor, diabetes (tacrolimus), gingival hyperplasia and hirsutism (cyclosporine); CYP3A4 interactions. mTOR inhibitors: sirolimus, everolimus (bind FKBP12 → block mTOR → ↓ IL-2 response) → kidney-sparing; pancytopenia, hyperlipidemia, poor wound healing, mouth ulcers; drug-eluting stents. Antimetabolites: mycophenolate (IMP dehydrogenase → ↓ guanine; GI upset, cytopenias, teratogen), azathioprine (6-MP; TPMT testing; allopurinol ↑ toxicity), methotrexate, cyclophosphamide (hemorrhagic cystitis → mesna). Glucocorticoids: ↓ NF-κB → ↓ cytokines. Biologic induction: basiliximab (IL-2Rα), antithymocyte globulin, belatacept (CD80/86).

DRUG

MECHANISM

USES

TOXICITY

Cyclosporine

Binds cyclophilin → inhibits calcineurin → no NFAT → ↓ IL-2

Transplant, psoriasis, RA, uveitis

Nephrotoxicity, hypertension, hyperkalemia, gingival hyperplasia, hirsutism, tremor

Tacrolimus

Binds FKBP12 → inhibits calcineurin

Transplant (first line), topical for eczema

Nephrotoxicity, neurotoxicity, post-transplant diabetes, hyperkalemia · no gingival hyperplasia

Sirolimus · everolimus

Bind FKBP12 → inhibit mTOR → block IL-2 signaling (G1 → S)

Kidney transplant, drug-eluting stents, LAM, some cancers

Pancytopenia, hyperlipidemia, hyperglycemia, impaired wound healing, oral ulcers · not nephrotoxic

Mycophenolate mofetil

Inhibits IMP dehydrogenase → ↓ guanine nucleotides (lymphocytes depend on de novo synthesis)

Transplant, lupus nephritis

GI upset, cytopenias, CMV, teratogen

Azathioprine

Prodrug of 6-mercaptopurine → blocks purine synthesis

Transplant, IBD, autoimmune hepatitis

Myelosuppression (TPMT deficiency), pancreatitis, hepatotoxicity · allopurinol (xanthine oxidase) ↑ toxicity

Methotrexate

DHFR inhibitor; low dose ↑ adenosine (anti-inflammatory)

RA, psoriasis, ectopic pregnancy, cancers

Mucositis, myelosuppression, hepatotoxicity, pneumonitis, teratogen · leucovorin rescue; folic acid

Cyclophosphamide

Alkylating agent (activated by liver)

Severe lupus nephritis, vasculitis, cancers

Hemorrhagic cystitis (acrolein → mesna), myelosuppression, infertility, bladder cancer

Glucocorticoids

↓ NF-κB and AP-1 → ↓ cytokines; lymphocyte and eosinophil apoptosis; demargination of neutrophils

Nearly all inflammatory and autoimmune disease, rejection

Cushing features, osteoporosis, hyperglycemia, avascular necrosis, cataracts, adrenal suppression, infections

Basiliximab

Anti-CD25 (IL-2Rα) monoclonal antibody

Induction in kidney transplant

Well tolerated

Antithymocyte globulin

Polyclonal antibodies deplete T cells

Induction, steroid-resistant rejection

Cytokine release, serum sickness, cytopenias

Belatacept · abatacept

CTLA-4-Ig binds CD80/86 → blocks costimulation

Kidney transplant · RA

PTLD in EBV-negative recipients (belatacept)

JAK inhibitors

Tofacitinib, baricitinib, ruxolitinib block cytokine signaling

RA, ulcerative colitis, GVHD, myelofibrosis

Zoster, thrombosis, lipids

Picture it — where each drug acts on a T cell

Immunosuppressant targetsCostimulation blockers and ATG act at the surface; calcineurin inhibitors stop NFAT from switching on IL-2; basiliximab blocks the IL-2 receptor; sirolimus blocks mTOR downstream of it; mycophenolate and azathioprine starve dividing lymphocytes of nucleotides; steroids shut down cytokine genes broadly.

Schematic diagrams, not to scale.

Mechanism — the drug map on a T cell

TCR + CD28⊣ belatacept, ATG

→

Calcineurin → NFAT⊣ cyclosporine, tacrolimus

→

IL-2 → IL-2R⊣ basiliximab

→

mTOR → cell cycle⊣ sirolimus

→

DNA synthesis⊣ mycophenolate, azathioprine

Signature toxicities

DRUG

SIGNATURE

CHECK

Cyclosporine

Gums, hair, kidney

Levels, creatinine

Tacrolimus

Kidney, diabetes, tremor

Levels, glucose

Sirolimus

Lipids, cytopenias, wounds

Lipids, CBC

Azathioprine

Marrow

TPMT genotype

Cyclophosphamide

Hemorrhagic cystitis

Mesna, urinalysis

How it's tested

COMMON CONFUSIONTacrolimus and sirolimus both bind FKBP12, but tacrolimus then blocks calcineurin (nephrotoxic) while sirolimus blocks mTOR (not nephrotoxic).

THE TRAPAdding azole antifungals or macrolides raises calcineurin-inhibitor levels (CYP3A4 inhibition) → acute nephrotoxicity; rifampin lowers them → rejection.

YOUR APPROACHDrug → step it blocks → main toxicity → interaction or genetic test needed before use.

If you see… think…

Gingival overgrowth and hirsutism in a transplant patient → cyclosporine

New diabetes and tremor after kidney transplant → tacrolimus

Kidney-sparing transplant drug used on coronary stents → sirolimus

Enzyme inhibited by mycophenolate → IMP dehydrogenase

Severe marrow toxicity from azathioprine + allopurinol → xanthine oxidase blocked

Test before starting azathioprine → TPMT activity

Hematuria after cyclophosphamide → hemorrhagic cystitis (give mesna)

Anti-CD25 induction antibody → basiliximab

CTLA-4-Ig used in kidney transplant → belatacept

Rising tacrolimus level after starting fluconazole → CYP3A4 inhibition