Action of immunosuppressive agents

Classes and targets

Grouped by where in the immune response they act - this is how the exam frames them

Class	Agents	Target
Corticosteroids	Prednisolone, methylprednisolone, dexamethasone	Transcription - broad cytokine suppression
Antiproliferatives	Azathioprine, mycophenolate, methotrexate, leflunomide	Nucleotide synthesis -> lymphocyte proliferation
Alkylating	Cyclophosphamide	DNA cross-linking - B cells > T cells
Calcineurin inhibitors	Ciclosporin, tacrolimus	IL-2 transcription in T cells
mTOR inhibitors	Sirolimus, everolimus	IL-2 signal transduction
Biologic - cytokine	Infliximab, adalimumab, etanercept, tocilizumab, ustekinumab, secukinumab	TNF, IL-6R, IL-12/23, IL-17
Biologic - cell depleting	Rituximab (CD20), alemtuzumab (CD52), ATG	B or T lymphocytes
Costimulation blockade	Abatacept (CTLA4-Ig), belatacept	CD80/86 - signal 2
Small molecule	Tofacitinib, baricitinib, upadacitinib	JAK-STAT

Signal 1 - TCR + MHC-peptide -> calcineurin -> NFAT -> IL-2 transcription
- Blocked by ciclosporin (cyclophilin), tacrolimus (FKBP12)
- Corticosteroids also suppress here
Signal 2 - CD28 : CD80/86 costimulation
- Blocked by abatacept, belatacept
Signal 3 - IL-2 binds IL-2R -> mTOR -> cell cycle entry
- Blocked by basiliximab (IL-2Ralpha), sirolimus/everolimus (mTOR)
Downstream proliferation requires nucleotide synthesis
- Blocked by azathioprine, mycophenolate, methotrexate

Bind cytosolic receptor -> nuclear translocation -> transrepression of NF-kB and AP-1
Inhibit synthesis/release of IL-1, IL-2, TNF-alpha, IFN-gamma, plus prostaglandins/leukotrienes and plasminogen activator
Lymphopenia by redistribution; neutrophilia by demargination (not infection)
Toxicity: hyperglycaemia, osteoporosis, infection, myopathy, cataract, adrenal suppression

Prodrug -> 6-mercaptopurine (inhibits de novo purine biosynthesis) -> thioguanine nucleotides incorporated into ribonucleotides
Antiproliferative on mitotically active cells, particularly lymphocytes
- Inhibits cytotoxic T cells and NK cells; induces T-cell apoptosis
Check TPMT (and NUDT15) before starting - deficiency -> profound myelosuppression
Allopurinol/febuxostat: xanthine oxidase blockade -> 6-MP accumulation -> reduce azathioprine dose to ~25%, or avoid
Toxicity: myelosuppression, hepatitis, pancreatitis, NMSC (photoprotection mandatory), lymphoma

Inhibits IMPDH -> blocks de novo guanosine synthesis
- Lymphocytes lack the salvage pathway -> selective
Toxicity: GI intolerance, cytopenias, teratogenic - pregnancy category X, mandatory contraception

Inhibits dihydrofolate reductase -> dec tetrahydrofolate -> dec thymidylate and purine synthesis -> dec DNA synthesis
- Anti-inflammatory effect at low dose is largely adenosine-mediated
Weekly dosing. Folic acid 5 mg on a different day
Toxicity: mucositis, cytopenias, transaminitis, pneumonitis, teratogenic
Avoid with trimethoprim - additive antifolate -> pancytopenia

Alkylating agent - cross-links DNA, arrests the cell cycle
Lymphocytopenia, B cells more than T cells; depletes plasma cells
Toxicity: haemorrhagic cystitis and bladder cancer (mesna + hydration), infertility (offer gamete storage), myelosuppression, MDS/AML
Cumulative dose matters - substitute rituximab where possible

Nephrotoxic, hypertension, tremor, hyperkalaemia, hypomagnesaemia
Ciclosporin: gum hypertrophy, hirsutism. Tacrolimus: diabetes, alopecia
CYP3A4 - azoles, macrolides, diltiazem raise levels; rifampicin, phenytoin drop them

Anti-TNF: screen for latent TB (IGRA + CXR) and HBV before starting; avoid in demyelination and in NYHA III-IV heart failure
Rituximab: hypogammaglobulinaemia, HBV reactivation, PML, blunted vaccine response
JAK inhibitors: MACE, VTE, malignancy and mortality signal in patients >=50 with a cardiovascular risk factor (ORAL Surveillance) -> use after a TNF inhibitor in that group; herpes zoster - vaccinate with recombinant Shingrix

Screen: TB, HBV/HCV, HIV, strongyloides serology if endemic exposure, varicella immunity
Live vaccines contraindicated - vaccinate >=4 weeks before starting
PJP prophylaxis if prednisolone >=20 mg/day for >4 weeks, or with cyclophosphamide/rituximab
Skin cancer surveillance, bone protection

Opportunistic infection - PJP, CMV, TB reactivation, invasive fungal, strongyloides hyperinfection
Malignancy - NMSC, EBV-driven post-transplant lymphoproliferative disease
Vaccine failure and live-vaccine complications
Drug interactions: allopurinol-azathioprine, trimethoprim-methotrexate, CYP3A4 with CNIs

Infection risk scales with net state of immunosuppression, not any single drug
Corticosteroid dose is the strongest single predictor of serious infection
Cumulative cyclophosphamide dose determines malignancy and infertility risk - track it in grams
Long-term: NMSC risk with azathioprine and CNIs is dose- and duration-dependent

11 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.