Immunopharmacology · Module 1 of 5

Immunopharmacology Foundations

Immune cells, cytokines, JAK-STAT signaling, and complement at a glance

Innate immune cells (neutrophils, macrophages, NK cells, mast cells, eosinophils) provide immediate non-antigen-specific defense and are the primary targets of TNF inhibitors, IL-1 antagonists, IL-6 inhibitors, and colony-stimulating factors; abatacept exploits the dendritic cell–T-cell interface by blocking CD80/CD86 co-stimulation required for full T-cell activation.
The NLRP3 inflammasome is the cytoplasmic sensor linking metabolic danger signals (urate crystals, ATP, cholesterol crystals, silica) to IL-1β release via caspase-1 cleavage; three drugs target this axis: anakinra (IL-1Ra, blocks IL-1α and IL-1β), canakinumab (anti-IL-1β mAb, ~26-day half-life), and rilonacept (soluble decoy receptor, approved for recurrent pericarditis and CAPS).
Cytokine targeting is the largest drug class in immunopharmacology: five TNF inhibitors (infliximab, adalimumab, etanercept, certolizumab, golimumab) differ in structure and placental transfer; tocilizumab and sarilumab block the IL-6 receptor alpha chain and suppress CRP so completely that procalcitonin must replace CRP for infection detection; dupilumab blocks IL-4Rα to simultaneously suppress IL-4 and IL-13 (type 2 inflammation).
JAK inhibitors (tofacitinib, baricitinib, upadacitinib) are oral ATP-competitive kinase inhibitors that block cytokine signaling at the intracellular level; they carry a class-wide black box warning for serious infections, MACE, VTE, malignancy, and mortality based on the ORAL Surveillance trial; Shingrix vaccination is strongly recommended before initiation.
Eculizumab and ravulizumab block C5 cleavage, preventing C5a generation and MAC formation while preserving C3b-mediated opsonization; meningococcal vaccination (MenACWY + MenB) at least 2 weeks before first dose is mandatory for all complement inhibitors due to the risk of rapid fatal encapsulated-organism infection.

ADCC = antibody-dependent cellular cytotoxicity · AS = ankylosing spondylitis · BAFF = B-cell activating factor · CAPS = cryopyrin-associated periodic syndromes · G-CSF = granulocyte colony-stimulating factor · GM-CSF = granulocyte-macrophage colony-stimulating factor · IBD = inflammatory bowel disease · IL = interleukin · JAK = Janus kinase · MAC = membrane attack complex · MACE = major adverse cardiovascular events · NK = natural killer · PNH = paroxysmal nocturnal hemoglobinuria · PsA = psoriatic arthritis · RA = rheumatoid arthritis · TNF = tumor necrosis factor · UC = ulcerative colitis · VTE = venous thromboembolism

Immune Cell Drug Targets

Macrophage / Monocyte

Innate Effectors

TNF inhibitors (5 agents)
IL-1 antagonists (anakinra, canakinumab, rilonacept)
IL-6 receptor inhibitors (tocilizumab, sarilumab)
Corticosteroids

T Cells

Adaptive Effectors

Calcineurin inhibitors (tacrolimus, cyclosporine)
mTOR inhibitors (sirolimus, everolimus)
JAK inhibitors (tofacitinib, baricitinib, upadacitinib)
Abatacept / belatacept (co-stimulation block)

B Cells / Plasma Cells

Humoral Arm

Rituximab (anti-CD20) — NK ADCC-mediated depletion
Belimumab (anti-BAFF) — reduces B-cell survival
IVIG — Fc receptor modulation
Daratumumab (anti-CD38) — plasma cell depletion

Eosinophils / Mast Cells

Type 2 Effectors

Dupilumab (anti-IL-4Rα) — blocks IL-4 + IL-13
Mepolizumab / reslizumab (anti-IL-5)
Benralizumab (anti-IL-5Rα)
Omalizumab (anti-IgE) — mast cell degranulation

Cytokine Axis → Drug

TNF-α Axis

Five Inhibitors

Infliximab — chimeric IgG1 mAb
Adalimumab — fully human IgG1 mAb
Golimumab — fully human IgG1 mAb
Etanercept — TNFR2 fusion protein; inactive in Crohn's / sarcoid
Certolizumab — PEGylated Fab, no Fc → no placental transfer; preferred in pregnancy

IL-23 / IL-17 Axis

Psoriasis / SpA

Ustekinumab — anti-p40 (blocks IL-12 + IL-23)
Guselkumab / risankizumab / tildrakizumab — anti-p19 (IL-23 selective)
Secukinumab / ixekizumab — anti-IL-17A
IL-17 inhibitors: avoid / contraindicated in active IBD

IL-1 Axis

Inflammasome Output

Anakinra — IL-1Ra; blocks IL-1α + IL-1β; daily SC; fastest offset for acute use
Canakinumab — anti-IL-1β mAb; ~26-day half-life; CAPS, gout, SJIA
Rilonacept — IL-1 trap; recurrent pericarditis + CAPS
Indications: gout, CAPS, pericarditis, atherosclerosis (canakinumab trial)

IL-6 Receptor Axis

Tocilizumab / Sarilumab

Block IL-6Rα chain → suppress CRP, fever, fibrinogen, Th17 differentiation
CRP no longer usable as infection biomarker — use procalcitonin
RA, giant cell arteritis, cytokine release syndrome (tocilizumab)

Type 2 Cytokines — IL-4 / IL-5 / IL-13

Dupilumab and Anti-IL-5 Agents

Dupilumab (anti-IL-4Rα): atopic dermatitis, asthma, CRSwNP, eosinophilic esophagitis, prurigo nodularis
Mepolizumab / reslizumab (anti-IL-5): severe eosinophilic asthma
Benralizumab (anti-IL-5Rα): depletes eosinophils via ADCC

JAK-STAT Signaling Pathway

Cytokine

Binds receptor

→

JAK (constitutive)

Trans-phosphorylation

→

STAT

Phosphorylated → dimerizes

→

Nucleus

Gene transcription

■

JAK Inhibitor

ATP-competitive block

JAK1 + JAK3

Tofacitinib

Blocks γ-c chain cytokines: IL-2, IL-4, IL-7, IL-15, IL-21
RA, PsA, UC, AS
ORAL Surveillance: index trial for class-wide BBW

JAK1 + JAK2

Baricitinib / Upadacitinib

Broader cytokine suppression including IFN pathways
JAK2 block → anemia risk (EPO signaling) and neutropenia (G-CSF signaling)
Baricitinib: RA, atopic dermatitis, alopecia areata
Upadacitinib: RA, IBD, AS, atopic dermatitis (selective JAK1)

Class-Wide Black Box Warning

JAK Inhibitor Risks

Serious infections — TB reactivation (screen first)
MACE and VTE (particularly in cardiovascular risk patients)
Malignancy (lung cancer, lymphoma)
Use after TNF inhibitor failure in rheumatic indications
Shingrix (recombinant zoster vaccine) before initiating

Complement Cascade and Drug Targets

3 Activation Pathways

Classical / Lectin / Alternative

→

C3 Convertase

C3 → C3a (anaphylatoxin) + C3b (opsonin)

→

C5 Convertase

C5 → C5a (chemotactic) + C5b

→

MAC (C5b-9)

Cell lysis

■

Anti-C5 Agents

Eculizumab / Ravulizumab

Anti-C5 Agents

Eculizumab / Ravulizumab

Block C5 cleavage → no C5a, no MAC formation
Preserve C3b-mediated opsonization (upstream intact)
Indications: PNH, aHUS, generalized myasthenia gravis (anti-AChR), NMOSD (anti-AQP4)
Ravulizumab: engineered extended half-life → dosing q8 weeks vs. eculizumab q2 weeks

Mandatory Safety Rule

Meningococcal Vaccination

MenACWY + MenB at least 2 weeks before first dose — required for all complement inhibitors
Terminal complement is the primary defense against encapsulated bacteria (Neisseria meningitidis)
Antibiotic prophylaxis recommended throughout therapy
Rapid fatal meningococcal disease possible without vaccination

Suggested References

Author / Source	Title	Publication
Katzung BG, ed.	Basic and Clinical Pharmacology, 15th ed. — Chapter on Immunopharmacology	McGraw-Hill; 2021
Brunton L, Knollmann B, Hilal-Dandan R, eds.	Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th ed.	McGraw-Hill; 2023
Janeway CA Jr, Travers P, Walport M, Shlomchik MJ	Immunobiology: The Immune System in Health and Disease, 9th ed.	Garland Science, New York; 2017. ISBN 9780815345053
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Gandhi NA, Bennett BL, Graham NMH, et al	Targeting key proximal drivers of type 2 inflammation in disease	Nat Rev Drug Discov. 2016;15(1):35–50
Miossec P, Kolls JK	Targeting IL-17 and Th17 cells in chronic inflammation	Nat Rev Drug Discov. 2012;11(10):763–776
O’Shea JJ, Schwartz DM, Villarino AV, et al	The JAK-STAT pathway: impact on human disease and therapeutic intervention	Annu Rev Med. 2015;66:311–328
Ytterberg SR, Bhatt DL, Mikuls TR, et al	Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis	N Engl J Med. 2022;386(4):316–326
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Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, et al	Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors	Blood. 2019;133(6):530–539