Interferons

1. Introduction

• Interferons (IFNs) are naturally occurring glycoproteins classified as cytokines that regulate immune responses.

• Discovered in 1957 for their ability to “interfere” with viral replication, hence the name.

• Produced by host cells in response to pathogens (especially viruses), tumor cells, and other immune triggers.

• Therapeutically, interferons are recombinant or synthetic proteins that mimic endogenous IFN activity to modulate immunity.

• They have antiviral, antiproliferative, and immunomodulatory properties.

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2. Classification

Interferons are grouped into three main types based on receptor specificity and sequence homology:

A. Type I Interferons

• Include IFN-α, IFN-β, IFN-ε, IFN-κ, and IFN-ω.

• Bind to the IFNAR receptor (interferon-α/β receptor).

• Major subtypes used therapeutically:

  • Interferon alfa (e.g., IFN alfa-2a, IFN alfa-2b, pegylated forms).

  • Interferon beta (e.g., IFN beta-1a, IFN beta-1b).

B. Type II Interferons

• Represented solely by IFN-γ.

• Binds to the IFNGR receptor.

• Primarily produced by activated T cells and NK cells.

C. Type III Interferons

• Include IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4.

• Bind to the IFNLR receptor.

• Limited therapeutic application but emerging role in viral hepatitis research.

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3. Mechanism of Action

• Bind to their respective cell surface receptors.

• Activate Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway.

• Induce transcription of interferon-stimulated genes (ISGs) → production of proteins that:

  • Inhibit viral replication (e.g., 2′,5′-oligoadenylate synthetase, protein kinase R).

  • Enhance antigen presentation via MHC molecules.

  • Activate immune cells (macrophages, NK cells, cytotoxic T cells).

• Inhibit cell proliferation and promote apoptosis in abnormal cells.

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4. Pharmacological Preparations

Type I Interferons

• Interferon alfa-2a – used for viral hepatitis, certain cancers.

• Interferon alfa-2b – similar indications; available in pegylated forms for longer half-life.

• Peginterferon alfa-2a/2b – polyethylene glycol conjugation prolongs plasma half-life, allowing weekly dosing.

• Interferon beta-1a / beta-1b – used for multiple sclerosis.

Type II Interferons

• Interferon gamma-1b – indicated for chronic granulomatous disease and severe malignant osteopetrosis.

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5. Therapeutic Indications

A. Antiviral

• Chronic hepatitis B and C (peginterferon alfa + ribavirin historically; now largely replaced by direct-acting antivirals for HCV).

B. Antineoplastic

• Hairy cell leukemia.

• Chronic myeloid leukemia (CML) – historical use.

• Kaposi’s sarcoma (HIV-associated).

• Malignant melanoma.

C. Immunomodulatory

• Multiple sclerosis (interferon beta).

• Chronic granulomatous disease (interferon gamma).

• Idiopathic pulmonary fibrosis (investigational in the past).

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6. Pharmacokinetics

• Administered parenterally (subcutaneous, intramuscular, or intravenous).

• Poor oral bioavailability due to degradation in the GI tract.

• Pegylation extends half-life and reduces dosing frequency.

• Renal and hepatic metabolism with proteolytic degradation.

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7. Contraindications

• Known hypersensitivity to interferons or formulation components.

• Severe psychiatric disorders (especially depression, suicidal ideation).

• Decompensated liver disease (especially in hepatitis C with cirrhosis).

• Severe cardiac disease.

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8. Adverse Effects

Common

• Flu-like symptoms (fever, chills, myalgia, fatigue).

• Injection site reactions.

• Headache, arthralgia.

Serious

• Depression, suicidal thoughts.

• Bone marrow suppression (leukopenia, thrombocytopenia, anemia).

• Hepatotoxicity.

• Autoimmune disorders (thyroiditis, lupus-like syndrome).

• Cardiotoxicity (rare arrhythmias, cardiomyopathy).

• Pulmonary toxicity (interstitial pneumonitis).

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9. Drug Interactions

• Myelosuppressive drugs – additive hematologic toxicity.

• Theophylline – interferons can increase serum levels by reducing clearance.

• Methadone – may increase methadone levels.

• CYP450 substrates – interferons can reduce CYP1A2 activity, affecting metabolism of drugs like warfarin and phenytoin.

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10. Monitoring

• CBC with differential regularly during therapy.

• Liver function tests.

• Thyroid function tests (risk of autoimmune thyroid disease).

• Depression screening.

• Viral load and disease markers depending on indication.

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11. Advantages

• Broad immunomodulatory and antiviral properties.

• Long track record of clinical use and defined safety protocols.

• Useful where targeted biologics are unavailable or ineffective.

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12. Limitations

• Significant systemic adverse effects limit tolerability.

• Parenteral administration may reduce patient adherence.

• Largely replaced by newer targeted agents in many indications (e.g., DAAs for HCV, targeted MS therapies).