Immunology and Immunotherapy Overview

Introduction

• The immune system protects against infections, but also causes diseases when overactive.

Learning Outcomes

• Understanding the importance of manipulating the immune system for treating various diseases
• Knowing the principles of immunomodulatory treatments for allergies and asthma
• Learning about anti-inflammatory drugs and their uses
• Learning about immunosuppressive drugs and their uses
• Understanding how monoclonal antibodies can be used as immunotherapeutic agents

Immunotherapy

• Manipulation of the immune response to treat diseases
• Can involve enhancing immunity (e.g., vaccination) or suppressing immune responses (e.g., allergic or autoimmune diseases)

Antihistamines

• Action: Blocking H1 histamine receptors to reduce vascular permeability, smooth muscle constriction, and sensory nerve stimulation (e.g., itching, sneezing)
• Produced mainly by mast cells
• Clinical uses: Type I hypersensitivity reactions (e.g., hay fever, rhinitis), allergic reactions
  • Note: Anaphylactic reactions should be treated with adrenaline.
• Urticaria/angioedema
• Types:
  • Sedative (1st generation): Chlorphenamine, diphenhydramine
  • Non-sedative (2nd generation): Cetirizine, terfenadine, loratidine
  • Can be used topically (e.g., nasal or eye drops) or systemically.

Asthmatic drugs

• Asthma drugs account for about 40 million community prescriptions annually.
• Bronchoconstriction is a major effect in asthma; treatment focused on beta 2 adrenoreceptor agonists (e.g., salbutamol).
• Inflammatory/allergic components can also be treated.
• Immunomodulatory drugs used in asthma treatment include steroids, leukotriene inhibitors, and sodium cromoglicate.

Steroids

• Major class of anti-inflammatory and immunosuppressive drugs
• Commonly given via inhalers such as beclometasone, budesonide, and fluticasone (also topical or systematic)
• Anti-inflammatory and Immunomodulatory effects of corticosteroids

Leukotriene receptor antagonists

• Leukotrienes contribute to asthma (smooth muscle contraction, mucus production, inflammatory cell recruitment)
• Antagonists (e.g., Montelukast, Zafirlukast) block these effects, potentially useful for exercise-induced asthma.

Sodium cromoglicate

• Stabilizes mast cell membranes, preventing degranulation.
• Mode of action not fully understood.

Asthma treatment overview

• Bronchoconstriction- Targeted drugs (Beta 2 agonists and others)
• Allergy/inflammation- Targeted drugs (steroids, leukotriene receptor antagonists, and sodium cromoglicate)

Anti-inflammatory drugs

• Work by suppressing non-specific inflammatory cells and mediators.
• Some have immunosuppressive properties inhibiting specific inflammatory cells.

Corticosteroids

• A major class of anti-inflammatory and immunosuppressive drugs
• Structurally similar to the glucocorticoid hormone cortisol

Side effects of corticosteroids

• Various side effects, notably significant in long-term use:
  • Glucocorticoid effects: Diabetes, Cushing's syndrome, adrenal suppression
  • Mineralocorticoid effects: Hypertension, sodium/water retention, potassium loss
  • Immunosuppressive effects: Increased susceptibility to infections, impaired wound healing
  • Other effects: Obesity, muscle wasting, growth arrest in children.

Non-steroidal anti-inflammatory drugs (NSAIDs)

• Wide group of drugs with analgesic and anti-inflammatory properties
• Anti-inflammatory action due to cyclooxygenase inhibition.
• Types: Salicylic acid derivatives (e.g., aspirin), propionic acid derivatives (e.g., ibuprofen, naproxen), non-propionic acid derivatives (e.g., indomethacin), selective COX-2 inhibitors (e.g., celecoxib).

NSAID Mechanism of Action

• Inhibit cyclooxygenase (COX), reducing prostaglandin production, which is linked to pain, inflammation, and fever.
  • COX-1 is "constitutive" (present in most tissues); COX-2 is "inducible" (produced in response to injury or inflammation).
  • NSAIDs generally inhibit both.

NSAID Adverse Drug Reactions (ADRs)

• Older NSAIDs have GI toxicity. Newer selective COX-2 inhibitors have cardiovascular side effects, so use should be carefully considered in patients with ischemic heart or cerebrovascular disease.

Tumor Necrosis Factor (TNF)

• One of several proteins causing tumor necrosis, plays a central role in multiple autoimmune diseases (rheumatoide arthritis, Crohn's disease).

TNF Functions

• TNF influences macrophages
• TNF affects endothelium, affecting vascular factors
• TNF affects hepatocytes
• TNF affects synoviocytes, causing cartilage degradation
• increased inflammation, cell infiltration, and angiogenesis.

TNF antagonists

• Monoclonal antibodies (e.g., infliximab, etanercept)
• Used for severe rheumatoid arthritis, Crohn's disease (infliximab more commonly used in Crohn's disease)
• Side effect: reactivation of latent tuberculosis; screening recommended prior to treatment.

Immunosuppressive agents

• Corticosteroids. Cytotoxic & anti-proliferative agents (e.g., cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil)
• Used in organ transplant rejection, rheumatoid arthritis, lupus, and other diseases.

Immunoglobulin (Ig)

• Immunomodulatory properties of intravenous immunoglobulin
• Increased clearance of autoantibodies through competitive binding to Fc receptors
• Activation of inhibitory Fc receptors on macrophages.
• Treatment for antibody deficiencies and diseases like Kawasaki disease, idiopathic thrombocytopenic purpura, and Guillain-Barré syndrome.

Monoclonal antibodies

• Table summarizing monoclonal antibodies, their target antigens, and diseases treated.
  • Rituximab (B-cell antigen) – B-cell leukemia/lymphoma, rheumatoid arthritis
  • Infliximab (TNF-α) – Crohn's disease, other inflammatory diseases
  • Omalizumab (IgE) – severe allergic asthma

Monoclonal Antibody Mechanisms of Action

• Methods of action of monoclonal antibodies used in therapy
  • Neutralizing target antigens
  • Inducing complement- or antibody-dependent cell-mediated cytotoxicity (ADCC).
  • Blocking cellular interactions.
  • Inducing apoptosis (programmed cell death) of target cells.
• High cost ($20,000/year for Herceptin).

This quiz covers key concepts in immunology, including the manipulation of the immune system for treating diseases such as allergies and asthma. Learn about the roles of antihistamines, immunosuppressive drugs, and monoclonal antibodies as therapeutic agents. Test your understanding of immunomodulatory treatments and their clinical applications.