Principles of Immunosuppression and Immunomodulation Lecture Notes PDF

# Principles of Immunosuppression and Immunomodulation ## University of Zakho Dr. Hakar A. Kareem Pharmacologist University of Zakho ## Learning Outcomes: - The importance of manipulation of the immune system in the treatment of a wide range of diseases - The principles of immunomodulatory treat...

# Principles of Immunosuppression and Immunomodulation ## University of Zakho Dr. Hakar A. Kareem Pharmacologist University of Zakho ## Learning Outcomes: - The importance of manipulation of the immune system in the treatment of a wide range of diseases - The principles of immunomodulatory treatments for allergy and asthma - Anti-inflammatory drugs and their uses - Immunosuppressive drugs and their uses - How (monoclonal) antibodies can be used as immunotherapeutic agents ## Introduction - Immune system has evolved to protect us against infections, overactive immune responses are also the cause of many diseases. ## Immunotherapy - Is the manipulation of the immune response to treat disease. It can involve either enhancing immunity (as in vaccination), or suppressing immune responses (as in the treatment of allergic or autoimmune diseases). ## Antihistamines - **Action:** Through blockage of H1 histamine receptors, leading to: - Inhibition of histamine-mediated vascular permeability and smooth muscle constriction, - Reduction in sensory nerve stimulation (itching, sneezing etc.). - **Histamine:** Produced mainly by mast cells. ## Antihistamines Clinical Uses: - **Type I (immediate / IgE-mediated) hypersensitivity reactions:** such as hay fever, perennial rhinitis, acute type I allergic reactions (remember that anaphylactic reactions should be treated with i.m. Adrenaline) - **Urticaria / angioedema** ## Antihistimes Types: - **Sedative (1st generation):** Chlorphenamine, diphenhydramin - **Non-sedative (2nd generation):** and have a longer lasting therapeutic activity (e.g. cetirizine, terfenadine, loratidine). - Can be given **topically** (eg nasal or eye drops) or **systemically**. ## Asthmatic Drugs - Asthma drugs currently account for approximately 40 million community prescriptions per year. - The major pathogenic effect in asthma is **bronchoconstriction**, and so the use of (mainly beta 2 adrenoreceptor agonsists (e.g. salbutamol) and other bronchodilators forms the mainstay of treatment. - However, in many cases, especially in children, there is an **inflammatory or allergic** component that can also be treated. The major immunomodulatory groups of drugs used in treating airways inflammation in asthma are **steroids, leukotriene inhibitors and Sodium cromoglicate.** ## Steroids - Represent a major class of **anti-inflammatory and immunosuppressive drug** in clinical use. - Most commonly given by inhaler (beclometasone, budesonide and fluticasone), topical, or systematically. - **Anti-inflammatory and Immunomodulatory effects of corticosteroids?** ## Leukotriene Receptor Antagonists - Leukotrienes are involved in inflammatory reactions, and may contribute to asthma in a number of ways: - Induction of smooth muscle contraction - Production of mucous - Recruitment of inflammatory cells - Leukotriene receptor antagonists (Montelukast; Zafirlukast) may therefore be of benefit in the treatment of asthma, by blocking these effects, are particularly helpful in exercise-induced asthma. ## Cromoglicate - It helps to stabilize the mast cell membrane, preventing mast cell degranulation. Its mode of action is not completely understood. ## Asthma A diagram is displayed which shows a tree diagram with the following branches: - **Bronchoconstriction** - B2 agonists & others - Steroids - **Allergy or inflammation** - Leukotriene receptor antagonists - Sodium cromoglicate Along each branch, a box with a picture of a medicine is displayed: - Asthma inhaler - Beclometasone inhaler - Montelukast tablets - Sodium cromoglicate inhaler ## Anti-inflammatory Drugs - Anti-inflammatory drugs work largely by blocking or suppressing functions of non-specific inflammatory cells (monocytes, macrophages, granulocytes) or proinflammatory mediators produced by these cells. In some cases (e.g. steroids) they may also have immunosuppressive properties (inhibition of specific immune cells or their mediators). ## Steroids - Corticosteroids represent a major class of anti-inflammatory and immunosuppressive drug in clinical use. - Structurally related to the glucocorticoid steroid hormone, cortisol. ## Side Effects of Corticosteroid Drugs (Especially in long term use): A table is displayed: | | | | | - | ----------------------------------------------------------------------------------------------------------- | -------------------------------------------------------------------------------------------------------------------------------------------------- | | **Glucocorticoid effects** | Diabetes; Cushing's syndrome and Cushingoid effects (moon face, skin striae, acne); Adrenal suppression/acute adrenal insufficiency in abrupt withdrawal | | | **Mineralocorticoid effects** | Osteoporosis; avascular necrosis of head of femur; Hypertension; sodium and water retention potassium loss | | | **Immunosuppressive effects** | Increased susceptibility to infections; Impaired wound healing; Obesity and muscle wasting; Growth arewst in children | | | **Others** | | Emotional disturbance; Enlarged sella turcica; Moon facies; Osteoporosis; Cardiac hypertrophy (hypertension); Buffalo hump; Obesity; Adrenal tumor or hyperplasia; Thin, wrinkled skin; Abdominal striae; Amenorrhea; Muscle weakness; Purpura; Skin ulcers (poor wound healing) | ## Non-steroidal anti-inflammatory drugs - (NSAIDs) represent a wide group of drugs. They have both analgesic and anti-inflammatory properties. The main anti-inflammatory properties of NSAIDs are due to inhibition of **cyclooxygenase**. A table is displayed: | Types of non-steroidal anti-inflammatory drug | Example(s) | | ----------------------------------------------- | ---------- | | Salicylic acid | Aspirin | | Propionic acid derivatives | Ibuprofen | | Non-propionic acid derivatives | Naproxen Indomethacin, Diclofenac | | Selective COX-2 inhibitors | Celocoxib, | ## NSAID Mechanism of action A diagram is displayed showing: - Arachidonic Acid - COX-1 ("Constitutive") - COX-2 ("Inducible") The diagram shows that arachidonic acid is broken down into prostaglandins by both COX-1 and COX-2. - **Prostaglandins from COX-1** contribute to GI mucosal protection and haemostasis. - **Prostaglandins from COX-2** act as mediators of pain, inflammation and fever. ## NSAIDs ADRs: - A major side effect of (older) NSAIDs is gastrointestinal toxicity. This is not found with the newer, selective COX-2 inhibitors. - However, COX-2 inhibitors have been found to have cardiovascular side effects, so should not be used in patients with ischemic heart disease or cerebrovascular disease. ## TNF - **Tumor necrosis factor:** One of multiple proteins capable of inducing necrosis *(death)* of **tumor,** have a wide range of proinflammatory actions, plays a central role in the pathogenesis of a number of autoimmune diseases, including rheumatoid arthritis and Crohn's disease. ## TNF Functions A diagram is displayed showing TNF at the center with arrows pointing to: - **Macrophages** - ↑ pro-inflammatory cytokines - ↑ chemokines - **Endothelium** - ↑ adhesion molecules - ↑ vascular endothelial growth factor (VEGF) - **Hepatocytes** - ↑ acute phase response - **Synoviocytes** - ↑ metalloproteinase synthesis Next to each arrow, the effects of TNF are described: - Increased inflammation - Increased cell infiltration - Increased angiogenesis - Increased CRP in serum - Articular cartilage degradation ## TNF Antagonists: - **Infliximab:** humanized monoclonal antibody against TNF. - **Etanercept** - Treating severe rheumatoid arthritis - Crohn's disease (Infliximab) - One important side effect is reactivation of latent tuberculosis. Patients should therefore be screened for latent TB prior to commencing treatment. ## Immunosuppressive Agents: - **Corticosteroids** - **Cytotoxic and anti-proliferative agents:** were introduced into clinical practice for the treatment of **cancer** in the 1950s. However, studies also showed that they have immunosuppressive activities, (autoimmune diseases) and inhibit organ transplant rejection. - The four cytotoxic immunosuppressive drugs most commonly used are cyclophosphamide, azathioprine, and methotrexate and mycophenolate mofetil. ## Some Immunological Diseases in Which Cytotoxic Drugs are Used: - Organ transplant rejection - Rheumatoid arthritis - Systemic lupus erythematosus - Membranous and membranoproliferative glomerulonephritis - Inflammatory bowel disease ## Immunoglobulin (Ig) An image is displayed of four different vials of Immunoglobulin (Ig). ## Immunomodulatory Properties of Intravenous Immunoglobulin: - **Mechanism of Action and Uses:** - Mechanism of action not fully understood. Different mechanisms have been proposed - Increased clearance of autoantibodies through *competitive binding* of fc receptors - Activation of *inhibitory fc receptor* on macrophages - **Uses:** - As replacement IG therapy for patients with primary and secondary antibody deficiencies. - Some diseases that failed to other forms of immunotherapy such as: - Kawasaki disease - Idiopathic thrombocytopenia - Guillain-Barre syndrome ## Monoclonal Antibodies | Monoclonal antibody | Target antigen | Disease setting(s) | |----------------------|-----------------------|-------------------------------------------------------| | Rituximab | (B-cell antigen) | B-cell leukaemia / lymphoma | | Infliximab | TNF-a | Rheumatoid arthritis; Crohn's disease | | Omalizumab | IgE | (severe) allergic asthma | ## Mechanisms of action of therapeutic monoclonal antibodies: - Neutralizing the target antigen - Inducing complement-mediated or antibody dependent (NK-mediated), - Blocking cellular interactions, or - Inducing apoptosis in their target cells. The limitation is more likely to be the cost of these drugs than the potential range of targets- one year's treatment with Herceptin costs about £20,000 per patient. ## Thanks ## References - Coursebook - The "Infection and Immunity" section of MEDICAL MICROBIOLOGY (17th Edition) - CLINICAL MEDICINE (Kumar and Clark, 5th and 6th Editions) section "Clinical Immunology"