Flashcards in Core Immunology - Immunomodulation and Immunosuppression (13) Deck (70):
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Immunomodulation
Manipulating the immune system using immunomodulatory drugs
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What is the therapeutic effect of immunomodulation?
- Immunopotentiation
- Immunosuppression
- Immunological tolerance
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Immunopotentiation
Enhancing immune response by adding another substance, increasing it's rate/prolonging duration
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Mechanisms of immunomodulation
Immunisation, replacement therapy, immune stimulants, immune suppressants, anti-inflammatory agents, allergen immunotherapy/desentisation, adoptive immunotherapy
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Biologics - immunomodulators
Medicine products produced using molecular biology techniques - recombinant DNA
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Classes of biologics immunomodulators
- Substances nearly identical to body's own key signalling proteins
- Monoclonal antibodies
- Fusion proteins
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Anti-TNF
- Adalimumab (human IgG)
- Infliximab (chimeric mouse-human IgG)
- Etanercept (fusion protein)
- Cetrolizumab (humanised)
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Immunopotentiation
Increase immune response by administration of another substance (increasing rate/prolonging duration)
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Examples of immunopotentiation
Immunisation, replacement therapies, immune stimulants
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Passive immunisation
Transfer of specific, high-titre antibody from donor to recipient, provides immediate but transient protection
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Problems with passive immunisation
Risk of transmission of viruses, serum sickness
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Types of passive immunisation
Pooled specific human Ig, animal sera (antitoxins and antivenins)
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Uses of passive immunisation
Hep B (prophylaxis and treatment), Botulism, VZV (pregnancy), Diphtheria, Snake bites
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Active immunisation
To stimulate the development of protective immune response from immunological memory
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Active immunisation immunogenic material
Weakened forms of pathogens, killed inactivated pathogens, purified materials (proteins, DNA), adjuvants
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Active immunisation problems
Allergy to any vaccine component, limited usefulness in immunocompromised, delay in achieving protection
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Replacement therapies - Pooled human Ig
Used in treatment of antibody deficiencies (IV/SC)
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Immune stimulation - G-CSF/GM-CSF
Act on bone marrow, to increase production of mature neutrophils
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Immune stimulation - IL-2
Stimulates T cell activation (rarely used)
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Immune stimulation a-INF
Hep C
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Immune stimulation B-INF
MS
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Immune stimulation y-INF
Intracellular infections (atypical mycobacteria), chronic granulomatous disease, IL-12 deficiency
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Interferon
Increases anti-viral response, occurs naturally, increase protein synthesis > increased resistance (makes you feel flu-like)
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Immunosuppression
- Cortiocosteroids
- Cytotoxic agents
- Anti-proliferative/activation agents
- DMARD's
- Biologic DMARD's
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Corticosteroids action
Decrease neutrophil margination, reduce cytokine production, inhibit phospholipase A2 (reduced arachidonic acid metabolites production), lymphopenia, decreases T cell proliferation and Ig production
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Corticosteroid side-effects
- Carb and lipid metabolism (diabetes and hyperlipidaemia)
- Reduced protein synthesis (poor wound healing)
- Osteoporosis
- Glaucoma and cataracts
- Psychiatric complications
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Uses of corticosteroids
- AI (connective tissue disorder, vasculitis, RA)
- Inflammatory (Crohn's, sarcoid, GCA/polymyalgia rheumatica)
- Lymphoma
- Allograft rejection
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Antimetabolites
Stop proliferation of T-cells - Azathioprine (AZA), Mycophenolate mofetil (MMF)
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Calcineurin inhibitors
Ciclosporin A (CyA), Tacrolimus (FK506)
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CyA
Binds to intracellular protein cyclophilin
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Tacrolimus
Binds to intracellular protein FKBP-12
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Calcineurin mode of actions
Prevent activation of NFAT, factors which stimulate cytokines (IL-2 and INFy) gene transcription
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M-TOR inhibitors
Sirolimus/rapamycin (structurally related to tacromilus)
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M-TOR mode of action
Inhibits target of rapamycin (Macrolide antibiotic), inhibits response to IL-2
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M-TOR effects on T cels
Can't proliferate, cell cycle arrests at GI-S phase
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Calcineurin/M-TOR side effects
Increased bp, nephrotoxicity, lymphomas, neurotoxicity, hirsutism (hair growth), hepatotoxicity, opportunistic infections, multiple drug interactions
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Antimetabolites
Inhibit nucleotide/purine synthesis
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AZA mechanism
Guanine anti-metabolite, rapidly converts > 6-mercaptopurine
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MMF mechanism
Non-competitive inhibitor of IMPDH, prevents production of guanosine triphosphate
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Antimetabolites effects on B and T cells
Impaired DNA production, prevents early stages of activated cell proliferation
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Antimetabolite uses
Allograft rejetion, SLE, vasculitis, IBD
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Cytotoxic antimetabolites
MTX and cyclophospamide
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Methotrexate mechanism
Folate antagonist
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Uses of methotrexate
RA, PsA, GvHD in BMT, RA, Polymyositis, Vasculitis
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Cyclophospamide mechanism
Cross-link DNA
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Cyclophospamide uses
SLE, vasculitis, Wagner's, CSS
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Side effects of MTX and Cyclophospamide
Bone marrow suppression, gastric upset, hepatitis, susceptibility to infections (MTX - pneumonitis, C-cystitis)
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Biological DMARD's
Biological Disease-Modifying Anti Rheumatic Drugs
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Types of biological DMARD's
Anti-cytokines (TNF, IL-6, IL-1), anti B-cell, anti- T cell activation, anti-adhesion molecules, complement inhibitors
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Anti-cytokines
- Anti-TNF (activate macrophages)
- Anti IL-6
- Anti IL-1
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Anti-TNF
Used: RA, Crohn's, Psoriasis, Ankylosing Spondylitis
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Anti IL-6
Tocilizumab, RA and adult onset still's disease
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Anti-TNF problems
Increased risk of TB
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Anti IL-6 problems
Control of serum lipids
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Anti IL-1 examples
Anakinra, Rilonacept, Canakinumab
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Anti IL-1 uses
AOSD and auto inflammatory syndromes
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Rituximab
Part mouse and part human chimeric mAB against CD20-B cell
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Rituximab uses
Lymphoma (B-cell origin), leukaemia, transplant rejection, autoimmune disorder (chemotherapy resistant diffuse large B-cell lymphoma)
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Adoptive immunotherapy
Bone marrow transplant or stem cell transplant
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Adoptive immunotherapy uses
SCID, lymphomas, leukaemias, inherited metabolic disorders (osteoporosis), AI
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Immunomodulators - allergy
Immune suppressants, allergen specific immunotherapy, anti-IgE monoclonal therapy, anti IL-5 monoclonal treatment
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Indications of allergy immunomodulators
- Allergic rhinoconjuctivitis not controlled
- Anaphylaxis to insect venom
- Steroids low response
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Mechanisms of allergy immunomodulators
Switching of immune response Th2 (allergic) > Th1 (non-allergic), development of T reg cells and tolerance
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Routes of allergy immunomodulators
SC/sublingual
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Side effects of allergy immunomodulators
Localised/systemic allergic reactions
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Monoclonal antibodies against allergies
Omalizumab and Mepolizumab
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Omalizumab
Against IgE
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Omalizumab uses
Asthma, chronic urticaria and angio-oedema
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Side effects of omalizumab
Severe systemic anaphylaxis
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