Core Immunology - Immunomodulation and Immunosuppression (13) Flashcards Preview

Clinical Pathology > Core Immunology - Immunomodulation and Immunosuppression (13) > Flashcards

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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Mepolizumab

Against IL-5, prevents eosinophil recruitment and activation

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