Immunomodulation and Immunosuppression Flashcards

1
Q

What is immunomodulation?

A

The act of manipulating the immune system using immunomodulatory drugs to achieve a desired immune response.

A therapeutic effect of immunomodulation may lead to immunopotentiation, immunosuppression, or induction of immunological tolerance.

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2
Q

What are immunomodulators?

A

Medicinal products produced using molecular biology techniques including recombinant DNA technology

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3
Q

What are the main classes of immunomodulators?

A
  • Substances that are (nearly) identical to the body’s own key signaling proteins
  • Monoclonal antibodies
  • Fusion proteins
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4
Q

Example of Human IgG1 monoclonal Ab –> Adalimumab

A
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5
Q

What is a chimeric antibody?

A

Chimeric antibodies are structural chimeras made by fusing variable regions from one species like a mouse, with the constant regions from another species such as a human being.

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6
Q

Define immunopotentiation?

A

Enhancement of immune responses.

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7
Q

3 examples of immunopotentiation?

A
  • Immunisation (Active, Passive)
  • Replacement therapies
  • Immune stimulants
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8
Q

What is passive immunisation?

A

Transfer of specific, high-titre antibody (pre-formed antibodies) from donor to recipient. Provides immediate but transient protection.

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9
Q

Problems with passive immunisation?

A
  • Transient protection
  • Risk of transmission of viruses
  • Serum sickness
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10
Q

3 types of passive immunisation?

A
  1. Convalescent plasma
  2. Pooled specific human immunoglobulin
  3. Animal sera (antitoxins an antivenins)
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11
Q

What is convalescent plasma?

A

Convalescent plasma is the antibody-rich plasma of someone who has recovered from an illness

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12
Q

What diseases is passive immunisation used in?

A
  • COVID19, Hep B prophylaxis and treatment
  • Botulism, VZV (pregnancy), diphtheria, snake bites
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13
Q

What is active immunisation?

A

To stimulate the development of a protective immune response and immunological memory

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14
Q

What material is involved in active immunisation?

A
  • Weakened forms of pathogens
  • Killed inactivated pathogens
  • Purified materials (proteins, DNA, RNA)
  • Adjuvants
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15
Q

Problems with active immunisation?

A
  • Allergy to any vaccine component
  • Limited usefulness in immunocompromised
  • Delay in achieving protection
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16
Q

What is pooled human immunoglobulin? What is it used to treat?

A

Intravenous immunoglobulin (IVIG) contains the pooled immunoglobulin G (IgG) immunoglobulins from the plasma of approximately a thousand or more blood donors.

IVIGs are sterile, purified IgG products manufactured from pooled human plasma and typically contain more than 95% unmodified IgG, which has intact Fc-dependent effector functions and only trace amounts of immunoglobulin A (IgA) or immunoglobulin M (IgM).

Used to treat antibody deficiency states

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17
Q

What is G-CSF/GM-CSF? When would it be used?

A

A glycoprotein that acts on bone marrow to increase the production of mature neutrophils.

You might have G-CSF after chemotherapy to help your white blood cells recover after treatment.

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18
Q

What is IFN-γ?

A

IFN-γ is a cytokine critical to both innate and adaptive immunity, and functions as the primary activator of macrophages, in addition to stimulating natural killer cells and neutrophils.

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19
Q

What is IFN-γ used to treat?

A

Can be useful in treatment of certain intracellular infections (atypical mycobacteria), also used in chronic granulomatous disease and IL-12 deficiency

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20
Q

What drugs are used for immunosuppression?

A
  • Corticosteroids
  • Cytotoxic/ agents
  • Anti-proliferative/activation agents
  • DMARD’s
  • Biological-DMARD’s
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21
Q

How do corticosteroids provide immunosuppression?

A
  • Decreased neutrophil margination (Margination refers to the prolonged transit of neutrophils through specific organs)
  • Reduced production of inflammatory cytokines
  • Inhibition phospholipase A2 (reduced arachidonic acid metabolites production)
  • Lymphopenia
  • Decreased T cells proliferation
  • Reduced immunoglobulins production
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22
Q

What are the side effects of corticosteroids?

A
  • Carbohydrate and lipid metabolism
    • Diabetes
    • Hyperlipidaemia
  • Reduced protein synthesis
    • Poor wound healing
  • Osteoporosis
  • Glaucoma and cataracts
  • Psychiatric complications
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23
Q

What are corticosteroids used to treat?

A
  • Autoimmune diseases
    • CTD, vasculitis, RA
  • Inflammatory diseases
    • Crohn’s, sarcoid, GCA/polymyalgia rheumatica
  • Malignancies
    • Lymphoma
  • Allograft rejection
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24
Q

What drugs target lymphocytes?

A
  • Antimetabolites
    • Azathioprine (AZA)
    • Mycophenolate mofetil (MMF)
  • Calcineurin inhibitors
    • Ciclosporin A (CyA)
    • Tacrolimus (FK506)
  • M-TOR inhibitors
    • Sirolimus
  • IL-2 receptor mABs
    • Basiliximab
    • Daclizumab
25
Q

What are antimetabolites?

A

Drugs that interfere with one or more enzymes or their reactions that are necessary for DNA synthesis. They affect DNA synthesis by acting as a substitute to the actual metabolites that would be used in the normal metabolism.

26
Q

What is Azathioprine (AZA)? Used to treat? Mechanism? Contraindications?

A
  • What –> Immunosuppressant
  • Used to treat –> Crohn’s disease, rheumatoid arthritis, suppression of transplant rejection, vasculitis, SLE
  • Mechanism –> Inhibits purine synthesis which are needed to produce DNA and RNA. Less DNA and RNA are produced for the synthesis of white blood cells.
  • Contraindications –> Is inactivated by thiopurine methyltransferase (TPMT)
27
Q

What are calcineurin inhibitors?

A
  • A family of three drugs (cyclosporine, tacrolimus, and pimecrolimus) used to suppress the immune system
28
Q

Mechanism of action of calcineurin inhibitors?

A
  • Cyclosporine (CyA) binds to intracellular protein cyclophilin
  • Tacromilus (FK506) binds to intracellular protein FKBP
  • Effects of both of these prevents activation of NFAT
    • Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response.

RESULT –> Reduced IL-2 production and IL-2 receptor expression and INFy, leading to a reduction in T-cell activation. This inibition is reversible.

29
Q

What is Sirolimus (rapamycin)? Mode of action?

A
  • Macrolide antibiotic with immunosuppressive effects
  • Mechanism:
    • Binds to FKBP12 and nhibits mammalian target of rapamycin (mTOR)
    • Inhibits response to IL-2 via action on mTOR
  • Result –> T cell effects –> Cell cycle arrest at G1-S phase
30
Q

Side effects of calcineurin/mTOR inhibitors?

A
  • Hypertension
  • Hirsutism
  • Nephrotoxicity
  • Hepatotoxicity
  • Lymphomas
  • Opportunistic infections
  • Neurotoxicity
  • Multiple drug interactions (induce P450)
31
Q

Clinical use of mTOR inhibitors?

A
  • Transplantation
    • Allograft rejection
  • Autoimmune diseases
32
Q

What is Mycophenolate mofetil (MMF)?

A
  • Antimetabolite
  • Prevents prooduction of guanine triphosphate preferentially in T and B lymphocytes –> inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation.
33
Q

T and B cells effects of antimetabolites?

A
  • Impaired DNA production
  • Prevents early stages of activated cells proliferation
34
Q

What is methotrexate? Mechanism?

A
  • Antimetabolite –> immunosuppressant
  • Mechanism:
    • Inhibits dihydrofolate reductase (an important enzyme in making nucleotides for DNA and RNA)
35
Q

What is methotrexate used in?

A
  • Used in high doses for cancer treatment –> starved of building blocks for making DNA that fuels cancer
    • Has negative effect on immune cells/hair cells as these all divide quickly to require DNA
  • Used in ectopic pregnancy as inhibition of production of DNA prevents growth of embryo
  • In low doses in inflammation (arthritis) due to negative effect on immune cells
    • RA, PsA, Polymyositis, vasculitis
    • GvHD in BMT
36
Q

What are cytotoxic drugs?

A

medicines that contain chemicals which are toxic to cells

37
Q

Side effects of cytotoxic drugs?

A
  • Bone marrow suppression
  • Gastric upset
  • Hepatitis
  • Susceptibility to infections
38
Q

What is cyclophosphamide? Used to treat?

A
  • A medication used as chemotherapy and to suppress the immune system
  • Used to treat:
    • Vasculitis (Wagner’s, CSS)
    • SLE
39
Q

Side effect of cyclophosphamide?

A

Cystitis

40
Q

Side effect of methotrexate?

A

Pneumonitis

41
Q

Immunosuppressive drugs are gradually being replaced by targeted therapies. Some examples:

A
  • Anti-cytokines (TNF, IL-6 and IL-1)
  • Anti-B cell therapies
  • Anti-T cell activation
  • Anti-adhesion molecules
  • Complement inhibitors
  • Check point inhibitors
42
Q

Pathogenesis and treatment of rheumatoid arthritis

A
43
Q

What is anti-TNF? What is danger?

A
  • Anti TNF therapy interferes with the action of TNF which is over-active in the body in people with inflammatory arthritis –> can reduce inflammation.
  • Used to treat: a number of other inflammatory conditions (Crohn’s, psoriasis, ankylosing spondylitis)
  • Caution –> can increase risk of TB
44
Q

What is anti-IL-6 (Tocilizumab)? Used to treat? Problem?

A
  • Blocks IL-6 receptor
  • Used in therapy of RA and AOSD
  • Mayb cause problems with control of serum lipids
45
Q

What is antiIL-1 used to treat?

A

Used in treatment of AOSD and autoinflammatory syndromes

46
Q

What is Rituximab?

A

A chimeric monoclonal antibody (part mouse part human) against the protein CD20, which is primarily found on the surface of immune system B cells. When it binds to this protein it triggers cell death.

Targeted therapy –> lowers the number of these B-cells, to reduce inflammation, pain, swelling and joint damage

47
Q

What is Rituximab used to treat?

A
  • Lymphomas, leukaemias
  • Transplant rejection
  • Autoimmune disorders
48
Q

What is adoptive immunotherapy? What is it used in?

A
  • Bone marrow transplant
  • Stem cell transplant
  • Uses:
    • Immunodeficiencies (SCID)
    • Lymphomas and leukaemias
    • Inherited metabolic disorders (osteopetrosis)
    • Autoimmune diseases
49
Q

What are checkpoint inhibitors?

A

Checkpoint inhibitors work by blocking checkpoint proteins from binding with their partner proteins. This prevents the “off” signal from being sent, allowing the T cells to kill cancer cells.

50
Q

mechanism of action of checkpoint inhibitors?

A

Tumour cells evade the immune system by downregulating the activity of T cells. Checkpoint inhibitors increase cytotoxic T-cell activity by expanding T-cell activation and proliferation. The eventual T-cell reactivation is responsible for the both anti-tumor response and the immune-related adverse events associated with these drugs.

51
Q

How are immunomodulators used in allergies?

A
  • Immune suppressants
  • Allergen specific immunotherapy
  • Anti-IgE monoclonal therapy
    • Approved for treatment of moderate to severe IgE-mediated (allergic) asthma
    • Neutralisation of free serum IgE
  • Anti-IL-5 monoclonal treatment
52
Q

What is allergen specific immunotherapy?

A

Immunotherapy involves exposing people to larger and larger amounts of allergen in an attempt to change the immune system’s response

53
Q

When is allergen specific immunotherapy used?

A
  • Allergic rhinoconjutivitis not controlled on maximum medical therapy
  • Anaphylaxis to insect venoms
54
Q

Mechanism of allergen specific immunotherapy?

A
  • Switching of immune response from Th2 (allergic) to Th1 (non-allergic)
  • Development of T reg cells and tolerance
55
Q

Side effects of allergen specific immunotherapy?

A

Localised and systemic allergic reactions

56
Q

Routes of administration of allergen specific immunotherapy?

A

SC or sublingual for aero-allergens

57
Q

What is Omalizumab? Used to treat?

A
  • Monoclonal antibody against IgE (anti IgE)
  • Used in treatment of asthma, chronic urticaria and angioedema
58
Q

What is Mepolizumab? Used to treat?

A
  • Monoclonal antibody (mAb) against IL-5
    • Prevents eosinophil recruitment and activation
  • Treatment in asthma