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2. CP - Core Immunology > (12) Immunomodulation and Suppression > Flashcards

(12) Immunomodulation and Suppression Flashcards

1
Q

What is the definition of immunomodulation?

A

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

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2
Q

A therapeutic effect of immunomodulation may lead to what?

A
  • immunopotentiation
  • immunosuppression
  • induction of immunological tolerance
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3
Q

What are the possible mechanisms of immunomodulation?

A
  • immunisation
  • replacement therapy
  • immune stimulants
  • immune suppressants
  • anti-inflammatory agents
  • allergen immunotherapy (desentisation)
  • adoptive immunotherapy
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4
Q

What are biologics?

A

Medicinal products produced using molecular biology techniques including recombinant DNA technology

An immunomodulator

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5
Q

What are the main classes of biologics?

A
  • substances that are (nearly) identical to the body’s own key signalling proteins
  • monoclonal antibodies
  • fusion proteins
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6
Q

What is adalimumab?

A

Human IgG1
Monoclonal antibody

Has a human constant domain (Fc) and a human variable domain (Fab region)

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7
Q

What is infliximab?

A

Chimeric mouse-human
IgG1 monoclonal antibody

Has a human constant domain and a murine variable domain

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8
Q

What is entanercept?

A

Fusion protein
Fc-TNFR2 extracellular domain

Has a human constant domain and a human TNFR2 extracellular domain

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9
Q

What is cetrolizumab?

A

Humanised monovalent Fab-PEG

Has a polyehtylene glycol (PEG) moiety, a human constant domain and a human variable domain

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10
Q

What is immunopotentiation?

A

Accentuation of the response to an immunogen by administration of another substance

  • immunisation - active and passive
  • replacement therapies
  • immune stimulants
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11
Q

What is the definition of passive immunisation?

A

Transfer of specific, high-titre antibody from donor to recipient

Provides immediate but transient protection

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12
Q

What are the problems with passive immunisation?

A
  • risk of transmission of viruses

- serum sickness

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13
Q

What is serum sickness?

A

An allergic reaction to an injection of serum, typically mild and characterised by skin rashes, joint stiffness, and fever

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14
Q

What are types of passive immunisation?

A
  • pooled specific human immunoglobin

- animal sera (antitoxins and antivenins)

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15
Q

What are the uses of passive immunisation?

A
  • hep B prophylaxis and treatment

- botulism, VZV (pregnancy), diphtheria, snake bites

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16
Q

What is the definition of active immunisation?

A

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

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17
Q

What are the immunogenic materials used in active immunisation?

A
  • weakened forms of pathogens
  • killed inactivated pathogens
  • purified materials (proteins, DNA)
  • adjuvants
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18
Q

What are the problems with active immunisation?

A
  • allergy to any vaccine component
  • limited usefulness in immunocompromised
  • delay in achieving protection
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19
Q

Give some examples of replacement therapies and immune stimulation

A
  • pooled human immunoglobin (IV or SC)
  • G-CSF/GM-CSF
  • IL-2
  • a-interferon
  • b-interferon
  • y-interferon
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20
Q

Pooled human immunoglobins can be used in replacement therapies/immune stimulation. When are they used?

A

Used in Rx of antibody deficiency states

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21
Q

G-CSF and GM-CSF can be used in immune stimulation. What are they and what do they do?

A

Granulocyte-colony stimulating factor

Granulocyte macrophage-colony stimulating factor

Glycoprotein that stimulates bone marrow to increase production of mature neutrophils

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22
Q

IL-2 can be used in immune stimulation. What does it do?

A

Stimulates T cell activation - rarely used

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23
Q

a-interferon can be used in replacement therapy/immune stimulation. What is it used for?

A

Main use in treatment of Hep C

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24
Q

b-interferon can be used in replacement therapy/immune stimulation. What is it used for?

A

Used in therapy of MS

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25
Q

y-interferon can be used in replacement therapy/immune stimulation. What can it be used for?

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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26
Q

What substances cause immunosuppression?

A
  • corticosteroids
  • cytotoxic agents
  • anti-proliferative/activatio agents
  • DMARDs
  • biologic DMARDs
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27
Q

What are DMARDs?

A

Disease-modifying antirheumatic drugs - commonly used in rheumatoid arthritis.

Decrease pain and inflammation, reduce or prevent joint damage, and preserve the structure and function of the joints

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28
Q

What is the action of corticosteroids (immunosuppression)?

A
  • decreased neutrophil margination
  • reduced production of inflammatory cytokines
  • inhibition of phospholipase A2 (reduced arachidonic acid metabolites production)
  • lymphopenia
  • decreased T cells proliferation
  • reduced immunoglobulins production
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29
Q

What is lymphopenia?

A

Lymphocytopenia, or lymphopenia, is the condition of having an abnormally low level of lymphocytes in the blood

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30
Q

What is thrombocytopenia?

A

Deficiency of platelets in the blood - causes bleeding into the tissues, bruising, and slow blood clotting after injury

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31
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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32
Q

What are the uses of corticosteroids?

A
  • Autoimmune disease (CTD, vasculitis, RA)
  • Inflammatory diseases (Crohn’s, sarcoid, GCA/polymyalgia rheumatica)
  • malignancies (lymphoma)
  • allograft rejection
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33
Q

T cells can be a target for immunosupression. What is the normal T cell pathway?

A
  • antigen presenting to T cell by APC
  • T cell binds the you get activation
  • IL-2 released and acts in an autocrine fashion, allowing T cell to further up regulate
  • mTOR allows cell cycle progression
  • T cell proliferation
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34
Q

CyA and tacrolimus are drugs used in T cell targeted immunosuppression. Where in the pathway do they act?

A

At T cell activation

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35
Q

Anti-IL-2 receptor antibodies are drugs used in T cell targeted immunosuppression. Where in the pathway do they act?

A

On the IL-2 receptor on the T cell to prevent further up regulation etc.

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36
Q

Sirolimus is a drug used in T cell targeted immunosuppression. Where in the pathway does it act?

A

Interferes with mTOR activation and therefore T cell cycle progression

37
Q

Azathioprine and MMF are drugs used in T cell targeted immunosuppression. Where int the pathway does it act?

A

It interferes with T cell proliferation

38
Q

Which 4 types of drugs are used in T cell targeted immunosuppression at different stages of the T cell pathway?

A
  • CvA, Tacrolimus
  • anti-IL-2 receptor mAbs
  • sirolimus
  • azathioprine, MMF
39
Q

Ciclosporin A (CyA) and Tacromilus (FK506) are drugs targeting lymphocytes. What type of drug are they?

A

Calcineurin inhibitors

40
Q

IL-2 receptor mAbs are drugs targeting lymphocytes. Give examples

A
  • basiliximab

- daclizumab

41
Q

Sirolimus is a drug targeting lymphocytes. It is a type of what type of drug?

A

M-TOR inhibitors

42
Q

Azathioprine (AZA) and mycophenolate mofetil (MMF) are drugs targeting lymphocytes. They are types of which type of drug?

A

Antimetabolites

43
Q

What are the 4 classifications of drugs targeting lymphocytes?

A
  • antimetabolites
  • calcineurin inhibitors
  • M-TOR inhibitors
  • IL-2 receptor mAbs
44
Q

What do the 2 calcineurin inhibitors bind to?

A

CyA = binds to intracellular protein cyclophilin

Tacrolimus (FK506) = binds to intracellular protein FKBP-12

45
Q

What is the mode of action of calcineurin inhibitors?

A
  • prevents activation of NFAT

- factors which stimulate cytokines (ie. IL-2 and INFy) gene transcription

46
Q

What are the T cell effects of calcineurin inhibitors?

A

Reversible inhibition of T cell-activation, proliferation and clonal expansion

47
Q

Sirolimus (rapamycin) is a macrolide antibiotic that does what?

A
  • also binds to FKB12 but has different effects

- inhibits mammalian target of rapamycin (mTOR)

48
Q

What is the mode of action of sirolimus?

A
  • inhibits response to IL-2
49
Q

What are the T cell effects of sirolimus?

A
  • cell cycle arrest at G1-S phase
50
Q

What are the calcineurin/mTOR side effects?

A
  • hypertension
  • hirsutism
  • nephrotoxicity
  • heptotoxicity
  • lymphomas
  • opportunistic infections
  • neurotoxicity
  • multiple drug interactions (induce P450)
51
Q

What is hirsutism?

A

Excessive hair growth in women

52
Q

What are clinical uses of calcineurin and mTOR inhibitors?

A
  • transplantation (allograft rejection)

- autoimmune diseases

53
Q

Generally, what do the antimetabolites do?

A

Inhibit nucleotide (purine) synthesis

54
Q

What does AZA (an antimetabolite) do?

A
  • guanine anti-metabolite

- rapidly converted into 6-mercaptopurine

55
Q

What does MMF (an anti-metabolite) do?

A
  • non-competitive inhibitor of IMPDH

- prevents production of guanosine triphosphate

56
Q

What are the T and B cell effects of AZA and MMF (anti-metabolites)?

A
  • impaired DNA production

- prevents early stages of activated cells proliferation

57
Q

Give some other examples of anti-metabolites and cytotoxic drugs

A
  • methotrexate (MTX) - folate antagonist

- cyclophosphamide - cross-link DNA

58
Q

What are the side effects of all cytotoxic drugs?

A
  • bone marrow suppression
  • gastric upset
  • hepatitis
  • susceptibility to infection
59
Q

What are side effects of cytotoxic drugs, specifically MTX?

A

pneumonitis

60
Q

What are the side effects of cytotoxic drugs, specifically cyclophosphamide?

A

cystitis

61
Q

What is cystitis?

A

Inflammation of the bladder, usually caused by a bladder infection

62
Q

What are the clinical uses of cytotoxics - AZA/MMF?

A
  • autoimmune diseases (SLE, vasculitis, IBD)

- allograft rejection

63
Q

What are the clinical uses of cytotoxics - MTX?

A
  • RA, PsA, polymyositis, vasculitis

- GvHD in BMT

64
Q

What are the clinical uses of cytotoxics - cyclophosphamide?

A
  • vasculitis (Wagner’s, CCS)

- SLE

65
Q

What are the different types of biologic DMARDs?

A
  • anti-cytokines (TNF, IL-6 and IL-1)
  • anti-B cell therapies
  • anti-T cell activation
  • anti-adhesion molecules
  • complement inhibitors
66
Q

Give 3 types of anti-cytokines

A
  • anti-TNF
  • anti-lL-6 (Tocilizumab)
  • anti-IL-1
67
Q

What is anti-TNF used for? (a biologic)

A
  • first biologics to be successfully used in the therapy of RA
  • used in other inflammatory conditions eg. Crohn’s, psoriasis, ankylosing spondylitis
68
Q

What is a caution of use of anti-TNF? ( a biologic)

A

Increased risk of TB

69
Q

What is anti-IL-6 (Tocilizumab) used for?

A
  • blocks IL-6 receptor

- used in therapy of RA and AOSD

70
Q

What is AOSD? (adult onset Still’s disease)

A

Rare systemic inflammatory disease characterized by the classic triad of persistent high spiking fevers, joint pain and a distinctive salmon-colored bumpy rash

71
Q

What problems may anti-IL-6 cause?

A

Problems with control of serum lipids

72
Q

What are 3 different agents of IL-1 that are available?

A
  • anakinra
  • rilonacept
  • canakinumab
73
Q

What is anti-IL-1 used for?

A

Used in treatment of AOSD and autoinflammatory syndromes

74
Q

What is rituximab?

A

Chimeric mAb against CD20-B cell surface

First approved in ‘97 for treatment of chemotherapy resistant DLCL

75
Q

What are the uses for rituximab?

A
  • lymphomas, leukaemias
  • transplant rejection
  • autoimmune disorders
76
Q

Give 2 examples of adoptive immunotherapy

A
  • bone marrow transplant (BMT)

- stem cell transplant (SCT)

77
Q

What are the uses of adoptive immunotherapy (BMT and SCT)?

A
  • immunodeficiencies (SCID)
  • lymphomas and leukaemias
  • inherited metabolic disorders (osteopetrosis)
  • autoimmune diseases
78
Q

What is osteopetrosis?

A

“stone bone”

an extremely rare inherited disorder whereby the bones harden, becoming denser - can cause bones to dissolve and break

79
Q

What types of immunomodulators are used in allergy?

A
  • immune suppressants
  • allergen specific immunotherapy
  • anti-IgE monoclonal therapy
  • anti-IL-5 monoclonal treatment
80
Q

What are indications for allergen specific immunotherapy?

A
  • allergic rhinoconjunctivitis not controlled on maximum medical therapy
  • anaphylaxis to insect venoms
81
Q

What are the mechanisms of allergen specific immnunotherapy?

A
  • switching of immune response from Th2 (allergic) to Th1 (non-allergic)
  • development of T reg cells and tolerance
82
Q

What are the routes of allergen specific immunotherapy?

A

SC or sublingual for aero-allergens

83
Q

What are the side effects of allergen specific immunotherapy?

A

Localised and systemic allergic reactions

84
Q

Which two monoclonal antibodies are used in immunomodulation for allergy?

A
  • omalizumab (mAb against IgE)

- mepolizumab (mAb against IL-5)

85
Q

Omalizumab is a monoclonal antibody against IgE. Which allergies is it used in?

A
  • asthma
  • chronic urticaria
  • angioedema
86
Q

What problems may arise when using omalizumab (a monoclonal antibody against IgE)?

A

May cause severe systemic anaphylaxis

87
Q

Mepolizumab is a monoclonal antibody against IL-5. What does it do?

A

Prevents eosinophil recruitment and activation

88
Q

What is mepolizumab (a monoclonal antibody against IL-5) not useful for?

A
  • limited effect on asthma

- no clinical efficacy in hypereosinophilic syndrome

2. CP - Core Immunology (7 decks)

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