(12) Immunomodulation and Suppression Flashcards Preview

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

Flashcards in (12) Immunomodulation and Suppression Deck (88):
1

What is the definition of immunomodulation?

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

2

A therapeutic effect of immunomodulation may lead to what?

- immunopotentiation
- immunosuppression
- induction of immunological tolerance

3

What are the possible mechanisms of immunomodulation?

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

4

What are biologics?

Medicinal products produced using molecular biology techniques including recombinant DNA technology

An immunomodulator

5

What are the main classes of biologics?

- substances that are (nearly) identical to the body's own key signalling proteins
- monoclonal antibodies
- fusion proteins

6

What is adalimumab?

Human IgG1
Monoclonal antibody

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

7

What is infliximab?

Chimeric mouse-human
IgG1 monoclonal antibody

Has a human constant domain and a murine variable domain

8

What is entanercept?

Fusion protein
Fc-TNFR2 extracellular domain

Has a human constant domain and a human TNFR2 extracellular domain

9

What is cetrolizumab?

Humanised monovalent Fab-PEG

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

10

What is immunopotentiation?

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

- immunisation - active and passive
- replacement therapies
- immune stimulants

11

What is the definition of passive immunisation?

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

Provides immediate but transient protection

12

What are the problems with passive immunisation?

- risk of transmission of viruses
- serum sickness

13

What is serum sickness?

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

14

What are types of passive immunisation?

- pooled specific human immunoglobin
- animal sera (antitoxins and antivenins)

15

What are the uses of passive immunisation?

- hep B prophylaxis and treatment
- botulism, VZV (pregnancy), diphtheria, snake bites

16

What is the definition of active immunisation?

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

17

What are the immunogenic materials used in active immunisation?

- weakened forms of pathogens
- killed inactivated pathogens
- purified materials (proteins, DNA)
- adjuvants

18

What are the problems with active immunisation?

- allergy to any vaccine component
- limited usefulness in immunocompromised
- delay in achieving protection

19

Give some examples of replacement therapies and immune stimulation

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

20

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

Used in Rx of antibody deficiency states

21

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

Granulocyte-colony stimulating factor

Granulocyte macrophage-colony stimulating factor

Glycoprotein that stimulates bone marrow to increase production of mature neutrophils

22

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

Stimulates T cell activation - rarely used

23

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

Main use in treatment of Hep C

24

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

Used in therapy of MS

25

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

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

26

What substances cause immunosuppression?

- corticosteroids
- cytotoxic agents
- anti-proliferative/activatio agents
- DMARDs
- biologic DMARDs

27

What are DMARDs?

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

28

What is the action of corticosteroids (immunosuppression)?

- 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

29

What is lymphopenia?

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

30

What is thrombocytopenia?

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

31

What are the side effects of corticosteroids?

- carbohydrate and lipid metabolism (diabetes, hyperlipidaemia)
- reduced protein synthesis (poor wound healing)
- osteoporosis
- glaucoma and cataracts
- psychiatric complications

32

What are the uses of corticosteroids?

- Autoimmune disease (CTD, vasculitis, RA)
- Inflammatory diseases (Crohn's, sarcoid, GCA/polymyalgia rheumatica)
- malignancies (lymphoma)
- allograft rejection

33

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

- 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

34

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

At T cell activation

35

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

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

36

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

Interferes with mTOR activation and therefore T cell cycle progression

37

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

It interferes with T cell proliferation

38

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

- CvA, Tacrolimus
- anti-IL-2 receptor mAbs
- sirolimus
- azathioprine, MMF

39

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

Calcineurin inhibitors

40

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

- basiliximab
- daclizumab

41

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

M-TOR inhibitors

42

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

Antimetabolites

43

What are the 4 classifications of drugs targeting lymphocytes?

- antimetabolites
- calcineurin inhibitors
- M-TOR inhibitors
- IL-2 receptor mAbs

44

What do the 2 calcineurin inhibitors bind to?

CyA = binds to intracellular protein cyclophilin

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

45

What is the mode of action of calcineurin inhibitors?

- prevents activation of NFAT
- factors which stimulate cytokines (ie. IL-2 and INFy) gene transcription

46

What are the T cell effects of calcineurin inhibitors?

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

47

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

- also binds to FKB12 but has different effects
- inhibits mammalian target of rapamycin (mTOR)

48

What is the mode of action of sirolimus?

- inhibits response to IL-2

49

What are the T cell effects of sirolimus?

- cell cycle arrest at G1-S phase

50

What are the calcineurin/mTOR side effects?

- hypertension
- hirsutism
- nephrotoxicity
- heptotoxicity
- lymphomas
- opportunistic infections
- neurotoxicity
- multiple drug interactions (induce P450)

51

What is hirsutism?

Excessive hair growth in women

52

What are clinical uses of calcineurin and mTOR inhibitors?

- transplantation (allograft rejection)
- autoimmune diseases

53

Generally, what do the antimetabolites do?

Inhibit nucleotide (purine) synthesis

54

What does AZA (an antimetabolite) do?

- guanine anti-metabolite
- rapidly converted into 6-mercaptopurine

55

What does MMF (an anti-metabolite) do?

- non-competitive inhibitor of IMPDH
- prevents production of guanosine triphosphate

56

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

- impaired DNA production
- prevents early stages of activated cells proliferation

57

Give some other examples of anti-metabolites and cytotoxic drugs

- methotrexate (MTX) - folate antagonist

- cyclophosphamide - cross-link DNA

58

What are the side effects of all cytotoxic drugs?

- bone marrow suppression
- gastric upset
- hepatitis
- susceptibility to infection

59

What are side effects of cytotoxic drugs, specifically MTX?

pneumonitis

60

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

cystitis

61

What is cystitis?

Inflammation of the bladder, usually caused by a bladder infection

62

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

- autoimmune diseases (SLE, vasculitis, IBD)
- allograft rejection

63

What are the clinical uses of cytotoxics - MTX?

- RA, PsA, polymyositis, vasculitis
- GvHD in BMT

64

What are the clinical uses of cytotoxics - cyclophosphamide?

- vasculitis (Wagner's, CCS)
- SLE

65

What are the different types of biologic DMARDs?

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

66

Give 3 types of anti-cytokines

- anti-TNF
- anti-lL-6 (Tocilizumab)
- anti-IL-1

67

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

- first biologics to be successfully used in the therapy of RA
- used in other inflammatory conditions eg. Crohn's, psoriasis, ankylosing spondylitis

68

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

Increased risk of TB

69

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

- blocks IL-6 receptor
- used in therapy of RA and AOSD

70

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

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

71

What problems may anti-IL-6 cause?

Problems with control of serum lipids

72

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

- anakinra
- rilonacept
- canakinumab

73

What is anti-IL-1 used for?

Used in treatment of AOSD and autoinflammatory syndromes

74

What is rituximab?

Chimeric mAb against CD20-B cell surface

First approved in '97 for treatment of chemotherapy resistant DLCL

75

What are the uses for rituximab?

- lymphomas, leukaemias
- transplant rejection
- autoimmune disorders

76

Give 2 examples of adoptive immunotherapy

- bone marrow transplant (BMT)
- stem cell transplant (SCT)

77

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

- immunodeficiencies (SCID)
- lymphomas and leukaemias
- inherited metabolic disorders (osteopetrosis)
- autoimmune diseases

78

What is osteopetrosis?

"stone bone"

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

79

What types of immunomodulators are used in allergy?

- immune suppressants
- allergen specific immunotherapy
- anti-IgE monoclonal therapy
- anti-IL-5 monoclonal treatment

80

What are indications for allergen specific immunotherapy?

- allergic rhinoconjunctivitis not controlled on maximum medical therapy
- anaphylaxis to insect venoms

81

What are the mechanisms of allergen specific immnunotherapy?

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

82

What are the routes of allergen specific immunotherapy?

SC or sublingual for aero-allergens

83

What are the side effects of allergen specific immunotherapy?

Localised and systemic allergic reactions

84

Which two monoclonal antibodies are used in immunomodulation for allergy?

- omalizumab (mAb against IgE)

- mepolizumab (mAb against IL-5)

85

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

- asthma
- chronic urticaria
- angioedema

86

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

May cause severe systemic anaphylaxis

87

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

Prevents eosinophil recruitment and activation

88

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

- limited effect on asthma
- no clinical efficacy in hypereosinophilic syndrome