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Year 2 Clinical Pathology > Immunomodulation and suppression > Flashcards

Immunomodulation and suppression Flashcards

1
Q

What is meant by immunomodulation?

A

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

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2
Q

What are the 3 possible outcomes of immunomodulation?

A

1) Immunopotentiation (enhancement of the immune response by increasing its rate or duration)
2) Immunosuppression
3) Induction of immunological tolerance

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3
Q

What are the 7 mechanisms of immunomodulation?

A

1) Immunization
2) Replacement therapy
3) Immune stimulants
4) Immune suppressants
5) Anti-inflammatory agents
6) Allergen immunotherapy (desensitization)
7) Adoptive immunotherapy

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4
Q

What are biologics?

A

Medicinal products produced using molecular biology techniques including recombinant DNA

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5
Q

What are the 3 main classes of biologics?

A

1) Substances that are (nearly) identical to the body’s own key signalling proteins
2) Monoclonal antibodies
3) Fusion proteins

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6
Q

Adalimumab is a Human IgG anti-TNF monoclonal Ab, what is its structure?

A

Human Fc portion and Human Fab portion that binds to TNF

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7
Q

Etanercept is a fusion protein anti-TNF monoclonal Ab, what is its structure?

A

Human Fc portion bound to a human TNFR2 (TNF receptor) which in the body serves to mop up extra TNF)

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8
Q

What is TNF?

A

An important pro-inflammatory cytokine

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9
Q

Infliximab is a chimeric mouse-human anti-TNF monoclonal Ab, what is its structure and how is it produced?

A

Mouse Fab portion
Human Fc portion
Mice are modified to produce a human Fc portion and are given TNF so produce an Ab against TNF with a mouse Fab portion and a human Fc portion

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10
Q

Cetrolizumab is a humanised monovalent Fab-PEG anti-TNF monoclonal Ab what is its structure?

A

Human Fab region bound to a polyethylene glycol - this makes the Fab region more stable and less digestible

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11
Q

What 3 treatments or processes lead to immunopotentiation?

A

1) Immunisation
2) Replacement therapies
3) Immune stimulants

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12
Q

What is passive immunisation?

A

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

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13
Q

What kind of protection does passive immunisation provide?

A

Immediate but transient protection

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14
Q

What are the 2 main problems with passive immunisation?

A

1) Risk of transmission of viruses (Ab are blood borne)

2) Serum sickness (occurs when suddenly a large number of immune complexes form within the circulation)

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15
Q

What are the 2 types of passive vaccinations?

A

1) Pooled specific human immunoglobulin

2) Animal sera

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16
Q

What are the 5 main uses of passive immunisation?

A

1) Hep B prophylaxis and treatment
2) Botulism
3) VZV (in pregnancy)
4) Diphtheria
5) Snake bites

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17
Q

What is active immunisation?

A

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

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18
Q

What are the 4 kinds of immunogenic material used in active immunisation?

A

1) Weakened forms of pathogens
2) Killed, inactivated pathogens
3) Purified materials (proteins, DNA)
4) Adjuvants

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19
Q

What are the 3 problems associated with active immunisation?

A

1) Allergy to any vaccine component
2) Limited usefulness in immunocompromised
3) Delay in achieving potential

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20
Q

What are the 6 types of immune replacement therapy?

A

1) Pooled human immunoglobulin
2) G-CSF/GM-CSF
3) IL-2
4) alpha-interferon
5) beta-interferon
6) gamma-interferon

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21
Q

What is pooled human immunoglobulin replacement therapy used in the treatment of?

A

Immune deficient states

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22
Q

What does G-CSF/GM-CSF replacement therapy do?

A

Acts on the bone marrow to increase production of mature neutrophils

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23
Q

What does IL-2 replacement therapy do, is it used often?

A

Stimulates T cell activation - rarely used

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24
Q

What is alpha-interferon replacement therapy used in the treatment of?

A

Hepatitis C

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25
Q

What is beta-interferon replacement therapy used in the treatment of?

A

MS

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26
Q

What can gamma-interferon replacement therapy be useful in the treatment of?

A

Certain intracellular infections (atypical mycobacteria), also used in the chronic granulomatous disease and IL-12 deficiency

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27
Q

What 5 types of drugs are immunosuppressants?

A

1) Corticosteroids
2) Cytotoxic agents
3) Anti-proliferative/activation agents
4) DMARDs
5) Biologic DMARDs

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28
Q

What are the 6 effects of corticosteroids on the immune system leading to immunosuppression?

A

1) Decreased neutrophil margination (movement into tissues)
2) Reduced production of inflammatory cytokines
3) Inhibition of phospholipase A2 (reduced arachidonic acid metabolites production)
4) Lymphopenia
5) Decreased T cell proliferation
6) Reduced immunoglobulins production

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29
Q

What are the 5 main side effects of corticosteroids?

A

1) Changes to carbohydrate and lipid metabolism (diabetes, hyperlipidaemia)
2) Reduced protein synthesis (poor wound healing)
3) Osteoporosis
4) Glaucoma and cataracts
5) Psychiatric complications

30
Q

What 4 kinds of diseases/conditions are corticosteroids used to treat?

A

1) Autoimmune diseases (CTD (connective tissue diseases), vasculitis, RA)
2) Inflammatory diseases (Crohn’s, Sarcoids, GCA/polymyalgia rheumatic)
3) Malignancies (lymphoma)
4) Allograft (human tissue graft) rejection

31
Q

What are the 4 classes of drugs targeting lymphocytes?

A

1) Antimetabolites
2) Calcineurin inhibitors
3) M-TOR inhibitors
4) IL-2 receptor mABs

32
Q

What is the mode of action of calcineurin inhibitors?

A

Bind to intracellular proteins
Prevents activation of NFAT - factor which stimulates cytokine (ie. IL-2 and INF-gamma) transcription
Reversible inhibition of T cell activation, proliferation and clonal expansion results

33
Q

What intracellular protein does the calcineurin inhibitor ciclosporin A bind to?

A

Cyclophillin

34
Q

What intracellular protein does the calcineurin inhibitor Tacrolimus bind to?

A

FKBP-12

35
Q

Once T cells have an antigen presenting cell presented to them by an APC, what 2 stages do they go through?

A

1) Activation - by autocrine cytokine IL-2
2) Proliferation - IL2 stimulates signalling pathway involving mTOR which allows cells to go into the cell cycle and proliferate

36
Q

What is the mode of action of sirolimus an MTOR-inhibitor?

A

Inhibits cell response to IL-2 by the MTOR pathway

Get cell arrest at the G1-S phase, ie. T cells are prevented from proliferating

37
Q

What are the 8 side effects of calcineurin/mTOR inhibitors?

A

1) Hypertension
2) Hirsutism (abnormal growth of hair on a woman’s face and body)
3) Nephrotoxicity
4) Hepatotoxicity
5) Lymphomas
6) Opportunistic infections
7) Neurotoxicity
8) Multiple drug interactions (induce p450)

38
Q

What are the 2 clinical uses of calcineurin/mTOR inhibitors?

A

1) Transplantation - allograft (human tissue graft) rejections
2) Autoimmune disease

39
Q

What is the mode of action of antimetabolites?

A 
Inhibit nucleotide (purine) synthesis
Have effects on T and B cells - impaired DNA production, prevents early stages of activated cells proliferation
40
Q

What is the mode of action of Azathioprine - an antimetabolites - specifically?

A

Guanine anti-metabolite, rapidly converted in 6-mercaptopurine

41
Q

What is the mode of action of Mycophenolate mofetil - an antimetabolite - specifically?

A

Non-competitive inhibitor of IMPDH

Prevents production of guanosine triphosphate

42
Q

What is the rough mode of action of the immunosuppressant methotrexate?

A

Folate antagonist

43
Q

What is the rough mode of action of the immunosuppressant cyclophosphamide?

A

Cross-link DNA

44
Q

What are the 4 side effects of all cytotoxic drugs?

A

1) Bone marrow suppression
2) Gastric upset
3) Hepatitis
4) Susceptibility to infections
(NB. they affect all rapidly dividing cells)

45
Q

What is the specific side effect of methotrexate (MTX)?

A

Pneumonitis

46
Q

What is the specific side effect of cyclophosphamide (a cytotoxic drug)?

A

Cystitis

47
Q

What are the clinical uses of azathioprine and MMF? 2

A

Autoimmune disease

Allograft rejection

48
Q

What are the clinical uses of methotrexate? 4

A

1) Rheumatoid arthritis
2) Polymyositis
3) Vasculitis
4) Graft vs Host disease in bone marrow transplant

49
Q

What are the 2 clinical uses of the cytotoxic drug cyclosphamide?

A

1) Vasculitis (Wagner’s, CSS)

2) SLE

50
Q

Biologic DMARDs fall into what 5 categories?

A

1) Anti-cytokines
2) Anti-B cell therapies
3) Anti-T cell activation
4) Anti-adhesion molecules
5) Complement inhibitors

51
Q

Name 3 anti-cytokines?

A

1) Anti-TNF
2) Anti-IL-6 (Tocilizumab)
3) Anti-IL-1

52
Q

What is Anti-TNF used to treat?

A

First to be used successfully in treatment of RA

No used in a number of other inflammatory conditions (Crohn’s, psoriaisis, ankylosing spondylitis)

53
Q

There increased risk of what infection when using anti-TNF drugs?

A

TB

54
Q

What 2 conditions are anti-IL-6 drugs used to treat?

A

RA, AOSD (Adult onset Still’s disease - rare form of arthritis)

55
Q

Anti-IL-6 drugs may cause problems with control of what substances in the body?

A

Serum lipids

56
Q

Anti-IL-1 drugs are used in the treatment of what 2 conditions?

A

AOSD (Adult onset Still’s disease)

Auto inflammatory sydromes

57
Q

Rituximab is a chimeric mAb against what?

A

CD20-B cell surface

58
Q

What are the 4 main uses of rituximab?

A

(First developed as treatment of chemotherapy resistant DLCL)

1) Lymphomas
2) Leukaemias
3) Transplant rejection
4) Autoimmune disorders

59
Q

Name 2 forms of adoptive immunotherapy?

A

1) Bone marrow transplant

2) Stem cell transplant

60
Q

Name the 5 main uses of adoptive immunotherapies (BMT and SCT)?

A

1) Immunodeficiencies
2) Lymphomas
3) Leukemias
4) Inherited metabollic disorders (osteopetrosis)
5) Autoimmune disorders

61
Q

Name the 4 kinds of immunomodulator treatments for allergy?

A

1) Immune suppressants
2) Allergen specific immunotherapy
3) Anti-IgE monoclonal therapy
4) Anti-IL-5 monoclonal treatment

62
Q

What is allergen specific immunotherapy?

A

People are given doses of an allergen in a controlled manner to inducer tolerance to that allergen, may be give subcutaneously or sublingually

63
Q

What is the mechanism of action of allergen specific immunotherapy?

A

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

64
Q

What are the possible side effects of allergen specific immunotherapy?

A

Localised and systemic allergic reactions

65
Q

Give 2 indications for allergen specific immunotherapy?

A

1) Allergic rhinoconjunctivitis not controlled on max medical therapy
2) Anaphylaxis to insect venoms

66
Q

Omalizumab is a mAb against what?

A

IgE

67
Q

Omalizumab is used in the therapy of what 3 conditions?

A

Used in asthma

Also useful in therapy of chronic urticaria and angioedema

68
Q

What is the possible major adverse effect of omalizumab?

A

May cause severe systemic anaphylaxis

69
Q

Mepolizumab is a mAb against what?

A

IL-5

70
Q

What is the mode of action of Mepolizumab?

A

Prevents eosinophil recruitment and activation

71
Q

Is Mepolizumab useful in the therapy of asthma?

A

No has limited effect on Asthma

72
Q

Is Mepolizumab used in the treatment of hypereosinophilic syndrome?

A

No, it has no clincal efficacy in the treatment of hypereosinophilic syndrome

Year 2 Clinical Pathology (64 decks)

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