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Immu > Immu 4: Immuno Modulating Therapies 2 > Flashcards

Immu 4: Immuno Modulating Therapies 2 Flashcards

1
Q

How do Corticosteroids inhibit Prostaglandins and hence have an anti-inflammatory effect ?

A

Corticosteroids INHIBIT Phospholipase A2

(Normaly)
Phospholipase A2 converts phospholipids into Arachidonic acid
Arachidonic acid is converted to Prostaglandins or leukotrienes by COX enzymes.
Prostaglandins cause Inflammation

So less phospholipase A2 = less Arachidonic acid = less Prostaglandins or leukotrienes = less inflammation

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2
Q

Give 2 examples of Eicosanoids ?

A

Prostaglandins
Leukotrienes

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3
Q

Side effects of corticosteroids

A
  • Diabetes
  • central obesity
  • moon face
  • lipid abnormalities
  • osteoporosis
  • hirsutism
  • adrenal suppression
  • Cataracts
  • glaucoma
  • peptic ulceration
  • pancreatitis
  • avascular necrosis of hip and knee
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4
Q

Give 3 examples of immune modulating functions of corticosteroids ?

A
  • Phospholipase A2: Inhibit Prostaglandin synthesis
  • Phagocytes: Inhibit Phagocyte entry into inflamed tissues, decreased phagocytosis, Phagocytes also release LESS proteolytic enzymes
  • Lymphocytes: Causes lymphopenia (Lymphocytes sequester in lymphoid tissues), Cytokine gene expression is BLOCKED by corticosteroids, promote apoptosis of lymphocytes
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5
Q

Give 3 examples of Anti-proliferative agents (stop cells proliferating by blocking DNA synthesis)?

A
  • Cyclophosphamide
  • Mycophenolate
  • Azathioprine
  • Methotrexate
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6
Q

What is the mechanism by which cyclophosphamide inhibits lymphocyte proliferation?

Which lymphocyte does this affect more?

A
  • alkylates guanine bases on DNA - damages DNA
  • Prevents cell replication particularly in rapidly dividing cells (cancer, lymphocytes)
  • Affects B > T cells
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7
Q

Give 3 examples of diseases in which Cyclophosphamide is indicated ?

A
  • SLE
  • GPA (granulomatosis with polyangitis) (wegner’s granulomatosis)
  • Cancers- Hodgkin’s lymphoma
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8
Q

Suggest 4 side effects of cyclophosphamide ?

What do these side effects mean for how the drug is used?

A

Toxic to proliferating cells

  • Hair loss
  • Sterility
  • Bone marrow suppression

Haemorrhagic cystitis - toxic to the bladder since toxic metabolite is excreted in the urine

Malignancy

  • bladder cancer
  • haem malignancies
  • non-melanoma skin cancer

Infection eg P. jirovecii

Given the side effects, this is why you would not use cyclophosphamide for long periods of time - Often started and induce remission with it. Then put onto azathioprine or mycophenolate

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9
Q

Describe the mechanism by which azathioprine inhibits DNA replication ?

Which lymphocyte does this target more?

A
  • Metabolised to 6-mercaptopurine which is a purine analogue, thus interferes with DNA production and inhibits proliferating cells
  • prevents DNA replication
  • preferentially inhibits T cell activation and proliferation

Affects T > B cells

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10
Q

Give 3 indications for azathioprine ?

A

Transplantation
auto-immune diseases
Crohn’s and UC

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11
Q

Which genetic polymorphism contraindicates the use of azathioprine because of risk of bone marrow suppression ?

A
  • Thiopurine methyl transferase (TPMT)
  • check for TPMT activity or gene variants before treatment is started
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12
Q

Side effects of azathioprine (3)

A
  • bone marrow suppression
  • hepatotoxicity
  • infection
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13
Q

What is an alternative to azathioprine used in transplantation ?

A

Mycophenolate Mofetil

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14
Q

mechanisms of mycophenolate mofetil

Which lymphocyte does this affect more?

A
  • blocks de novo nucleotide synthesis
  • prevents replication of DNA

prevents B > T cell proliferation

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15
Q

Which particular virus are pts on Mycophenolate mofetil more at risk of? (2)

A
  • herpes virus reactivation
  • JC virus (this can then cause Progressive multifocal leukoencephalopathy)
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16
Q

indications for mycophenolate mofetil use (2)

A

transplantation
AI diseases and vasculitis

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17
Q

Which virus can cause Multifocal leukoencephalopathy infection in the immunocompromised patient ?

A

JC virus

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18
Q

How does plasmapheresis work ?

A

Patients blood is separated and the plasma is treated to remove immunoglobulins and is then re-infused

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19
Q

When is Plasmaphoresis indicated ?

A

In Severe antibody-mediated disease where the known pathogenic antibodies can be removed

  • Severe transplant rejection (antibodies against donor HLA)
  • Severe acute myasthenia gravis (anti-AChR antibodies)
  • Goodpasture’s syndrome (anti-glomerular basement membrane antibodies)
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20
Q

Downside of plasmaphoresis

A
  • The problem with taking the antibody out is that there are still B and T cells, so they will still go on to produce the antibody. Rebound antibody production limits the efficacy
  • Therefore, it is usually given with an anti-proliferative agent
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21
Q

What is the role of IL2 in the T cell response ?

A

IL2 causes T cell proliferation

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22
Q

How does ciclosporin or tacrolimus inhibit T cell proliferation ?

A
  • Cyclosporin is a calcineurin inhibitor.
  • It blocks IL2 production
  • Thereby inhibiting T cell proliferation
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23
Q

Downside of tacrolimus or ciclosporin

A

they are nephrotoxic and induce hypertension (issue in kidney transplants)

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24
Q

How do Anti-thymocyte globulins cause T cell depletion ?

Downside to them

A
  • Thymocytes (lymphocytes from human thymus) are injected into rabbits
  • Rabbits produced antibodies to the thymocytes
  • The antibodies are retrieved and injected into humans to cause a non-specific immune response against T cells

Downside: very non-specific

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25
Q

Which cells are affected by Rituximab ?

A

B cells (depletes mature B cells - NB plasma cells will be retained and so can produce antibodies)

Rituximab targets CD20 a B cell marker

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26
Q

Which disease is characterised by a IL6 producing tumour

What drug can therefore be used for this?

A

Castleman’s disease

Tocilizumab, Sarlimumab (blocks IL-6 receptor)

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27
Q

List 4 diseases in which anti-TNF alpha antibodies (infliximab) is indicated ?

A
  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Psoriasis/psoriatic arthritis
  • IBD
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28
Q

Explain what effect RANK L binding to RANK receptors has on bone ?

A
  • RANKL produced by Osteoblasts binds to RANK receptor on osteoclast precursors causing them to differentiate into Osteoclasts.
  • This causes increased bone resorption
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29
Q

What is Osteoprotegrin (OPG) and what role does it have in controlling bone resorption ?

A
  • OPG is secreted by Osteoblasts and is a decoy receptor for RANKL to reduce activation and differentiation of Osteoclasts.
  • Hence inhibiting bone resorption
  • Regulator for RANKL pathway
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30
Q

What is the mechanism by which Denosumab works in Osteoporosis treatment ?

A
  • Monoclonal antibody to RANKL so that it cant bind to RANK receptor on osteoclast precursors.
  • This reduces Osteoclast resorption of bone
31
Q

What is a complication of osteoporosis treatment with denosumab ?

A

Avascular necrosis of the jaw

32
Q

Name a drug that prevents DNA replication especially of T cells

When is this drug used?

A

Mycofenylate mofetil

Used as alternative to azothioprine in transplantation suppression

33
Q

Which immuno modulating drug causes a transient increase in neutrophil count ?

A

Prednisolone

34
Q

Which immuno modulating drug can cause gingival hypertrophy as a side effect?

A

Ciclopsporin

35
Q

List 3 side effects of methotrexate ?

A

Pneumonitis
pulmonary fibrosis
cirrhosis

36
Q

A patient with signs of severe myasthenia gravis requires ventilation. Which one of the following would be the most suitable treatment ?

A) Corticosteroids
B) Ciclosporin
C) Tacrolimus
D) Plasmapheresis

A

D) Plasmapherisis

can remove the Ach receptor antibodies in the blood so is useful initially. Later needs acetylcholinesterase inhibitors.

37
Q

Name a monoclonal antibody drug that targets IL-2 to prevent T cell proliferation. This drug is used prophylactically in allograft transplant.

A

Basiliximab

Targets CD25 on the alpha chain of IL-2 which stops T-cell proliferation if they are presented with donor HLA.

38
Q

Name a drug that is a CTLA4- IgG fusion protein and is used in the treatment of rheumatoid arthritis resistant to DMARDs ?

What condition can this be used for?

A

Abatacept

  • A fusion protein between CTLA4 and Immunoglobulin IgG.
  • Binds to CD80 and CD86, which prevents CTLA4 or CD28 on T cells from binding to CD80 and CD86
  • Binds to APCs to prevent them from stimulating and activating T cells.

Can be used for rheumatoid arthritis

39
Q

Name 2 drugs used to treat malignant melanoma ?

A

Ipilimumab (Antibody specific for CTLA4)
Pembrolizumab (Antibodies specific for PD-1)

40
Q

Which drug works by inhibiting phospholipase A2 ?

A

Prednisolone

41
Q

Which mutation if present can cause severe neutropenia with azathioprine treatment ?

A

TPMT

(can’t metabolise azathioprine)

42
Q

Which 2 drugs, other than steroids, can be used in transplant rejection?

A
  • OKT3 Muromonab (CD3 inhibitor mouse monoclonal antibody)
  • ATG (anti thymocyte globulin)

(can also do plasmapheresis if antibody mediated rejection or IVIG - NB the above is for cellular rejection)

43
Q

List 2 drugs that can be given before transplant (induction)

3 drugs for baseline suppression

A
  • Basiliximab (anti-CD25)
  • Alemtuzumab (anti CD52)
  • Calcineurin inhibitor (tacrolimus, ciclosporin)
  • PLUS mycophenolate mofetil OR azathioprine
  • PLUS steroids (prednisolone)
44
Q

What is Ustekinumab used for ?

A

Psoriasis and Crohn’s
-Targets IL12 and IL23

45
Q

what are the effects of steroids on phagocytes (4)

A
  • decreased traffic of phagocytes into inflamed tissue
  • reduce the expression of adhesion molecules on the endothelium –> transient increase in neutrophil count
  • decreased phagocytosis
  • decreased release of proteolytic enzymes
46
Q

what are the effects of steroids on lymphocyte function (4)

A
  • lymphopaenia - sequestration of lymphocytes into lymphoid tissue
  • blocks cytokine gene expression
  • decreased antibody production
  • promotes apoptosis
47
Q

what is the role of calcineurin inhibitors

A
  • eg ciclosporin and tacrolimus
  • prevent T cell signalling
  • IL2 acts on T cells and prevents T cell activation and proliferation
  • side effects = nephrotoxicity, hypertension, neurotoxicity, diabetogenic, dysmorphic features
48
Q

What is an example of JAK inhibitor?

what is the role of JAK inhibitors?

2 conditions they can be used in?

A

Example: Tofacitinib

  • interferes with JAK-STAT signalling
  • inhibits the production of inflammatory molecules in response to cytokines
  • Condition: rheumatoid arthritis, psoriatic arhtritis
49
Q

What is an example of PDE4 inhibitor?

what is the role of PDE4 inhibitors

A

Apremilast

  • PDE4 important for the metabolism of cAMP
  • So apremilast leads to increase in cAMP
  • cAMP activates Protein Kinase A pathway which prevents activation of transcription factors
  • leads to decrease in cytokine production
  • used in psoriasis and psoriatic arthritis
50
Q

what is the role of basiliximab

A
  • antibody directed against CD25
  • prophylaxis of allograft rejection
  • targets IL2 receptor
  • inhibits T cell proliferation
51
Q

What drug can you use before and after transplant surgery?

How does this help?

A

Basiliximab (anti CD-25)

BLOCKS the action of T cells, so T cells cannot proliferate well in response to antigen exposure - prophylaxis for allograft rejection

52
Q

what is the role of abatacept

A
  • receptor made form a fusion of CTLA4 + IgG Fc component
  • binds CD80 and CD86 - reduced T cell activation
  • used for rheumatoid arthritis
53
Q

what is natalizumab

A

antibody against alpha 4 integrin
inhibits leukocyte migration
used in MS

54
Q

what is tocilizumab / Sarlimumab

Conditions it can be used for (2)

A
  • antibody against IL6 receptor
  • reduced activation of macrophages, T cells, B cells and neutrophils

Castleman’s disease, rheumatoid arthritis

55
Q

list agesnts that target cytokines (4)

A
  • ustekinumab - antibody to p40 subunit of IL12 and IL23
  • secukinumab - antibody to IL17A
  • Guselkumab - Antibody against p19a subunit of IL-23
  • denosumab - antbody against RANKL (osteoporosis)
56
Q

which vaccines should not be given to immunosuppressed people (4)

A

polio
measles (MMR)
BCG
yellow fever

57
Q

What drug can be used for prophylaxis for allograft rejection?

A

Basiliximab- anti-CD25

NB CD25 is a chain in the IL-2 recetor on T cells (this receptor very important for T cell clonal expansion)

58
Q

4 examples of Anti-TNFalpha Antibodies

A

Infliximab, Adalimumab, Certolizumab, Golimumab

59
Q

2 groups of drugs that target anti-TNFalpha

3 conditions these are effective against

A
  • anti-TNFalpha antibodies: Infliximab, Adalimumab, Certolizumab, Golimumab
  • TNFalpha antagonist: Etanercept
  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Psoriasis and psoriatic arthritis
60
Q

Which cytokine is pivotal in inflammation?

A

TNF-alpha (blocking it has very therapeutic effects in inflammatory conditions)

61
Q

Tx options for psoriasis (6)

A
  • anti-TNFalpha ABx: Infliximab, Adalimumab, Certolizumab, Golimumab
  • TNFalpha antagonist: Etanercept
  • IL-12 and IL-23 antibody: Ustekinumab
  • Antibody to IL-17alpha: Secukinumab
  • calcineurin inhibitor: ciclosporin
  • PD4 blocker: Apremilast
62
Q

2 groups of drugs to target T cell surface markers

A
  • Rabbit anti-thymocyte globulin
  • Basiliximab (anti-CD25)
63
Q

1 group of drug to target B cells

A

Rituximab (anti-CD20)

64
Q

1 drug for Lymphocyte migration

A
  • Vedolizumab (anti-a4b7 integrin)
65
Q

1 group of drug to block Monocytes, neutrophils, B cells and T cells

A
  • Tocilizumab, Sarlimumab (anti IL-6 receptor)
66
Q

Role of Vedolizumab

What does it target

Condition it can be used for

A
  • Target cell migration of lymphocyes
  • Antibody specific for a4b7 integrin - Vedolizumab inhibits T cell (and leukocytes in general) migration by inhibiting the action of a4b7
  • Condition: IBD
67
Q

What lymphocyte targetting drug can you take to treat IBD?

Which drug targeting cytokines can you take to treat Crohn’s specifically?

A
  • Vedolizumab- Antibody specific for a4b7 integrin
  • inhibits T cell (and leukocytes in general) migration by inhibiting the action of a4b7
  • Ustekinumab- Antibody against the p40 subunit of IL-12 and IL-23
68
Q

1 group of drug to target TNFalpha cytokine

A

Anti-TNFa Antibodies: Infliximab, Adalimumab, Certolizumab, Golimumab

69
Q

1 drug to target TNFalpha receptor (TNF antagonist)

A

Etanercept

70
Q

Drug to target IL-12 and IL-23 cytokines

A

Ustekinumab

71
Q

Drug to target IL-23 cytokine

A

Guselkumab

72
Q

Drug to target IL17 cytokine

A

Secukinumab

73
Q

Which immunosuppressive drug in particular can increase R of TB infection?

A

TNFalpha antagonist (Etanercept) and anti-TNFalpha antibodies (Infliximab, Adalimumab, Certolizumab, Golimumab)

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