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YEAR 5: IMMUNO > Immuno: Immune modulating therapies 2 > Flashcards

Immuno: Immune modulating therapies 2 Flashcards

1
Q

List some approaches to suppressing the immune system.

A
  • Steroids
  • Anti-proliferative agents
  • Plasmapheresis
  • Inhibitors of cell signalling
  • Agents directed against cell surface antigens
  • Agents directed at cytokines
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2
Q

what is prednisolone

A

synthetic glucocorticoid

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3
Q

What is the difference between prednisolone and prednisone?

A

Prednisone is mainly used in the US - it is metabolised to prednisolone in the liver

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4
Q

How much endogenous steroid does the body produce per day?

A

Equivalent to 3-4 mg of prednisolone

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5
Q

Describe the effects of steroids on:

  1. Prostaglandins
  2. Phagocytes
  3. Lymphocyte Function
A
  1. Prostaglandins
    • Inhibits phospholipase A2
    • Phospholipase A2 is responsible for the conversion of phospholipids into arachidonic acid (which will then be converted to eicosanoids by COX)
    • Inhibiting phospholipase A2 leads to a reduction in arachidonic acid and prostaglandin formation and, hence, a reduction in inflammation
    • (same pathway as NSAIDS)
  2. Phagocytes - innate immunity
    • Decrease traffic of phagocytes to inflamed tissue (reduces the expression of adhesion molecules on the endothelium)
    • This leads to a transient increase in neutrophil count
    • Decreased phagocytosis
    • Decreases proteolytic enzymes
  3. Lymphocyte Function - adaptive imunity
    • Lymphopaenia (sequestration in lymphoid tissue)
    • Blocks cytokine gene expression
    • Decreased antibody production
    • Promotes apoptosis
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6
Q

effect of steroids on WBC

A

neutrophilia
leukoapenia

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7
Q

List some side-effects of corticosteroids.

A
  • Central obesity
  • Moon face
  • Easy bruising
  • Thin skin
  • Osteoporosis
  • Diabetes
  • Cataracts
  • Glaucoma
  • Peptic ulceration
  • Immunosuppression
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8
Q

List some examples of anti-proliferative agents.

A
  • Cycophosphamide
  • Mycophenolate
  • Azathioprine
  • Methotrexate
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9
Q

What is the mechanism of action of cyclophosphamide?

A
  • Alkylates the guanine base of DNA which damages the DNA and prevents replication (affects B cells more than T cells)

Most toxic - antiproliferative

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10
Q

List some indications of cycolphosphamide.

A
  • Multisystem connective tissue disease
  • Vasculitis
  • Anti-cancer
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11
Q

List some side-effects of cyclophosphamide.

A
  • Toxic to proliferating cells - bone marrow suppression, sterility (mainly males), hair loss
  • Haemorrhagic cystitis - due to toxic metabolic (acrolein) in the urine
  • Malignancy - bladder cancer, haematological malignancy, non-melanoma skin cancer
  • Teratogenic
  • Infection (e.g. PCP)
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12
Q

Fertility consideration with cyclophosphamide

A

sperm and egg freezing

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13
Q

Abx prophylaxis with cyclophosphamide, or long-term steroids

A

Co-trimoxazole

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14
Q

Outline the mechanism of action of azathioprine.

A
  • Metabolised by the liver to 6-mercaptopurine
  • Blocks de novo purine synthesis (e.g. adenine and guanine)
  • Prevents DNA replication
  • Preferntially inhibits T cell activation and proliferation

Toxic to proliferating cells

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15
Q

List some indications for azathioprine.

A
  • Transplantation
  • Autoimmune
  • Autoinflammatory (e.g. Crohn’s)
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16
Q

List some side-effects of azathioprine.

A
  • Bone marrow suppression
  • Hepatoxicity
  • Infection
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17
Q

Which precaution must you take before starting a patient on azathioprine?

A

Check TPMT activity - 1 in 300 individuals have TPMT polymorphism which means that they are unable to metabolise azathioprine leading to bone marrow suppression.

Also check blood count after starting therapy

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18
Q

Outline the mechanism of action of mycophenolate mofetil.

A
  • Blocking de novo nucleotide synthesis
  • Prevents replication of DNA
  • Affects T cell proliferation more than B cells
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19
Q

List some indications for mycophenolate mofetil.

A
  • Transplantation
  • Autoimmune disease
  • Vasculitis
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20
Q

List some side-effects of mycophenolate mofetil.

A
  • Bone marrow suppression
  • Teratogenic
  • Infection - particularly HSV reactivation and Progressive multifocal leukoencephalopthy caused by JC virus
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21
Q

Describe how plasmapheresis works.

A
  • The patient’s blood is passed through a separator where the pathogenic immunoglobulins are removed and the plasma is reinfused
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22
Q

What is the main issue with plasmapheresis?

A
  • Rebound antibody production - although antibodies have been removed, the plasma cells are still there

NOTE: therefore, anti-proliferative agents are often given alongside plasmapheresis

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23
Q

List some indications for plasmapheresis.

A
  • Severe antibody-mediated disease - Type II hypersensitivity
    (e.g. Goodpasture’s, acute myasthenia gravis, severe transplant rejection)
24
Q

Describe the mechanism of action of calcineurin inhibitors.

A
  • Normally, TCR engagement leads to increased cytoplasmic calcium which binds to calmodulin leading to the activation of calcineurin
  • Calcineurin then activates NFATc resulting in the upregulation of IL2
  • Calcineurin inhibitors block this pathway, thereby blocking IL2 production
25
Q

Give two examples of calcineurin inhibitors.

A
  • Ciclosporin
  • Tacrolimus
26
Q

What are the main side-effects of calcineurin inhibitors?

A

Hypertension and nephrotoxicty (also diabetes, neurotoxic and dysmporphic facies)

27
Q

Give an example of a JAK inhibitor.

A

Tofacitinib (JAK1 and JAK2 inhibitor)

28
Q

Describe the mechanism of action of JAK inhibitors.

A
  • Interferes with the JAK-STAT pathway which is important in transducing signals from cytokine binding
  • This influences gene transcription and reduces the production of inflammatory mediators
  • Effective in rheumatoid arthritis, ABD, atopic eczema

Can be taken orally (unlike monclonal anitbodies)
But are less specific than monoclonal a tibodies –> more side effects

29
Q

Give an example of a PDE4 inhibitor.

A

Apremilast

30
Q

Describe the mechanism of action of PDE4 inhibitors.

A
  • PDE4 is important in the metabolism of cAMP
  • PDE4 inhibitors result in increased levels of cAMP which activates PKA and prevents the activation of transcription factors
  • This leads to a decrease in cytokine production
  • Effective in psoriasis and psoriatic arthritis
31
Q

For each of the following monoclonal antibodies, state the antigen that they are targeting:

  1. Basiliximab
  2. Abatacept
  3. Rituximab
  4. Natalizumab
  5. Tocilizumab
A
  1. Basiliximab = anti-CD25
  2. Abatacept = CLTA4-Ig
  3. Rituximab = anti-CD20
  4. Natalizumab = anti-α4 integrin
  5. Tocilizumab = anti-IL6 receptor

Don’t need to remember the names

32
Q

what monoclonal antibody is safe to use in patients with history of malignancy

A

Rtiuximab - anti-CD20

33
Q

What does the suffix (-cept) mean?

A

It is made up of a receptor at the end of an IgG Fc portion

34
Q

Describe how anti-thymocyte globulin is made. What is it used for?

A
  • Human thymocytes (lymphocytes from the thymus gland) are sampled and injected into a rabbit which produces a variety of antibodies against thymocytes
  • This is injected into patients and it is very effective at targeting T cells (but it is not very specific)
  • This leads to T cell depletion and it is effective in allograft rejection
35
Q

List some side-effects of anti-thymocyte globulin.

A
  • Infusion reactions
  • Leukopaenia
  • Infection
  • Malignancy
36
Q

Describe the mechanism of action and the use of basiliximab.

A
  • Targets IL2 receptors alpha chain (aka CD25)
  • This part of the receptor is specific for IL2
  • Results in inhibition of T cell proliferation
37
Q

Describe the mechanism of action of abatacept.

A
  • It is made from the fusion of CTLA4 and IgG Fc
  • APCs bind to CTLA4 (inhibitor) and CD28 via CD80 and CD86 receptors
  • Abatacept binds to CD80 and CD86 receptors and prevents engagement with T cells thereby reducing T cell activation
  • It is effective in rhumatoid arthritis
38
Q

Describe the mechanism of action of rituximab.

A
  • Targets CD20 which is found on mature B cells
  • This results in depletion of mature B cells
39
Q

List some indications for rituximab.

A
  • Lymphoma
  • Rheumatoid arthritis
  • SLE

NOTE: it is given as two IV doses every 6-12 months

40
Q

Describe the mechanism of action of natalizumab.

A
  • Antibody against alpha-4 integrin
  • Alpha-4 integrin is expressed with beta-1 or beta-7
  • This complex binds to VCAM1 or MadCAM1 to mediate rolling and arrest of leukocytes
  • Blocking this integrin inhibits leukocyte migration
41
Q

What is the main indication of natalizumab?

A

Multiple sclerosis

42
Q

Describe the mechanism of action of tocilizumab.

A
  • Antibody against IL6 receptor
  • Results in reduced activation of macrophages, T cells, B cells and neutrophils
43
Q

What are the main indications of tocilizumab?

A
  • Castleman’s disease (IL6-producing tumour)
  • Rheumatoid arthritis
44
Q

List three types of anti-TNFα antibodies.

A
  • Infliximab
  • Adalimumab
  • Certolizumab
  • Golimumab
45
Q

Which antigens are targeted by the following monoclonal antibodies:

  1. Ustekinumab
  2. Secukinumab
  3. Denosumab
A
  1. Ustekinumab
    • IL12
    • IL23
  2. Secukinumab
    • IL17
  3. Denosumab
    • RANKL
46
Q

What is TNF-alpha?

A

It is a critical molecule in the cytokine cascade responsible for the inflammatory response in inflammatory conditions

47
Q

List some uses of anti-TNFα antibodies.

A
  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Psoriasis
  • IBD
48
Q

List some side-effects of anti-TNFα antibodies.

A
  • Infusion reactions
  • Infection
  • Lupus-like conditions
  • Demyelination
  • Malignancy
49
Q

Describe the mechanism of action of etanercept.

A
  • It is a decoy receptor that mops up TNFα thereby inhibiting its action
  • NOTE: it is given as a SC injection
  • Used in rheumatoid arthritis, psoriasis and ankylosing spondylitis
50
Q

Describe the mechanism of action of ustekinumab.

A
  • Antibody against the p40 subunit that is found in IL12 and IL23
  • These cytokines mainly act on NK cells and T cells thereby modulating their activity
  • Used in psoriasis and Crohn’s disease
51
Q

Describe the mechanism of action and uses of secukinumab.

A
  • Antibody to IL17A thereby inhibiting its effect
  • Indications include psoriasis and ankylosing spondylitis
52
Q

Describe the mechanism of action of denosumab.

A
  • RANKL is produced by osteoblasts and it acts on RANK receptors on osteoclasts
  • It promotes osteoclast differentiation and function –> increased bone resorption
  • Osteoprotegrin is a natural decoy receptor for RANKL which regulates the system
  • Denosumab binds to RANKL and reduces osteoclast differentiation and function

NOTE: it is used for osetoporosis and is administered as SC injections every 6 months

53
Q

List some side-effects of denosumab.

A
  • Injection site reactions
  • Infection
  • Avascular necrosis of the jaw
54
Q

List some types of infusion reaction.

A
  • Urticaria
  • Hypotension
  • Tachycardia
  • Wheeze
    (IgE-mediated- type 1 hypersensitivity)
  • Headache
  • Fever
  • Myalgia
55
Q

**

What interleukins are relevant to atopy

A

IL4, 5, 13

Good antibody targets in management

56
Q

What infections are screened prior to starting immunosuppressive treatment

A

TB - history, CXR, TB interferon gamma for previous exposure, latent TB needs treatment

Hep B, Hep C - Hep B core antibody, Hep C antibody –> further investigation for virus infectino if +ve

HIV - check serology

John Cunningham Virus (JCV) - common polyomavirus can reactive in brean –> infects + destroys oligodendrocytes –> Progressive multifocal leukomalacia

57
Q

What malignancies are you potentially at increased risk of with immunosuppression

A

melanoma

EBV reactivation –> lymphoma

YEAR 5: IMMUNO (12 decks)

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