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YEAR 5: Immunopathology PM (COPY) > 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 daily endogenous steroid secretion equivalent to in prednisolone?

A

Equivalent to 3-4 mg prednisolone

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3
Q

What is the effect of steroids on prostaglandins?

A

Corticosteroids inhibit phospholipase A2

  • Phospholipase A2 converts phospholipids into arachidonic acid which is subsequently converted into prostaglandins and leukotrienes by cyclo-oxygenases
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4
Q

What is the effect of steroids on macrophages?

A
  • Decreases macrocyte trafficking to site of inflammation
  • Decreased endothelial adhesion molecule expression (results in transient neutrophilia)
  • Decreases phagocytosis
  • Decreases release of proteolytic enzymes
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5
Q

What is the effect of steroids on lymphocytes?

A
  • Lymphopenia
  • Blocks cytokine gene expression
  • Decreases antibody production
  • Promotes apoptosis
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6
Q

List some adverse-effects of corticosteroids.

A
  • Metabolic: diabetes, central obesity, moon face, lipid abnormalities, osteoporosis, hirsuitism, adrenal suppression
  • Other: cataracts, glaucoma, peptic ulceration, pancreatitis, avascular necrosis
  • Immunosuppression: infection
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7
Q

List some examples of anti-proliferative agents.

A
  • Cyclophosphamide
  • Mycophenolate
  • Azathioprine
  • Methotrexate
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8
Q

What is the mechanism of action of cyclophosphamide?

A

Alkylates the guanine base of DNA which inhibits replication

Affects B cells more than T cells

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9
Q

List some indications of cyclophosphamide.

A
  • Multisystem connective tissue disease (e.g. lupus)
  • Vasculitis
  • Anti-cancer (NHL)
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10
Q

List some adverse-effects of cyclophosphamide.

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

Most toxic antiproliferative

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11
Q

Outline the mechanism of action of azathioprine.

A
  • Metabolised by the liver to 6-mercaptopurine
  • Blocks de novo purine synthesis by inhibiting HGPRT

Hypoxanthine-guanine phosphoribosyltransferase

Preferentially inhibits T cell activation and proliferation

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12
Q

List some indications for azathioprine.

A
  • Transplantation
  • Autoimmune disease (e.g. RA)
  • Autoinflammatory disease (e.g. Crohn’s)
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13
Q

List some adverse-effects of azathioprine.

A
  • Bone marrow suppression
  • Hepatoxicity (indiosyncratic and uncommon)
  • Infection (less so than cyclophosphamide)
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14
Q

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

A

Check TPMT activity

  • TPMT required for azathioprine inactivation and metabolism
  • 1 in 300 individuals have TPMT polymorphism which means that they are unable to metabolise azathioprine leading to severe bone marrow suppression

TPMT - thiopurine methyltransferase

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15
Q

What drug interacts dangerously with azathioprine?

A

Allopurinol - inhibits xanthine oxidase

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16
Q

Outline the mechanism of action of mycophenolate mofetil.

A

Blocking de novo purine nucleotide synthesis by inhibiting IMPDH thus preventing DNA replication (thus inhibiting proliferation of T and B lymphocytes)

Inosine-5′-monophosphate dehydrogenase

Affects T cell proliferation more than B cells

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17
Q

List the indication for mycophenolate mofetil.

A

Transplant immunosuppression

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18
Q

List some adverse-effects of mycophenolate mofetil.

A

Bone marrow suppression

Infection

  • Herpes virus reactivation
  • Progressive multifocal leukoencephalopathy (JC virus)
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19
Q

Describe how plasmapheresis works.

A

The patient’s blood is passed through a cell separator where the autoreactive immunoglobulins are removed and cells and plasma are reinfused

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20
Q

What is the main issue with plasmapheresis?

A

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

Therefore, anti-proliferative agents are often given alongside plasmapheresis

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21
Q

List some indications for plasmapheresis.

A

Severe antibody-mediated disease

  • Goodpasture’s disease
  • Severe acute myasthenia gravis
  • Antibody-mediated tranplant rejection
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22
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 IL-2
  • IL-2 acts back on T cells to stimulate activation and proliferation

Calcineurin inhibitors block this pathway, thereby blocking IL -2 production

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23
Q

Give two examples of calcineurin inhibitors.

A
  • Ciclosporin
  • Tacrolimus
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24
Q

List some indications for calcineuin inhibitors

A
  • Transplantation
  • Rheumatoid arthritis
  • Severe atopic eczema
  • Psoriasis and psoriatic arthritis
  • IBD (UC)
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25
Q

What are the adverse-effects of calcineurin inhibitors?

A
  • Increased risk of infection
  • Hypertension
  • Nephrotoxicty
  • (also diabetes, neurotoxic and dysmporphic facies)
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26
Q

What is the function of mTOR inhibitors and give an example?

A

Sirolimus - inhibits T cell activation and proliferation

27
Q

Give an example of a JAK inhibitor.
Describe the mechanism of action of JAK inhibitors.

A

Tofacitinib (JAK1 and JAK3 inhibitor)

  • Inhibits JAK-STAT signalling (associated with cytokine receptors)
  • Influences gene expression thus inhibiting the production of inflammatory molecules
28
Q

What are some indications for JAK inhibitors?

A
  • Rheumatoid arthritis
  • Ulcerative colitis
  • Psoriatic arthritis
  • Axial spondyloarthritis
29
Q

Give an example of a PDE4 inhibitor.

A

Apremilast

30
Q

What are some indications for PDE4 inhibitors?

A
  • Psoriasis
  • Psoriatic arthritis
31
Q

For each of the following monoclonal antibodies, their basic mechanism of action

  1. Basiliximab
  2. Abatacept
  3. Rituximab
  4. Vedolizumab
  5. Natalizumab
A
  1. Basiliximab = anti-CD25 (alpha chain of IL-2 receptor)
  2. Abatacept = CLTA4-Ig
  3. Rituximab = anti-CD20
  4. Vedolizumab = anti-alpha4beta7 integrin
  5. Natalizumab = anti-alpha4beta1 integrin
32
Q

What does the suffix (-cept) mean?

A

It is made up of a receptor fused to immunoglobulin

33
Q

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

A
  • Human thymocytes (T cells and their precursors) are injected into a rabbit which produces a variety of antibodies against thymocytes
  • This is then injected into patients and leads to T cell depletion
  • It is effective in allograft transplant rejection
34
Q

List some adverse-effects of anti-thymocyte globulin.

A
  • Infusion reactions
  • Leukopaenia
  • Infection
  • Malignancy
35
Q

Describe the mechanism of action of basiliximab/daclizumab. What is the indication for its use?

A
  • Targets CD25 (alpha chain of IL-2 receptor)
  • Blocks IL-2R thus inhibiting T cell activation and proliferation
  • Used as a prophylaxis against transplant rejection
36
Q

What are some adverse effects of basilximab/daclizumab?

A
  • Infusion reaction
  • Infection
  • Increases long term malignancy risk
37
Q

Describe the mechanism of action of abatacept. What condition is it used for?

A

Used in rheumatoid arthritis

  • APCs bind to T cell CTLA4 (inhibitory) and CD28 (stimulatory) via CD80 and CD86 receptors
  • Abatacept binds to CD80 and CD86 and prevents CD28 engagement thus inhibiting co-stimulation required for T cell activation
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
  • No effect on plasma cells
39
Q

List some indications for rituximab.

A
  • B cell Lymphoma
  • Rheumatoid arthritis
  • SLE

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

40
Q

What are some adverse-effects of rituximab?

A
  • Infusion reaction
  • Infection (PML)
  • Exacerbation of CVD
41
Q

Describe the mechanism of action of vedolizumab.

A
  • Antibody that blocks alpha4beta7 integrin
  • Inhibits leukocyte migration to site of inflammation
42
Q

What is vedolizumab used for?

A

Inflammatory bowel disease

43
Q

What are some adverse-effects of vedolizumab?

A
  • Infusion reaction
  • Hepatotoxic
  • Infection (PML)
  • Risk of malignancy
45
Q

Describe the mechanism of action of tocilizumab.

A
  • Antibody against IL-6 receptor
  • Results in reduced activation of macrophages, neutrophils, T cells, and B cells
46
Q

What are the main indications of tocilizumab?

A
  • Castleman’s disease (IL-6-producing tumour)
  • Rheumatoid arthritis
  • Giant cell arteritis
47
Q

List three types of anti-TNFα antibodies.

A
  • Infliximab
  • Adalimumab
  • Certolizumab
  • Golimumab

Given SC
Infliximab can also be IV

48
Q

What is TNF-alpha?

A

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

49
Q

List some uses of anti-TNFα antibodies.

A
  • IBD (UC and Crohns)
  • Ankylosing spondylitis
  • Rheumatoid arthritis
  • Psoriasis and psoriatic arthritis
  • Familian Mediterranean fever
50
Q

List some side-effects of anti-TNFα antibodies.

A
  • Infusion reactions
  • Infection (TB reactivation, HBV, HCV)
  • Lupus-like conditions
  • Demyelination
  • Malignancy

Screen for latent TB before starting

51
Q

Describe the mechanism of action of etanercept. What are some indications for its use?

A
  • It is a decoy receptor that mops up TNFα thereby inhibiting its action
  • Used in psoriasis and psoriatic and rheumatoid arthritis, and ankylosing spondylitis

NOTE: it is given as a SC injection

52
Q

Describe the inflammasome pathway

53
Q

What conditions is the IL-23 and IL-17 pathway important for?

A

Ankylosing spondylitis, psoriasis and psoriatic arthritis, IBD (not IL-17)

54
Q

Which antibodies inhibit IL-17 and IL-23?

A

Secukinumab - IL-17
Guselkumab - IL-23

55
Q

Which interleukins integral to the pathophysiology of asthma and eczema?

A

IL-4, IL-5, IL-13 are key cytokines in Th2 and eosinophil responses

56
Q

Which antibodies can be used in the treatment of asthma and eczema?

A

Dupilumab - IL-4
Mepolizumab - IL-5
Tralokinumab - IL-13

57
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, thereby leading to 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

It is used for osteoporosis

58
Q

What adverse reactions are common across immunosuppressive agents?

A
  • Infusion and injection site reactions (biologics)
  • Increased risk of acute infection
  • Increased risk of chronic infection reactivation
  • Increased of malignancy
  • Increased risk of auto-immunity
59
Q

List some types of infusion reaction.

A

IgE mediated (T1 hypersensitivity)

  • Urticaria
  • Hypotension
  • Tachycardia
  • Wheeze

Non-T1 hypersensitivity

  • Headache
  • Fever
  • Myalgia
60
Q

Describe injection site reactions

A
  • Peak at 48 hours
  • Reslts in cutaneous necrosis
  • May also occur at previous injection sites (recall reactions)
  • Mixed cellular infiltrate (CD8 cells)
  • Not generally IgE or immune complexes
61
Q

Describe the infection risk possed by immunosuppressive therapy and its management

A
  • Risk of infection often >2x background risk
  • Prevent with hygiene precautions and vaccination (avoid live vaccines)
  • Temporarily stop immunosuppression in case of infection
  • Consider atypical organisms and use appropriate antibiotics
62
Q

Which diseases should you screen for before starting immunosuppression

A
  • TB - Quantiferon
  • HBV, HCV - serology
  • HIV - serology
63
Q

What is JC virus and why is it dangerous in immunosuppression?

A
  • John Cunningham Virus
  • Common polyomavirus - majority of population has been exposed to it
  • Usually kept well under control by immune system
  • In the case of severe immunosuppression, the virus can reactivate and destory oligodendrocytes, leading to PML
64
Q

What malignancies are associated with immunosuppression?

A
  • Lymphoma (EBV)
  • Non-melanoma skin cancer (HPV)
  • Melanoma

Risks appear lower with targeted forms of immunosuppression than with regimes used in transplantation

YEAR 5: Immunopathology PM (COPY) (12 decks)

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