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Arjun's PM copy-Immunopathology > 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
What are the adverse-effects of calcineurin inhibitors?
- Increased risk of infection - Hypertension - Nephrotoxicty - (also diabetes, neurotoxic and dysmporphic facies)
26
What is the function of mTOR inhibitors and give an example?
Sirolimus - inhibits T cell activation and proliferation
27
Give an example of a JAK inhibitor. Describe the mechanism of action of JAK inhibitors.
Tofacitinib (JAK1 and JAK3 inhibitor) - Inhibits JAK-STAT signalling (associated with cytokine receptors) - Influences gene expression thus inhibiting the production of inflammatory molecules
28
What are some indications for JAK inhibitors?
- Rheumatoid arthritis - Ulcerative colitis - Psoriatic arthritis - Axial spondyloarthritis
29
Give an example of a PDE4 inhibitor.
Apremilast
30
What are some indications for PDE4 inhibitors?
- Psoriasis - Psoriatic arthritis
31
For each of the following monoclonal antibodies, their basic mechanism of action 1. Basiliximab 2. Abatacept 3. Rituximab 4. Vedolizumab 5. Natalizumab
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
What does the suffix (-cept) mean?
It is made up of a receptor fused to immunoglobulin
33
Describe how anti-thymocyte globulin is made. What is it used for?
* 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
List some adverse-effects of anti-thymocyte globulin.
* Infusion reactions * Leukopaenia * Infection * Malignancy
35
Describe the mechanism of action of basiliximab/daclizumab. What is the indication for its use?
* 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
What are some adverse effects of basilximab/daclizumab?
- Infusion reaction - Infection - Increases long term malignancy risk
37
Describe the mechanism of action of abatacept. What condition is it used for?
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
Describe the mechanism of action of rituximab.
* Targets CD20 which is found on mature B cells * This results in depletion of mature B cells * No effect on plasma cells
39
List some indications for rituximab.
* B cell Lymphoma * Rheumatoid arthritis * SLE ## Footnote NOTE: it is given as two IV doses every 6-12 months
40
What are some adverse-effects of rituximab?
- Infusion reaction - Infection (PML) - Exacerbation of CVD
41
Describe the mechanism of action of vedolizumab.
- Antibody that blocks alpha4beta7 integrin - Inhibits leukocyte migration to site of inflammation
42
What is vedolizumab used for?
Inflammatory bowel disease
43
What are some adverse-effects of vedolizumab?
- Infusion reaction - Hepatotoxic - Infection (PML) - Risk of malignancy
44
45
Describe the mechanism of action of tocilizumab.
* Antibody against IL-6 receptor * Results in reduced activation of macrophages, neutrophils, T cells, and B cells
46
What are the main indications of tocilizumab?
* Castleman's disease (IL-6-producing tumour) * **Rheumatoid arthritis** * Giant cell arteritis
47
List three types of anti-TNFα antibodies.
* **Infliximab** * Adalimumab * Certolizumab * Golimumab ## Footnote Given SC Infliximab can also be IV
48
What is TNF-alpha?
It is a critical molecule in the cytokine cascade responsible for the inflammatory response in inflammatory conditions
49
List some uses of anti-TNFα antibodies.
* IBD (UC and Crohns) * Ankylosing spondylitis * Rheumatoid arthritis * Psoriasis and psoriatic arthritis * Familian Mediterranean fever
50
List some side-effects of anti-TNFα antibodies.
* Infusion reactions * Infection (**TB reactivation**, HBV, HCV) * Lupus-like conditions * Demyelination * Malignancy ## Footnote Screen for latent TB before starting
51
Describe the mechanism of action of etanercept. What are some indications for its use?
* It is a decoy receptor that **mops up TNFα** thereby inhibiting its action * Used in **psoriasis and psoriatic and rheumatoid arthritis, and ankylosing spondylitis** ## Footnote NOTE: it is given as a SC injection
52
Describe the inflammasome pathway
53
What conditions is the IL-23 and IL-17 pathway important for?
Ankylosing spondylitis, psoriasis and psoriatic arthritis, IBD (not IL-17)
54
Which antibodies inhibit IL-17 and IL-23?
Secukinumab - IL-17 Guselkumab - IL-23
55
Which interleukins integral to the pathophysiology of asthma and eczema?
IL-4, IL-5, IL-13 are key cytokines in Th2 and eosinophil responses
56
Which antibodies can be used in the treatment of asthma and eczema?
Dupilumab - IL-4 Mepolizumab - IL-5 Tralokinumab - IL-13
57
Describe the mechanism of action of denosumab.
* 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
What adverse reactions are common across immunosuppressive agents?
- 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
List some types of infusion reaction.
IgE mediated (T1 hypersensitivity) * Urticaria * Hypotension * Tachycardia * Wheeze Non-T1 hypersensitivity * Headache * Fever * Myalgia
60
Describe injection site reactions
- 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
Describe the infection risk possed by immunosuppressive therapy and its management
- 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
Which diseases should you screen for before starting immunosuppression
- TB - Quantiferon - HBV, HCV - serology - HIV - serology
63
What is JC virus and why is it dangerous in immunosuppression?
- 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
What malignancies are associated with immunosuppression?
- Lymphoma (EBV) - Non-melanoma skin cancer (HPV) - Melanoma ## Footnote Risks appear lower with targeted forms of immunosuppression than with regimes used in transplantation

Arjun's PM copy-Immunopathology (12 decks)

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