Treatments for the overactive immune response

Question 1

What is an immunomodulatory drug?

Answer 1

a drug that stimulates, suppresses or modifies the immune system

Question 2

Give an example of an immune stimulating drug

Answer 2

Interferon omega used in severe infections

Question 3

Give examples of the use of drugs to modify the immune system

Answer 3

Allergy immunotherapy, increase T-regulatory cells, decrease IgE and decrease T-helper cells
Specific cancer treatments may increase immune response to tumour.

Question 4

Describe the use of drugs to suppress the immune system. Give examples

Answer 4

Often a broad treatment affecting many parts of the immune system (e.g. steroid medication)
Some newer drugs are targeted (e.g. Lokivetmab – a specific monoclonal antibody for IL-31).

Question 5

Describe steroids as a broad acting immunosuppressant agent

Answer 5

Most commonly used immunosuppressive agent
Use alone or in combination with other agents
Well-tolerated in cats, less well in dogs and horses
Wide range of effects

Question 6

What is the mode of action of steroids as an immunosuppressant

Answer 6

Bind to glucocorticoid receptors in the cytoplasm (expressed by nearly all nucleated cells)
Then translocate to nucleus
Cause activation or inhibition of gene transcription (effects differ by cell type)
Also non-genomic effects - e.g., makes membranes on immune cells less likely to express contents

Question 7

What are the principal effects of steroids as an immunosuppressant?

Answer 7

Anti-inflammatory/immunomodulatory effect
Metabolic effect

Question 8

Describe the anti-inflammatory/immunomodulatory effect of steroids

Answer 8

reduced protein synthesis - fewer antibodies
Suppress leukocytes e.g. granulocytes, mast cells and monocyte-macrophages via membrane stabilisation preventing mediator release + lowers rate of phagocytosis
Inhibit metabolic pathways e.g. production of IL-1, IL-6 and TNF-alpha
Down-regulate expression of Fc receptors (antibody binding sites)
Suppress T-cell function and induce T-cell apoptosis
Suppress B-cell function and reduce antibody production

Question 9

Describe the metabolic effect of steroids

Answer 9

gluconeogenesis, protein catabolism, lipolysis, increased blood glucose, increased blood proteins, fat redistribution and insulin resistance
enhanced secretion of gastric acid
cutaneous atrophy
calcium mobilisation (calcinosis cutis)

Question 10

Give examples of drugs used to suppress the immune system

Answer 10

Steroids
Azathioprine
Chlorambucil
Mycophenolate mofetil
Ciclosporin
Leflunomide
Olcacitinib

Question 11

Describe the action of azathioprine as an immunosuppressant agent

Answer 11

Metabolised in the liver to 6-mercaptopurine & other metabolites
DNA damage by inclusion of metabolites into DNA backbone - Affects rapidly growing bone marrow and immune cells
Classified as cytotoxic

Question 12

How is azathioprine metabolised in the body

Answer 12

Metabolised in the liver to 6-mercaptopurine & other metabolites
The drug is further metabolised by 3 enzyme systems

Both xanthine oxidase & thiopurine methyl transferase (TPMT) → inactive metabolites
Some people and dogs have no TPMT → leading to much more likely / inevitable side effects.

Question 13

What are the side effects of azathioprine?

Answer 13

Myelosuppression:
- mild anaemia and lymphopaenia (expected, ensure monitoring)
Pancreatitis
Hepatotoxicity

Do not use in cats

Question 14

Describe the use of chlorambucil as an immunosuppressant

Answer 14

Alkylating agent
Cytotoxic effect - cross-linking of DNA
Slow acting
Less toxic than azathioprine (myelosuppression still possible)

Question 15

What are the adverse effects of chlorambucil?

Answer 15

anorexia
vomiting
diarrhoea

Question 16

Describe the action of mycophenolate mofetil as an immunosuppressant agent

Answer 16

Inhibits de novo purine synthesis and suppresses both T & B cells
Fast acting

Question 17

What are the adverse effects of mycophenolate mofetil

Answer 17

acute severe gastrointestinal toxicity
Potential hepatitis

Question 18

Describe the effect and use of ciclosporin as an immunosuppressant

Answer 18

Potent T-cell suppressor
Licenced for atopic dermatitis in the dog & non-flea hypersensitivity disease in the cat
Slow rate of onset
Metabolised by P450 enzyme

Question 19

Describe the mode of action of ciclosporin as an immunosuppressant

Answer 19

Ciclosporin binds to the cytosolic cyclophilin
Ciclosporin-cyclophilin complex inhibits calcineurin (prevents dephosphorylation of NF‑AT)
Reduces activation of IL-2 and related cytokines.
Leads to reduced effector T-cell function

Question 20

What are the adverse effects of ciclosporin?

Answer 20

vomiting and diarrhoea, hirsuitism, gum hyperplasia and reduced immunity

Question 21

Describe how leflunomide acts as an immunosuppressant

Answer 21

Inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH)
prevents the expansion of activated and autoimmune lymphocytes

Question 22

What are the adverse effects of leflunomide?

Answer 22

Diarrhoea, lethargy, unexplained haemorrhage, thrombocytopenia, and increased liver enzymes

Question 23

Describe the mode of action of oclacitinib as an immunosuppressant

Answer 23

Acts by inhibiting JAK-1 preventing cytokine receptor signalling for cytokines using the IL-2 and IL-6 family receptors (wide range of cytokine signals blocked including IL-2, IL-10, IL-4, IL-13 and IL-31)

Question 24

Describe the use of oclacitinib as an immunosuppressant

Answer 24

Licenced for canine atopic dermatitis and allergic skin disease
At higher doses, increasingly used for a range of immune-mediated diseases
Used as does not have metabolic effect of steroids – better for either later (maintenance use) or in non-critical diseases

Question 25

What are the adverse effects of oclacitinib?

Answer 25

diarrhoea (uncommon), neutropenia and haematological abnormalities

Question 26

What naturally occuring supplements can be used to treat immune mediated diseases?

Answer 26

Omega 3 fatty acids Vit E Vit D Glutamine Arginine

Question 27

Describe the use of omega 3 fatty acids in immune mediated disease treatment

Answer 27

Reduce production of inflammatory mediators Induces synthesis of anti-inflammatory factors attenuates the inflammatory and innate immune responses Used in inflammatory skin disease and protein losing nephropathy in dogs and cats rather than IMD

Question 28

Describe the use of Vit E in treating immune mediated diseases

Answer 28

adjunct antioxidative treatment useful in cases of sterile pyogranulomatous panniculitis

Question 29

Describe the use of Vitamin D in treatment of immune mediated diseases

Answer 29

enhances and potentiates immune response against pathogens (innate immunity) modulation of the adaptive immune system via effects on T cells activation and antigen presenting cells

Question 30

What are the adverse effects of vitamin D as a treatment for IMD?

Answer 30

hypercalcaemia and eventual renal failure

Question 31

Describe the role of glutamine in the immune response

Answer 31

Considered to be a non-essential amino acid (not required in diet) In diseased states glutamine can become essential Important roles: - preferred energy source for enterocytes - vital roles in nitrogen metabolism, immune modulation and anti–oxidant function

Question 32

When should steroids be used to treat IMD?

Answer 32

Steroids used to treat acute or life-threatening cases Other drugs added later as steroid-sparing drugs

Question 33

What is the use of using other drugs as steroid-sparing drugs?

Answer 33

Used to reduce adverse effects of steroids e.g. azathioprine or chlorambucil May be slower to work, but more targeted e.g. ciclosporin (T-cell) May be used when other options have failed e.g. mycophenolate mofetil, oclacitinib or leflunomide

Question 34

What should be considered when deciding on immunomodulatory therapy?

Answer 34

Phase of treatment: induction vs maintenance Seriousness: life threatening or not Mechanisms of immunological damage

Question 35

Why does the mechanism of immunological damage need to be considered when deciding treatment for IMD?

Answer 35

Humoral mechanisms - Antibody mediated damage most important Cellular mechanisms - T-cell and natural killer cell damage most important Drugs may have a direct or indirect effect on these mechanisms Drugs with an indirect effect are usually better for maintenance.

Question 36

Describe the stages of immunosuppressive therapy (CTMM)?

Answer 36