Treatments for the overactive immune response Flashcards
What is an immunomodulatory drug?
a drug that stimulates, suppresses or modifies the immune system
Give an example of an immune stimulating drug
Interferon omega used in severe infections
Give examples of the use of drugs to modify the immune system
Allergy immunotherapy, increase T-regulatory cells, decrease IgE and decrease T-helper cells
Specific cancer treatments may increase immune response to tumour.
Describe the use of drugs to suppress the immune system. Give examples
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).
Describe steroids as a broad acting immunosuppressant agent
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
What is the mode of action of steroids as an immunosuppressant
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
What are the principal effects of steroids as an immunosuppressant?
Anti-inflammatory/immunomodulatory effect
Metabolic effect
Describe the anti-inflammatory/immunomodulatory effect of steroids
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
Describe the metabolic effect of steroids
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)
Give examples of drugs used to suppress the immune system
Steroids
Azathioprine
Chlorambucil
Mycophenolate mofetil
Ciclosporin
Leflunomide
Olcacitinib
Describe the action of azathioprine as an immunosuppressant agent
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
How is azathioprine metabolised in the body
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.
What are the side effects of azathioprine?
Myelosuppression:
- mild anaemia and lymphopaenia (expected, ensure monitoring)
Pancreatitis
Hepatotoxicity
Do not use in cats
Describe the use of chlorambucil as an immunosuppressant
Alkylating agent
Cytotoxic effect - cross-linking of DNA
Slow acting
Less toxic than azathioprine (myelosuppression still possible)
What are the adverse effects of chlorambucil?
anorexia
vomiting
diarrhoea
Describe the action of mycophenolate mofetil as an immunosuppressant agent
Inhibits de novo purine synthesis and suppresses both T & B cells
Fast acting
What are the adverse effects of mycophenolate mofetil
acute severe gastrointestinal toxicity
Potential hepatitis
Describe the effect and use of ciclosporin as an immunosuppressant
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
Describe the mode of action of ciclosporin as an immunosuppressant
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
What are the adverse effects of ciclosporin?
vomiting and diarrhoea, hirsuitism, gum hyperplasia and reduced immunity
Describe how leflunomide acts as an immunosuppressant
Inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH)
prevents the expansion of activated and autoimmune lymphocytes
What are the adverse effects of leflunomide?
Diarrhoea, lethargy, unexplained haemorrhage, thrombocytopenia, and increased liver enzymes
Describe the mode of action of oclacitinib as an immunosuppressant
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)
Describe the use of oclacitinib as an immunosuppressant
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
What are the adverse effects of oclacitinib?
diarrhoea (uncommon), neutropenia and haematological abnormalities
What naturally occuring supplements can be used to treat immune mediated diseases?
Omega 3 fatty acids
Vit E
Vit D
Glutamine
Arginine
Describe the use of omega 3 fatty acids in immune mediated disease treatment
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
Describe the use of Vit E in treating immune mediated diseases
adjunct antioxidative treatment useful in cases of sterile pyogranulomatous panniculitis
Describe the use of Vitamin D in treatment of immune mediated diseases
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
What are the adverse effects of vitamin D as a treatment for IMD?
hypercalcaemia and eventual renal failure
Describe the role of glutamine in the immune response
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
When should steroids be used to treat IMD?
Steroids used to treat acute or life-threatening cases
Other drugs added later as steroid-sparing drugs
What is the use of using other drugs as steroid-sparing drugs?
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
What should be considered when deciding on immunomodulatory therapy?
Phase of treatment: induction vs maintenance
Seriousness: life threatening or not
Mechanisms of immunological damage
Why does the mechanism of immunological damage need to be considered when deciding treatment for IMD?
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.
Describe the stages of immunosuppressive therapy (CTMM)?
