Therapeutics for managing the over active immune response Flashcards
Why and why is it necessary to manage an overactive immune response
When there is the inappropriate or extreme triggering of the immune system leading to generation of antibodies and/or T cells directed against self-antigens
-> marked local or systemic inflammatory response -> tissue destruction and clinical disease which can be life-threatening
In primary or idiopathic immune-mediated disease treatments to control the overactive immune response are indicated
BUT in secondary immune-mediated disease, any treatment should ideally be directed against the trigger factor if at all possible
What is an immunomodulatory drug
A substance that
stimulates or suppresses the immune system
effective immune stimulation is very challenging to achieve safely
is used to modify the immune response to help with managing immune-mediated disease or in treatments for cancer
What is a ‘specific’ immunomodulatory drug
A drug targeted against a specific component of the immune system:
Specificity is determined by
ability to bind to;
an immune protein to prevent interaction with a receptor eg monoclonal antibodies
a receptor without activating it effectively blocking the receptor
ability to specifically inhibit inflammatory cytokines eg interleukin 1 receptor antagonist (IL-1RA)
NOT CURRENTLY USED BY VETS:
Vets lack:
pharmacological data to support the use of drugs used in people
licensed drugs ie appropriately safe and approved
What is an immune suppressive drug
Traditionally we have used high dose glucocorticoids (steroid treatment) as 1st line treatment for immune suppression in dogs and cats with immune mediated diseases (IMDs)
Considered to have a broad effect ie not specific or targeted
Other non-specific immunomodulatory drugs (“steroid sparing drugs”) are often used in combination with glucocorticoids
they reduce the side effects of steroid treatment by enabling a reduction in steroid dose
How are glucocorticoids used for immune suppression
Prednisolone most commonly used
Effects are dose dependent:
Anti inflammatory dose:
Inhibits release of pro inflammatory cytokines
Stabilises granulocyte cell membranes
Immune suppressive dose:
Targets macrophage function
down regulates Fc receptor expression
reduces phagocytosis of opsonised red blood cells (rbcs coated with antibody or complement in IMHA) and platelets
Decreases antigen processing
suppresses T cell function and induces apoptosis of T cells
might inhibit B-cell antibody production in longer-term
Clinical use of glucocorticoids
1st line treatment for most IMD (eg 1ry IMHA) in dogs and cats because:
Rapid onset of action
Cheap and available compared to many drugs
Licensed for use in dogs and cats
Most vets are very familiar with and therefore feel comfortable prescribing this drug
Adverse effects of glucocorticoids
Inevitable due to wide distribution of GC receptors in the body
Immune suppression contributes to ↑ risk of bacterial infection:
aggravated by other signs relating to glucocorticoid excess eg polyuria -> urine with low USG -> better environment for bacteria -> UTI; changes in the skin -> pyoderma
Increased risk of thrombosis and thromboembolic disease
cumulative risk in IMHA patients which already have ↑ risk of thromboembolism- already in hypercoagulative state
Iatrogenic (ie drug induced) hyperadrenocorticism (“Cushing’s disease”)
Even if severe adverse effects, treatment must be ↓ slowly or -> iatrogenic hypoadrenocorticism (Addison’s disease)
Examples of additional immune suppressive agents are often used to enable a reduction in the prednisolone dose
ciclosporin
azathioprine (NEVER in cats)
chlorambucil
mycophenolate
leflunomide
Some nutrients can modulate inflammation and the immune response
How does vitamin D affect the immune system
Vitamin D deficiency: risk factor related to the development of IMDs in people (rheumatoid arthritis; systemic lupus erythematosus; multiple sclerosis; type I diabetes mellitus)
Vitamin D is involved in;
enhancing and potentiating the immune response against pathogens (innate immunity)
modulation of the adaptive immune system via effects on:
T cell activation
Function of antigen presenting cells, especially dendritic cells
Unclear if vitamin D has any role in managing immune-mediated disease in people. “Watch this space” for dogs and cats?
How do omega 3 fatty acids affect the immune system
Reduce production of inflammatory mediators
Incorporation in synthesis of anti inflammatory factors attenuates the inflammatory and innate immune responses
Current clinical use by vets: managing inflammatory conditions and protein-losing nephropathy in dogs and cats rather than IMD
Evidence from human medicine suggests a role in critical illness:
Enteral supplementation suggested improved outcome in early sepsis
Larger scale studies with meta-analysis were less convincing but were still quite small studies
How does glutamine affect the immune system
Traditionally considered to be a non-essential amino acid ie can be produced and therefore not required in the 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
Arginine might have similar immune enhancing properties in people with critical illness
Mode of action of ciclosporine
Blocks transcription of genes required for T cell activation
Decreases IL-2 production-> decreased clonal proliferation T cells (+therefore Bcells)
-> less of other cytokines (IL-3,IL-4, granulocyte colony stimulating factor, tumour necrosis factor), alters function of granulocytes, macrophages, NK cells, eosinophils and mast cells
clinical use of ciclosporine
Rapid onset of action
Steroid sparing effects ie. often used in combination with prednisolone
Licences fro use in atopic dermatitis but use in IMDs is also increasing
Adverse effects of ciclosporine
Mild gastrointestinal signs- usually self limitiing if dose is decreased for a few days
INCREASED risk of infection
INCREASED risk of thromboembolism
Other less likely effects: gingival hyperplasia, lymphoproliferative diseases
Mode of action in azathioprine (NEVER use in cats)
Cytotoxic drug which inhibts DNA and RNA synthesis
Main effect likely on cell mediated immunity: decreased lymphocyte numbers and T cell dependent antibody synthesis
