Immunomodulation Flashcards
When three times is immune modulation needed?
Immune suppression- reducing inflammatory response, reducing allergic response, supression of innapropriate immune response
Enhance host immune response- to infection, vaccination, enhance immune response against neoplasia
Future- administration of immune system elements- invoke/limit response in degenerative disease
What are the 4 types of hypersensitivity reactions and what causes them?
Type I- IgE and MCT mediated
Type II- IgG mediated
Type III- immune complex disease
Type IV- cytotoxic T cell mediated
What are the 2 sources of antigens which cause immune mediated disease?
Idiopathy/autoimmunity
Exogenous antigen
What is the difference between anti-inflammatories compared to immunosuppressive medications?
Anti-inflammatories- act to block some effector mechanism of innate immune system
Immunosuppressive- Mainly act to reduce function of adaptive immune system, reduce lymphocyte proliferation/limit effect
What are the three main groups of drugs in veterinary practice?
Drugs which:
Inhibit cytokine gene expression
Inhibit IL-2 production/action
Inhibits DNA synthesis
What is the ‘first’ line of immunosuppressive drugs?
Glucocorticoids
Describe the chemical features of glucocorticoids and where are they metabolised and excreted?
Lipophilic and highly protein bound
Metabolised by the liver
Excreted by the kidneys
What is the mechanism of action of glucocorticoids?
Bind to Glucocorticoid receptor in cytoplasm- transit to nucleus, bind to DNA influencing transcription of genes in many tissues
Stabilise mast cell membranes reducing degranulation
Reduce pro-inflammatory cytokine production- reduced IL-2- reduced lymphocyte numbers esp CD4+
Down regulate Fc receptor expression on macrophages
Reduce antigen presentation
What does the effect of glucocorticoids depend on?
Dose anf formulation
What are the three commonly used glucocorticoids and what are their potency compared to cortisol?
Prednisolone- 5x
Methylprednisolone- 7x
Dexamethasone- 35x
How can glucocorticoid side effects be reduced?
Topical administration
What systemic effects are caused by glucocorticoids?
Stimulate gluconeogenesis
Suppress inflammation
Alter fat, protein and CHO metabolism
Suppress HPA axis
What are the adverse effects of glucocorticoids?
Skin thinning, comedones, calcinosis cutis Weight gain, Protein/muscle loss Polyphagia Laminitis? Panting HPAA Lethargy/euphoria PU/PD GI bleeding Hyper-coagulability
When are glucocorticoids contraindicated?
Uncontrolled infections Diabetes mellitus Corneal and GI ulcers Heart disease Burns Pregnancy
Why are glucocorticoids not used for long term treatment of immune diseases?
Balancing effective treatment against side effects can be impossible
Prolonged use suppresses HPA axis
Where is IL-2 produces and what does it stimulate?
Produced by Th (CD4+) cells
Stimulates clonal proliferation and activation of T cells
B cell proliferation
Activity of innate immune cells- macro, NK cells
Which two IL-2 inhibition drugs are commonly used in practice?
Ciclosporin
Tacrolimus
What is the mode of action of the IL-2 inhibition drugs?
Block calcineurin activation giving reduced IL-2 production
How is ciclosporin administered and how can the dose be reduced?
Topical, oral or parenteral
Co-administration with ketoconazole can reduce the required dose
How is tacrolimus usually administered?
Most commonly topical administration
Where are are ciclosporin and tacrolimus?
Metabolised by liver cytochrome P450 enzymes
Excreted in bile
What are the adverse effects of ciclosporin and tacrolimus?
Transient vomiting
Possible increase in risk neoplasia
Opportunistic infections
What drugs inhibit DNA synthesis?
Azathioprine
Mycophenolate mofetil
Leflunomide
What is the mode of action of azathioprine?
Inhibits purine synthesis, inhibition of DNA and RNA synthesis land therefore alterations in cell metabolism- reduces TH1 mediated immunity
Slow onset of actions 7-35 days
