Clinical Uses Of Cytokines (and Anti-cytokines) Flashcards
What is the problem with the functional roles of cytokines?
They are pleomorphic, have multiple effects on multiple different cell types
What are direct effects of cytokines?
Change proliferation rate of target cell e.g. interferons anti-proliferative for leukaemia cells
What regulatory effects can cytokines have?
Change cell activity e.g. IL15 stimulation of NK and cytotoxic T cells
Change the nature of a response e.g. CD4+ switching
What are the 3 different forms of receptor for IL-2?
Low affinity just alpha chain
IL-2 receptor beta chain that interacts with common gamma chain
High affinity receptor - alpha, beta, gamma all expressed on same surface at the same time
Why may it be difficult to achieve desired response to cytokines by systemic administration of high doses?
Because cytokines generally work in an autocrine or paracrine way
How can cytokines be produced in other biologics?
Bacterial expression
Eukaryotic expression
What is the considerations for bacterial expression cytokines?
Folding correct
No glycosylation - doesn’t always matter
What is the consideration for cytokines with eukaryotic expression?
Glycosylation, but may not be perfect
How can you produce a cytokine using recombinant DNA methods and what are the pros?
Use of cloned gene (ensures biologically active protein is produced)
Not glycosylated
Opportunity for modification
Large scale production is possible
What is the con of making cytokines by recombinant DNA methods?
Expensive
What is the substitution to make a cytokine more stable?
Substitution of serine for cysteine in IL2
What was the first cytokine to be produced by recombinant technology?
IL2
What were the applications for IL-2?
Stimulating T and NK responses in renal cell carcinoma, melanoma
What does IL2 act on?
T regs , ILC2
What do low concentrations of IL2 tend to do?
Be more of a drive towards Treg
What do high concentrations of IL2 tend to do?
Push production of effector cells
What can blocking IL2 or CD25 common gamma chain do?
Trigger drive towards autoimmune response
What do the mutated versions of IL-2 now interact with?
Instead of high affinity receptor, they interact more with moderate affinity receptor
What happens when you stimulate the medium affinity receptor for IL-2 more?
Tends to stimulate cytotoxic T cells and NK cells rather than Tregs whihc is better in cancer treatment
How do you increase half life of IL-2?
Adding on albumin
How many antibdoies can bind IL-2 with their antigen combining sites?
Two
What do antibodies binding to IL-2 do?
Biases activation either towards strong immune response or more tolerance, so dont have to use mutated versions of IL-2
What does polyethylglyclo do to cytokines?
Gives better half-life
What does cytokines linked to Fc portion do?
Increases stability and also may be able to target particular cell types
What are three ways of altering cytokine-receptor interactions?
Neutralising cytokines through antibodies or antagonists
Using a receptor antagonist
Activating anti-inflammatory pathways
What is tozolizumab used for?
Is an antibody that binds to IL-6 receptor, it blocks binding of IL-6
How does IL-1 and its receptor work?
Have receptor and accessory protein and needs both to interact to send signal
What does anakinra do?
Is a receptor antagonist for IL-1 receptor but doesn’t interact with accessory protein
What does rilonacept do?
Is formed from two parts of the receptor and mops up both IL-1 beta and alpha in the serum, so can no longer interact with receptor
What does canakinumab do?
One of the first antibodies to mop up IL-1 beta so none interact with receptors
Which cytokine has been proposed for MS?
IFN beta
Why might IFN beta be useful in MS?
Can stop T cells from adhering to blood brain barrier, less likely to go into brain but also promotes anti inflammatory cytokine production
What may be used if you are having chemotherapy and having neutropenia?
GM-CSF as it can boost neutrophil levels
What is the toxicity around IL-2 in the NHS?
Vascular leak syndrome, unpredictable, requires intensive care for all patients
