Clinical Uses Of Cytokines (and Anti-cytokines)

Question 1

What is the problem with the functional roles of cytokines?

Answer 1

They are pleomorphic, have multiple effects on multiple different cell types

Question 2

What are direct effects of cytokines?

Answer 2

Change proliferation rate of target cell e.g. interferons anti-proliferative for leukaemia cells

Question 3

What regulatory effects can cytokines have?

Answer 3

Change cell activity e.g. IL15 stimulation of NK and cytotoxic T cells
Change the nature of a response e.g. CD4+ switching

Question 4

What are the 3 different forms of receptor for IL-2?

Answer 4

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

Question 5

Why may it be difficult to achieve desired response to cytokines by systemic administration of high doses?

Answer 5

Because cytokines generally work in an autocrine or paracrine way

Question 6

How can cytokines be produced in other biologics?

Answer 6

Bacterial expression
Eukaryotic expression

Question 7

What is the considerations for bacterial expression cytokines?

Answer 7

Folding correct
No glycosylation - doesn’t always matter

Question 8

What is the consideration for cytokines with eukaryotic expression?

Answer 8

Glycosylation, but may not be perfect

Question 9

How can you produce a cytokine using recombinant DNA methods and what are the pros?

Answer 9

Use of cloned gene (ensures biologically active protein is produced)
Not glycosylated
Opportunity for modification
Large scale production is possible

Question 10

What is the con of making cytokines by recombinant DNA methods?

Answer 10

Expensive

Question 11

What is the substitution to make a cytokine more stable?

Answer 11

Substitution of serine for cysteine in IL2

Question 12

What was the first cytokine to be produced by recombinant technology?

Answer 12

IL2

Question 13

What were the applications for IL-2?

Answer 13

Stimulating T and NK responses in renal cell carcinoma, melanoma

Question 14

What does IL2 act on?

Answer 14

T regs , ILC2

Question 15

What do low concentrations of IL2 tend to do?

Answer 15

Be more of a drive towards Treg

Question 16

What do high concentrations of IL2 tend to do?

Answer 16

Push production of effector cells

Question 17

What can blocking IL2 or CD25 common gamma chain do?

Answer 17

Trigger drive towards autoimmune response

Question 18

What do the mutated versions of IL-2 now interact with?

Answer 18

Instead of high affinity receptor, they interact more with moderate affinity receptor

Question 19

What happens when you stimulate the medium affinity receptor for IL-2 more?

Answer 19

Tends to stimulate cytotoxic T cells and NK cells rather than Tregs whihc is better in cancer treatment

Question 20

How do you increase half life of IL-2?

Answer 20

Adding on albumin

Question 21

How many antibdoies can bind IL-2 with their antigen combining sites?

Answer 21

Two

Question 22

What do antibodies binding to IL-2 do?

Answer 22

Biases activation either towards strong immune response or more tolerance, so dont have to use mutated versions of IL-2

Question 23

What does polyethylglyclo do to cytokines?

Answer 23

Gives better half-life

Question 24

What does cytokines linked to Fc portion do?

Answer 24

Increases stability and also may be able to target particular cell types

Question 25

What are three ways of altering cytokine-receptor interactions?

Answer 25

Neutralising cytokines through antibodies or antagonists
Using a receptor antagonist
Activating anti-inflammatory pathways

Question 26

What is tozolizumab used for?

Answer 26

Is an antibody that binds to IL-6 receptor, it blocks binding of IL-6

Question 27

How does IL-1 and its receptor work?

Answer 27

Have receptor and accessory protein and needs both to interact to send signal

Question 28

What does anakinra do?

Answer 28

Is a receptor antagonist for IL-1 receptor but doesn’t interact with accessory protein

Question 29

What does rilonacept do?

Answer 29

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

Question 30

What does canakinumab do?

Answer 30

One of the first antibodies to mop up IL-1 beta so none interact with receptors

Question 31

Which cytokine has been proposed for MS?

Answer 31

IFN beta

Question 32

Why might IFN beta be useful in MS?

Answer 32

Can stop T cells from adhering to blood brain barrier, less likely to go into brain but also promotes anti inflammatory cytokine production

Question 33

What may be used if you are having chemotherapy and having neutropenia?

Answer 33

GM-CSF as it can boost neutrophil levels

Question 34

What is the toxicity around IL-2 in the NHS?

Answer 34

Vascular leak syndrome, unpredictable, requires intensive care for all patients