Immune Modulators (Immune suppressants 1)

Question 1

What is Rapamycin (sirolimus)? What is it used for?

Answer 1

Rapamycin is an immune suppressant (aka Sirolimus) -It binds to FKBP- but doesn’t inhibit IL 2 production , it binds to targets of rapamycin (mTOR1) - which leads to a reduced expression of adhesion molecules including the sphingosine 1 phosphate receptor

Question 2

Under what circumstance would you use rapamycin?

Answer 2

• Used to avoid transplant rejection - *cannot use Tacrolimus with this drug b/c it competes*

Question 3

Streptokinase- what is it used for?

Answer 3

‘unclog your arteries’ - as a plumber would say

Question 4

What is balloon angioplasty

Answer 4

• physically unblock an artery by inflating a balloon into the artery- but doesn’t prevent reclogging

Question 5

What is a stent?

Answer 5

Mini scaffold that is inserted into the vessel - holds the vessel open - doesn’t prevent reclusion of the vessel however.

Question 6

What is intimal hyperplasia?

Answer 6

When smooth muscle grows around a stent- recludes the artery

Question 7

What do we coat stents in to prevent intimal hyperplasia?

Answer 7

We coat the stent in rapramycin to prevent this.

Question 8

What is Denileukin Diftitox?

Answer 8

It is IL2 and diphtheria toxin fusion protein - in certain leukemias there are high levels of the IL2 receptors - so we give this drug and it will target the leukaemia cells majority and then the diphtheria will degrade cell

Question 9

What is the ‘two man rule ‘ in the immune response?

Answer 9

called ‘Co-stimulation ‘ - T cell receptor cannot trigger activation alone - it requires CD28 and B7 to interact as well

Question 10

What is Abatacept - how does it work?

Answer 10

it is a CTLA 4 fusion protein - which binds to B7 preventing interaction with CD28 - disabling the ‘co-stimulatory’ action of the T-cell - It is approved for the treatment of Rheumatoid arthritis -

Question 12

What is Belatacept - what is it used for?

Answer 12

It is structually similar to abatacept - but it has a higher affinity for CD86 - it is approved for organ transplantation immune supressant - but not for RA

Question 13

What is Ipilimumab? What is it used for?

Answer 13

monoclonal antibody that binds to CTLA 4 and blocks the inhibitory pathway - approved for melanoma treatment

Question 14

What is Alefacept?

Answer 14

It is another fully human fusion protein - LFA-3 and Fc portion of IgG1

it is approved for plaque psoriasis - but not currently on the market -

Question 15

What are Anti-CD28 antibodies used for?

Answer 15

They were shown in animal models to icnrease the type 2 helper cells and regulatory T cells - they showed benefit in animal autoimmune disease models … but in clinical trials they had serious adverse effects- produced Cytokine storm - and a systemic inflammatory response syndrome

Question 16

What is SIRS?

Answer 16

systemic inflammatory response syndrom

defined as 2 or more of…

• Fever > 38 or <36
• heart rate > 90 beats a minute
• respiratory rate of more than 20 breaths/min
• Abrnormal WBC

This is due to the activation of pro-inflammatory cytokines like TNF, IL1, or IFN

Question 17

What is the role of Adhesion molecules in immune therapy?

Answer 17

Immune cells must adhere to target to be effective. Full activation often requires adhesion which is mediated by families of adhesion receptors like Integrins and Immunoglobin superfamily.

Question 18

What is Efalizumab? What is it used for?

Answer 18

monoclonal antibody- blocks T cell binding to endothelial cells

used to treat psoriasis

Question 19

what is Natalizumab? (Tysabri)

Answer 19

monoclonal antibody - binds to alpha 4 integrins - thought to block binding of inflammaotry cells to endothelium - prevents infiltration by lymphocutes into the brain - In clinical trials, however, we saw cases of PML -

Question 20

What is PML?

Answer 20

Progressive multifocal leukoencephalopathy

• due to reactivation of JC virus in the brain -

high mortality

*lots of people have the JC virus and don’t know b/c asymptomatic, but when it’s reactivated there is a 50% mortality rate*

Question 21

What is REMS?

Answer 21

it is a ‘Risk Evaluation and Mitigation Strategy”

• as a doctor, if you wanted to put someone on a risky drug, you have to talk to the pharmecuetical company- discuss it with them - come up with a plan before putting them on a drug.

The EMA equivalent is a risk management plan- which is essentially a leaflet that explains the risk factors and contra indications?

-Is this just a way for pharmaceutical companies to get risky drugs on the market? “Nevermind the dead clinical trial participants! I have a billion dollar drug to sell! “

Question 22

What is the point of REMS?

Answer 22

These strategies- yes they are a way for pharmeceutical companies to sell potentially deadly drug-

BUT! Some patients are willing to risk it - for relief of their conditions like Muscular sclerosis. They would take a risk of death if it would relieve their symptoms-

This allows potentially life saving drugs to be put on the market- even though they may not be super safe

Question 23

What is the role of S1P?

Answer 23

S1P triggers lymphocyte egress from lymphoid tissue -

* potential target for therapeutic immune supression *

Question 24

What is Fingolimod? What is it used for?

Answer 24

it is a a S1P receptor agonist - but it internalizes the S1P receptor so they are no longer available for binding on the surface of these ceslls - therefore it reduces the hyperactivity of astrocytes!

Yay immune suppressants !

Approved for MS -

Question 25

What are the side effects of Fingolimod?

Answer 25

They have potential risks to the heart - and there may be evidence of PML - there is of course risk of infection -

Question 26

What is Siponimod used for?

Answer 26

It binds to all but two S1P receptors - it doesn’t have the cardiac toxicity associated with other S1P agonists - so it’s promising for immune suppression

Question 27

What does TNF stnad for?

Answer 27

tumor necrosis factor

Question 28

What are three ways of blocking TNF?

Answer 28

• bind to receptor and block TNF binding
• Bind to TNF and block binding to receptor
• Block TNF synthesis

Question 29

What drug blocks TNF synthesis?

Answer 29

Thalidomide

Question 30

What are anti-TNF drugs used to treat?

Answer 30

The are immune suppressants - currently used in the treatment of RA - ex) infliximab

also used for

• psoriatic arthritis
• psoriasis
• Chron’s disease
• ulcerative colitis

Question 31

What is a risk associated with anti-TNF drugs?

Answer 31

Patients with a latent form of TB are at an increased risk of TB infection - therefore you screen for latent TB before placing patients on anti-TNF drugs

Question 32

What is imiquimod?

Answer 32

topical drug used for genital warts- it promotes an imune response by infiltration of immune cells - induces apoptosis

Question 33

What is Intravenous IgG? (IVIG)

Answer 33

it is purified IgG from pooled plasma - used as immune suppressant - blocks Tcepilson (which binds to IgE and causes degranulation and anaphalactic shock) - thus has anti inflammatory activity

approved for immune thrombocytopenia, multifocal motor neuropathy etc.

Question 34

List some cytokines that are commonly targeted!

Answer 34

IL-1 - targeted in treatments for RA

IL-6 - targeted in treatments for RA

CD20 - targeted by Rituximab

CD3- targeted by OKT3 Muromonab in organ transplants

CD52- targeted by alemtuzumab - targeted in MS and leukemia

Question 35

Which drugs are the most commonly used for organ transplant?

Answer 35

1) tacrolimus
2) Mycophenolate

*know both of these in detail *