Immune Modulators (Immune suppressants 1) Flashcards
What is Rapamycin (sirolimus)? What is it used for?
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
Under what circumstance would you use rapamycin?
- Used to avoid transplant rejection - *cannot use Tacrolimus with this drug b/c it competes*
Streptokinase- what is it used for?
‘unclog your arteries’ - as a plumber would say
What is balloon angioplasty
- physically unblock an artery by inflating a balloon into the artery- but doesn’t prevent reclogging
What is a stent?
Mini scaffold that is inserted into the vessel - holds the vessel open - doesn’t prevent reclusion of the vessel however.
What is intimal hyperplasia?
When smooth muscle grows around a stent- recludes the artery
What do we coat stents in to prevent intimal hyperplasia?
We coat the stent in rapramycin to prevent this.
What is Denileukin Diftitox?
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
What is the ‘two man rule ‘ in the immune response?
called ‘Co-stimulation ‘ - T cell receptor cannot trigger activation alone - it requires CD28 and B7 to interact as well
What is Abatacept - how does it work?
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 -
What is Belatacept - what is it used for?
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
What is Ipilimumab? What is it used for?
monoclonal antibody that binds to CTLA 4 and blocks the inhibitory pathway - approved for melanoma treatment
What is Alefacept?
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 -
What are Anti-CD28 antibodies used for?
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
What is SIRS?
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
What is the role of Adhesion molecules in immune therapy?
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.
What is Efalizumab? What is it used for?
monoclonal antibody- blocks T cell binding to endothelial cells
used to treat psoriasis
what is Natalizumab? (Tysabri)
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 -
What is PML?
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*
What is REMS?
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! “
What is the point of REMS?
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
What is the role of S1P?
S1P triggers lymphocyte egress from lymphoid tissue -
* potential target for therapeutic immune supression *
What is Fingolimod? What is it used for?
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 -
What are the side effects of Fingolimod?
They have potential risks to the heart - and there may be evidence of PML - there is of course risk of infection -
What is Siponimod used for?
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
What does TNF stnad for?
tumor necrosis factor
What are three ways of blocking TNF?
- bind to receptor and block TNF binding
- Bind to TNF and block binding to receptor
- Block TNF synthesis
What drug blocks TNF synthesis?
Thalidomide
What are anti-TNF drugs used to treat?
The are immune suppressants - currently used in the treatment of RA - ex) infliximab
also used for
- psoriatic arthritis
- psoriasis
- Chron’s disease
- ulcerative colitis
What is a risk associated with anti-TNF drugs?
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
What is imiquimod?
topical drug used for genital warts- it promotes an imune response by infiltration of immune cells - induces apoptosis
What is Intravenous IgG? (IVIG)
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.
List some cytokines that are commonly targeted!
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
Which drugs are the most commonly used for organ transplant?
1) tacrolimus
2) Mycophenolate
*know both of these in detail *
