cytokine therapeutics Flashcards
Learn two to four for exam
Lecture’s objectives
- Understand what a cytokine is, its role, its mechanisms of action, its traits
- Recognise cytokines of the innate and of the adaptive immune system
- Understand the role of cytokines in inflammation; pro- vs anti- inflammatory cytokines
- Be able to describe the effects of different cytokines in disease
- Know at least two examples of cytokine therapeutics used for the treatment of diseases
what is cytokine
are small molecular weight protein secreted by cells of innate and adaptive immune system
what are different cytokines
- interleukins ( IL-1,2,3,4,5, and 6)
- interferons (IFN y )
- TNF (alpha and beta)
cytokine properties
- mean of communication of cells and tissues
- they are not stored in the cells but briefly newly synthesized
cytokines functions
when they are activated they can act in 3 different ways;
- Autocrine: act on cells that produce it
- paracrine; act on cells nearby those that produce it
-endocrine: act on cells that are in different tissue to those that produce it and it can depend on their ability to circulate in the blood and their half-life
what is pleiotropy, redundancy, synergy and antagonism
-pleiotropy is when the same cytokine have many different effect on different cell types.
-redundancy is when different cytokines has same effect on one cell type.
-synergy is when effect of two cytokines together on one cell type is greater than the effect of one cytokine alone.
-antagonism is when effect of one cytokine inhibit those of others
is it tru that there is no one cytokine- one cell rule and why
yes, because same cytokine is made by different cell types and cytokine is made by many cell type
is cytokine receptors found on many cell types
yes
is all interleukine cytokine but not all cytokines are interleukine
yes
which type of cytokine are produced as results of innate and adaptive immune system
- innate: interferon type 1, IL-1 and IL-6
- adaptive: interferon-gama, IL-2, IL-4, and IL-5
what are cytokines that stimulate immature leukocytes growth and differentiation
IL-3
what response does cytokine mediate
inflammation
when does inflammation response initiated
within hours of infection
what are those inflammation response
- induce blood clotting: to limit spread of infection
- repair injured tissues
- destroy invading microorganism: by delivering additional effector cells from the blood to the site of infection
how is inflammation induced
when sensor cells (DC, macrophage, neutrophils) detect Ag they release mediator (cytokines, cytotoxicity) to kill the infection
what are chemokines
they are subgroup of secreted proteins that act as chemo-attractants
what is the role of chemokines
they attract cells bearing chemokines receptor out of blood stream to the infection site
what are Pro-inflammatory vs anti-inflammatory cytokines. and give the example of each
- Pro-inflammatory : initiate the immune response against the infection.
ex: IL-1, IL-6, IL-12 and TNF-alpha - anti-inflammatory cytokines: they control and inhibit the release of pro-inflammatory mediator. or limit inflammatory response.
ex: IL-4,IL-10, IL-13 and TGF beta
why is it important to have balance between Pro-inflammatory and anti-inflammatory cytokines
if there is too high Pro-inflammatory this lead to pepsis caused by dis-regulated immune response
if there is too high anti-inflammatory this lead to immunosuppression which lead to reduction of immune system response
what is the side effect of disturbing the production of cytokine
it can lead to pepsis and immunosuppression
what does activated macrophage lead to
secrete of range of cytokine
what produce pro and anti-inflammatory cytokines
T cells
where does cytokine get signal from
their receptor
how does Cytokine signaling works
- cytokines are produced either by T cells or macrophage
- cytokine binds to extracellular receptor
- receptor activation: cytokine binding induce dimerization or trimerization of receptor subunits
- receptor transduction: activated receptor transmits the signal to the intracellular environment
- cell response
what are cytokines receptor families
- type 1 (homodimeric ) and 2 (heterodimeric with/out common chain) cytokine receptor
- TNFs receptor
- chemokine receptor
why does cytokines receptor form hetero dimer or trimer
- because receptors are shared by multiple cytokines
and multiple receptor has to be activated simultaneous to give effect
Cytokine effects in disease
cytokine regulate immune response and maintain balance btn the health and diseases but dysregulation of cytokine production and signalling can lead to diseases development ad progression
what is IL-1 family
composed of 11 members and is both pr and anti- infammatory members
what is the function of IL-1 family
- promote the activity of cells of innate immune system
- activate and reinforce T cells function
ex; T helper 11 cells require IL-1 to differentiate from naive T cells
IL-1α and IL-1β
- IL-1β: secreted and distributed systematically and are produced by macrophage. f(x) in inducing fever
-IL-1α: acts locally and produced by endothelial cells. f (x), its important in priming T cells
IL-18 and IL-33
- IL-18: are expressed in DC and macrophage. they require caspase 1 to be activated. f(x), help in promoting inflammation and defense against inflammatory diseases.
-IL-33: expressed in endothelial cells. f (x) leads to production of helper T activating cytokines, display strongly immunomodulatory function, response to environment stresses and contribute to tissue homeostasis.
between inflammation and circulation where there more/less production of IL-18
-inflammation there is more production of IL-18 compared ti IL-18BP
-circulation: which is the normal condition there is more IL-18BP
IL-6
IL-6 & IL-11 belongs in the same family.
are expressed by phagocytes, T cells, B cells and endothelial cells. f(x): they involve in maturation of B cells to antibody producing plasma cells, T cells activation (differentiation and regulation of Th2 and Treg )
why is IL-6 the most important cytokine
because it has different effects in different diseases. ex: inflammatory diseases, IL-6 blockade
what is the function of IL-6 blockade
inhibit diseases development in animals
TNFα
is considered as pleiotropic cytokines because it have different side effect on different cell type which are : pro-inflammation, cell proliferation (cell grow and divide to produce new cells), anti viral and immunoregulatory (regulate immune system to maintain the balance-homeostasis) effects.
is secreted by activated macrophage
where do we use Anti-TNF therapies
are mainly for autoimmune diseases
IL-2
is pleiotropic cytokines, produced by CD4 and CD8 T cells, NK cells and activated DCs.
f(x): as T cells growth factor, mediate differentiation of naive T cells into memory T cells.
where does IL-2 used
in cancer therapy
what is the cos of cytokines
-pepsis due to dysregulation
-cytokine storm
- small half life: limit they efficacy
-small dose of IL-2 drive the imbalance between autoimmune and immune tolerance.
that’s why is given at late stage to re stimulate the immune response.
what is cytokine storm
is over reaction of immune system where it release excess amount of cytokines into the blood stream. which lead to wide spread inflammation and tissue damage.
Why are many immunotherapies given at a late disease stage?
due to :
-cytokine storm risk
-immune system status: for late stage especially in cancer the immune system maybe more suppressed or dysfunctional. so immune therapy can be used to boost or reprogram immune system.
Why are they given to specific subcategories of diseased patients?
this ensure that therapy is targeting the right patient based on their cytokines and immune profile
Questions to think and reflect upon
1. Are there “good” and “bad” cytokines?
2. Can we use one cytokine therapy to treat many different types of diseases?
3. Any other reason that cytokine therapeutics are not as efficacious as desired? (Think of pleiotropy)
4. How else can we use the cytokine therapeutics, to take a greater advantage of them?
- yes, there is bad and good cytokine. good one promote the immune response against pathogen and bad one due to dysregulation it can lead to diseases.
- No, due to the pleiotropic effect because cytokine that work in one condition can be ineffective to another condition.
- based on pleiotropy: due to multiple effects of cytokine it can lead to over stimulation of immune response which cause increase in inflammation which results in side effects like tissued damage.
- research on pleiotropy when cytokine has multiple effect it can lead to development of new therapeutic
- personalize medicine: according to patient target
- combine therapy with cytokine can lead to increase of efficacy
What are two examples of cytokine therapeutics used in disease treatment?
- anti-TNF therapies: this work by neutralizing TNF, a pro-inflammatory cytokine that play significant role in improving skin plaques in psoriasis patients.
- IL-6 inhibitor: this therapy target IL-6 another pro-inflammatory cytokine involves in inflammatory diseases by reducing inflammation and improving symptoms in affected patients.
