8. Cytokines and chemokines Flashcards
What are cytokines?
Soluble mediators that are produced by a tissue or a cell and acts at a distance (from micrometres to several cm)
How do cytokines act?
All cytokines act by ligating their receptor (often two subunits) and triggering a signaling cascade leading to activated transcription of specific genes
What determines cell differentiation and haematopoiesis?
cytokines
GM-CSF - multipotential haematopoietic stem cell
SCF, G-CSF, IL-6 = mast cell
GM-CSF -> myeloblast
EPO-> erythrocyte
TPO, IL-11 -> megakaryocyte
T-lymphocyte - Il-2
What are interferons?
Anti-viral mediators – Interferons, identified (1957) as products of virus-infected cells that interfere with viral replication
IFN-alpha (made by lymphocytes)
IFN-beta (made by fibroblasts)
IFN-gamma (made by lymphocytes & NK cells)
IFN-gamma is a very poor antiviral molecule.
Immune activators
Lymphocyte-activating cytokines (IL-1)
T cell growth factors (IL-2, -7, -9, -15; they share a co-receptor)
Macrophage-activating cytokines (IFN-gamma)
Cytotoxins
Cytotoxins: identified as products of activated lymphocytes or macrophages that can kill tumor cells
tumor necrosis factor; TNF, also known as TNF-alpha
TNF is, in fact, a very poor antitumor molecule.
Don’t be mislead by the name
What happened with TNF as an anticancer agent?
In the 1980s TNF was cloned and produced with the hope it would be an anticancer agent. However, it turned out to be too toxic
Same story for IL-1, as a lymphocyte activator tested in AIDS
Do the effector molecules made by T cells differ?
The three main types of armed effector T cells produce distinct sets of effector molecules with different functions. Th1 (T-helper) and Th2 cells act mainly by activating other cells (see previous lectures on innate immunity)
CD8 T cells produce
cytotoxic effector molecules e.g. perforin, granzymes
Th1 cells produce
macrophage activating effectormolecules e.g. IFN-gamma and TNF-alpha
Th2 cells produce
B-cell activating effector molecules
e.g. IL-4, IL-5, IL-10, TGF-Beta
Activated Th1 cell cytokines
IFN-gamma and CD40 ligand Fas ligand or LT-alpha IL-2 IL-3 and GM-CSF TNF-alpha and LT-beta
Immune-stimulating cytokine deficiency cause immunosuppression
component of the IL-2, IL-4 and IL-7 receptorsX-linked SCID (severe combined immunodeficiency) is caused by the genetic inactivation (by mutation) of one receptor that is a common signalling
How did they find out that TNF is an inflammatory mediator?
Studying immunopathegenesis of cachexia during infection
activated macrophages produce an inflammatory mediator (cytokine) that, among other things, induced cachexia.
When they had its sequence, they found it was identical to TNF
Cardinal signs of inflammation
heat swelling redness pain tissue damage
What causes the cardinal signs of inflammation?
biological action of inflammatory cytokines (IL-1, IL-6, TNF…) on the vascular endothelium, or through production of prostaglandins or chemokines.
Inflammation
Macrophages encountering bacteria in the tissues are triggered to release cytokines that increase the permeability of blood vessels, allowing fluid and proteins to pass into the tissues.
They produce chemokines that direct the migration of neutrophils to the site of infection.
The stickiness of the endothelial cells of the blood vessels is also changed, so that cells adhere to the blood vessel wall and are able to crawl through it; first neutrophils and then monocytes are shown entering the tissue from a blood vessel.
The accumulation of fluid and cells at the site of infection causes the redness, swelling, heat, and pain, known collectively as inflammation. Neutrophils and macrophages are the principal inflammatory cells. Later in an immune response, activated lymphocytes may also contribute to inflammation.
TNF-mediated diseases
1-Septic shock 2-Multiple organ failure 3-Respiratory distress syndrome 4-Rheumatoid arthritis 5-Inflammatory bowel disease 6-Graft-versus-host rejection 7-Diabetes 8-Pulmonary fibrosis
(where TNF is a pathogenic mediator and where inhibition of TNF is protective in animal models)
Which cytokines are involved in allergy?
While Th1 cytokines are important in inflammatory diseases, Th2 cytokines are important in allergic diseases
The Th1/Th2 differentiation
is often viewed as a balance
TH1 cytokines from CD4
IFN-gamma, IL-12, IL23
TH2 cytokines from CD4
IL4
TH1 cytokines
IFN-gamma -> inflammation
TH2 cytokines
IL4, IL5, 9 and 13
allergy
anti-inflammation
TH17 cytokines
IL17 -> inflammation
Treg cytokines
IL-10, inhibit activity of other T cells
anti-inflammation
Chemokines
Chemotaxis
Discovered originally by neutrophils chasing bacteria
Then to explain infiltration of leukocytes
Important in the homing and migration of cells of the immune system (= role in development)
Examples of some chemokines
MCP-1/CCL-2
IL-8
CCL2 effect
causes macrophages to accumulate at site of infection - by chemotaxis
Therapeutic use of interferons
IFN-gamma Macrophage activation
IFN-beta (MS) “immunomodulation”
Host defence therapeutic uses
Host defense
IL-2 (melanoma, renal cell carcinoma)
IFN-alpha (hairy cell leukemia, Kaposi, viral hepatitis)
Haematopoiesis cytokines used in therapy
GM-CSF (myeloreconstitution following bone marrow transplant, chemotherapy-induced neutropenia)
G-CSF (chemotherapy-induced neutropenia)
IL-11 (thrombocytopenia in oncology)
EPO (anaemia)
Cytokines pathogenesis
Anti-TNF and sTNFR (R.A., Chron’s, ulcerative colitis, psoriasis)
IL-1Ra (rheumatoid arthritis, cryopyrin-associated periodic syndromes, CAPS)
Anti-IL-6, IL-6R (R.A.),
Anti-IL-17, -12, -23 (psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn)
Anti-IL-5 (Reslizumab, Mepolizumab; approved FDA 2016-2017) for asthma and eosinophilic granulomatosis
Anti-IL-4R (Dupilumab; approved FDA 2017 for atopic dermatitis (eczema)
Types of cytokine inhibitors
Cytokine inhibitors include: antibodies anti-cytokine or their soluble receptors (to mop them up); antibodies to their receptor (to block their binding site)
Antireceptor antibodies
Anti-TNF (infliximab, adalimumab...) Anti-IL-1R (rilonacept) Anti-IL-6R (tocilizumab, sarilumab...) Anti-IL-17R (brodalumab) Anti-IL-12/IL-23 (ustekinumab, briakinumab)
Anti-cytokine antibodies
Anti-IL-1beta (canakinumab)
Anti-IL-6 (siltuximab)
Anti-IL-17 (ixekinumab, secukinumab)
Soluble receptors
Soluble TNFR (etanercept)
IL-1R antagonist
anakinra
What is an example of an antibody that targets more than one thing?
Ustekinumab is an antibody directed against the p40 subunit of IL-12 and IL-23, so it inhibits both.
Approved for psoriasis and Crohn’s disease
Side effects of anti-cytokine therapy
Side effects of anti-TNF, anti-IL-17, anti-IL-6 include increased susceptibility to TB and serious opportunistic infections, including listeria, pneumocystosis and others
