Regulating Immune Response: Cytokines Flashcards
How do these Cytokines direct certain cell differentiation stages of hematopoiesis?
- GM-CSF
- EPO
- TPO (thrombopoietin)
- G-CSF
- IL-2
- IL-5
- IL-11
What is the role of Interferons?
- name them, site of production
- 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 is a poor anti-viral molecule made by lymphocytes & NK cells
What is the mechanism of action of IFN?
- 2′,5′-oligoadenylate synthetase 1 (OAS1) is expressed at low constitutive levels
- is upregulated by type I interferons (IFNs) via the ISRE, IFN-stimulated response element.
- OAS1 protein accumulates in the cell cytoplasm as an inactive monomer.
- Following activation by viral double-stranded RNA (dsRNA), the enzyme oligomerizes to form a tetramer that synthesizes 2′,5′-oligoadenylates
- that, in turn, activate the constitutively expressed inactive ribonuclease L (RNaseL).
- The binding of 2′,5′-oligoadenylates to RNaseL triggers the dimerization of enzyme monomers and this then enables RNAseL to cleave cellular (and viral) RNAs.
What Cytokines are mediators of host cell defence?
- IFN - antiviral (apart from gamma)
- IL - antitumour (+ IFN gamma)
Give examples of Immune activators for the following cells
- lymphocytes
- T cells
- Macrophages
- Lymphocyte-activating cytokines (IL-1)
- T cell growth factors (IL-2, -7, -9, -15; they share a co-receptor)
- Macrophage-activating cytokines (IFN-gamma)
What is the role of TNF?
- a pro-inflammatory factor
What is X-linked SCID?
- cause?
- X-linked SCID (severe combined immunodeficiency) is caused by the genetic inactivation (by mutation) of one receptor that is a common signalling component of the IL-2, IL-4 and IL-7 receptors
- “Bubble children”
What are the most common TND-mediated diseases - where inhibition of TNF is protective
(8)
- Septic shock
- Multiple organ failure
- Respiratory distress syndrome
- Rheumatoid arthritis
- Inflammatory bowel disease
- Graft-versus-host rejection
- Diabetes
- Pulmonary fibrosis
Which cytokines are significant in allergy?
- Th2 roles
- Th2 cytokines are important in allergic diseases
- these are two variations of CD4+ T cells
- IL-4 meditation leads to Th2 cells
- is anti-inflammatory
- IL-4,5,9,13
What are the T cell subsets and what are the main cytokines do they release?
- what is their main action?
(4)
What are Chemokines?
- importance?
- two main ones and their role
- chemotactic cytokines
- chemotaxis is a migration towards a gradient
- important in the homing and migration of cells of the immune system
- MCP-1 (monocyte chemotactic protein)
- attracts monocytes
- IL-8 (Interleukin-8)
- attracts neutrophils
What is the therapeutic use of Chemokines?
- the IFNs
- GM-CSF
- G-CSF
- IL-2,11
- EPO
- IFN-gamma Macrophage activation
- chronic granulosa disease
- IFN-beta (MS) “immunomodulation”
- multiple sclerosis
Host defence
- IL-2 (melanoma, renal cell carcinoma)
- IFN-alpha (hairy cell leukaemia, Kaposi, viral hepatitis)
Hemopoiesis
- GM-CSF (myeloreconstitution following bone marrow transplant, to treat chemotherapy-induced neutropenia)
- G-CSF (chemotherapy-induced neutropenia)
- IL-11 (thrombocytopenia in oncology)
- EPO (anaemia)
What is the use of specific cytokine inhibitors in certain inflammatory pathogenesis?
- TNF
- IL-1,4,5,6,12,17,23
- 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 (rheumatoid arthritis),
- 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)
What are the 4 main approaches to block cytokines?
- 1) antibody to the cytokine (middle);
- 2) antibody to their receptors so that the cytokine can’t bind anymore (left);
- 3) soluble (decoy) receptors that bind the cytokine (because they are receptors) but, not being on the membrane, do not signal and thus compete with the membrane receptor
- 4) A fourth way is a receptor antagonist. This exists in nature for IL-1 (IL-1 receptor antagonist, IL-1Ra).*
- IL-1Ra acts as a competitive inhibitor
* not an antibody it is a chemokine
What are the Anti-receptor antibodies?
(6)
- Anti-TNF (infliximab, adalimumab…)
- Anti-IL-1R (rilonacept)
- Anti-IL-6R (tocilizumab, sarilumab…)
- Anti-IL-17R (brodalumab)
- Anti-IL-12/IL-23 (ustekinumab, briakinumab)
What are the Anti-cytokine antibodies?
(3)
- Anti-IL-1beta (canakinumab)
- Anti-IL-6 (siltuximab)
- Anti-IL-17 (ixekinumab, secukinumab)
Give an example of a soluble receptor inhibitor
- SolubleTNFR (etanercept)
