Lecture 22 Cytokines as Therapeutics Flashcards
What are cytokines?
These are proteins, polypeptides, or glycopeptides.
These are signalling molecules that mediate interactions between cells of the immune system.
These mediate immune, inflammatory responses as well as hematopoiesis.
These act at the nano to pico molar range.
How are cytokines classed?
Cell of origin:
lymphokine, monotone
Function: chemokine: chemotaxis GM-CSF (colony stimulating factors) Interleukins Interferons Tumor necrosis factors.
Structural or sequence homology
What is a main issue with how cytokines are classified?
Various cell types can secrete the same cytokine and one cytokine can have various functions depending on which cell secreted it.
What are the general effects in a Th1 response?
Pro-immunity
Pro-inflammatory
Il-2, TNFa, INFy
What are the general effects of the Th2 response?
Repair and recovery of tissues damaged by infection and inflammation.
Allergic response
Anti-inflammatory
Il-4, Il-10, Il-13
How does Th1/Th2 balance/imbalance affect an immune response?
An imbalance other than present during infection is associated with autoimmune diseases, hypersensitivity, and cancer.
Normal Th1 prevalence is pro-inflamatory whereas Th2 prevalence is anti-inflammatory.
What is Il-2?
AKA T cell growth factor.
Binds IL-2 receptor on lymphocytes
Pro-inflammatory cytokine induces Th1 response.
Secreted by Cd4+ cells
Results in expansion and proliferation of lymphoid cells esp. B and NK cells.
Induces secretion of other cytokines like TNF as well as antibodies.
Role in antiviral/bacterial immune response.
Role in selection of regulatory T cells.
Role in suppression of self-anti-self recognition to maintain tolerance.
Also has role in promoting apoptosis, Th2, and other immunosuppressive actions.
What are some therapeutic uses of Il-2?
Metastatic renal cell carcinoma
Acute myeloid leukaemia
Why are the therapeutic uses of IL-2 limited?
It has toxicity when used outside of its natural role.
It can induce:
Autoimmune disorders
Capillary leak syndrome
Cardiac, CNS, Renal and liver toxicity.
What are interferons and what are the main types?
These are secreted in response to and interfere with viral replication.
Type 1: INF-a/B
Type 2: INF-y
What is the immunostimulatory role of type 1 interferons?
These induce resistance to viral replication in cells.
These promote the Th1 response
These induce secretion of IL-15 (ligand) by macrophages which act on receptors on NK cells promotes their differentiation in order to kill virus infected cells.
Il-15 also promotes differentiation of memory T cells.
NK cells are induced by type 1 interferon actions to secrete type 2 interferon INF-y among other things.
What are the roles of Type 2 Interferons?
INF-y is secreted by NK cells.
This is immunostimulatory, activating antigen presenting cells and increases proliferation of other cells in the Th1 response.
This is a potent inflammatory cytokine.
This targets macrophages in tissues resulting in further macrophage activation.
Macrophages become more efficient at phagocytosis and destruction of pathogens and are induced to secrete inflammatory cytokines themselves.
There are also some immunosupressive roles:
What are the immunosuppressive functions of type 1 INFs?
These act to increase IL-10, which inhibits secretion of inflammatory cytokines.
These act to decrease IL-12 leading to a decrease in stimulation of inflammation.
Il 12 is secreted by macrophages to cause the activation and recruitment of NK cells into effector NK cells which then act on macrophages and other cells in the infected tissue to produce a heightened state of inflammation.
What are some therapeutic uses for INF?
infections diseases, cancers, autoimmune diseases
Hep B, C, hair cell leukaemia
What are some potential issues with use of INF?
May precipitate autoimmune diseases like:
auto-immune thyroiditis
lupus
rheumatoid arthritis.
Treatment with cytokines mimics the natural progress of some diseases where these cytokines are upregulated.
What is INF-a2a used for and how does it help?
Hep C (acute and chronic)
Hep B (chronic)
Leukemias (chronic myeloid and hair cell leukaemia.
Lymphoma (non-hodgkin’s)
Mechanism: this decreases cell proliferation and differentiation and decreases replication of virus-infected cells.
What are some side effects of INF a2a use?
Immunosuppression (easier infection)
Myelosuppression
autoimmune diseases
Headache, fatigue, fever
How is INF-a2a currently formulated?
PEGylated INF-a2a (Pegasys) for subcutaneous injection
What is INF-a2b used for and how does it act?
Chronic Hep B and C
Hair cell leukaemia
Non-Hodgkin’s lymphoma
Decreases cell proliferation and differentiation
Decreases virally-infected cell replication.
What are some major adverse effects of INF-a2b?
Allergic and hypersensitivity reactions.
Chest pain
Fatigue, fever, headache.
Myelosuppression.
How is INF-a2b formulated?
INF-a2b (Intron A) for IM so SC injection
PegIntron for SC injection.
What therapeutic use does INF-B have and how does it act?
relapsing MS
Anti-viral and immunoregulatory properties.
What are major adverse effects of INF-B use?
Cardiovascular (HTN, tachyarrhythmia)
Myelosuppression (anemia and leukopenia)
Allergic and Hypersensitivity reactions
How is INF-B formulated?
INF-B1a (Avonex) for IM
INF-B1b (Betaseron) for SC
What are G-CSF and GM-CSF used for?
These are used for neutropenia or low levels of neutrophils present especially after chemo, AIDS, and post bone-marrow transplant.
These are also used when harvesting peripheral blood stem cells.
How do G-CSF and CM-CSF work?
C-CSF binds CD114
CM-CSF binds CD116
Binding stimulates granulocytes (neutrophils etc) and macrophages to proliferate in bone marrow.
What common adverse effects do G-CSF and GM-CSF commonly have?
Nausea and vomitting (questionable) Bone pain (due to simulation of growth of bone marrow, in legs usually)
How is G-CSF formulated?
Filgrastim (Neupogen)
PEG-filgrastim (Neulasta)
This has a longer half life and less dosage.
How is GM-CSF formulated?
Sargramostim (Leukine) for SC injection
What is Erythropoietin? When is it used and how does it work?
This is a CSF in RBC production.
This is used for anemia especially due to chemotherapy or chronic renal failure.
This binds to the erythropoietin receptor and stimulates erythroid cell proliferation.
How is erythropoietin formulated?
Epoetin-a (Eprex) and Darbepoeitn-a (Aranesp) for SC injection
What is the major adverse effect of erythropoietin use?
Pure red cell aplasia (PRCA)
This can occur due to overstimulation which results in less RBC maturation (the opposite effect?)
Congestive heart failure, myocardial infarction, deep vein thrombosis, pulmonary embolism, stroke, seizures can occur as the blood gets thicker with more RBCs and complicate or exacerbate these conditions.
The blood becomes more prone to clotting.
What is anti-cytokine therapy?
This acts to inhibit the activity of pro-inflamatory cytokines like TNF by binding to the cytokines or their receptors.
What are some anti-TNG drugs?
Etanercept
Infliximab
Adalimumab
Certolizumab
What are some Anti-IL-2 drugs?
Daclizumab (off market)
Basoliximab
Aldesleukin
What is Etanercept (Enbrel) and how does it act as an anti-TNF agent?
This is a fusion protein of the extracellular part of the TNF receptor linked to the FC portion of an Ig which acts to compete for binding of and induce destruction of INF. This reduces the amount of circulating TNF (a and B).
SC injection.
What is Etanercept used for and what problems might it cause?
Ankylosing spondylitis (inflammation and fusing of spine)
Moderate to severe plaque psoriasis
Rheumatoid arthritis
Can cause secondary cancers, reactivation of latent infections, allergic and hypersensitivity reactions.
What are infliximab and adalimumab and what are they used for?
These are anti-TNF antibodies used for ankylosing spondylitis,
rheumatoid arthritis,
psoriasis
chrohn’s disease and ulcerative colitis (infliximab only)
What type of antibodies are infliximab and adalimumab and how do they act?
Infliximab (Remicade) is a chimeric mAb for IV infusion.
Adalimumab (Humira) is a fully human mAb for SC injection
These bind to circulating TNF-a effectively reducing its concentration.
What are the major adverse effects of infliximab and adalimumab?
Reactivation of latent infections
opportunistic infections
lymphoma and other malignancies
infusion reaction for infliximab
allergic and hypersensitivity reactions (more likely for the chimeric infliximab)
What is Daclizumab, how does it work, and what is it used for?
This is a humanized mAb that binds to the Tac-a or CD25 subunit of the IL-2 receptor on activated lymphocytes preventing binding of IL-2.
This is sues in acute organ rejection prophylaxis esp. after kidney transplant.
How is daclizumab formulated and what are some of its adverse effects?
Daclizumab (Zenapax) is no longer available in NA.
It may cause allergic and hypersensitivity reactions.
Also, can cause elevated fasting blood glucose levels.
What is Basiliximab, what is it used for, and how does it work?
This is a chimeric mAb that binds to CD25 on the IL-2 receptor preventing Il-2 binding.
This is used in acute organ rejection prophylaxis mainly, nit also used in other solid organ transplants and against acute graft-versus-host disease.
How is Basiliximab formulated and what are some of its major adverse effects?
Basiliximab (Simulect) is formulated as an IV infusion.
It may cause allergic and hypersensitivity reaction, opportunistic infections, secondary malignancies, HTN, peripheral edema, hyperglycaemia, electrolyte changes.
What is Anakinra?
This is an IL-1 receptor antagonist used as a later treatment for gout and immunosuppression post organ transplant.
What is Ustekinumab?
This is a human mAb against IL-12 and IL-23 used in moderate to severe plaque psoriasis.
What is Certolizumab?
This is a PEGylated Fab- fragment against TNF used in the treatment of Crohn’s disease.
What is Mepolizumab?
This is an expensive last resort treatment for asthma and eosinophilic esophagitis (inflammation for the esophagus due to eosinophils).
This is a humanized anti-IL-5 mAb
What is Tocilizumab?
This is a humanized anti-Il-6 mAb used in the treatment of severe forms of Rheumatoid arthritis where conventional treatments have failed.
What is Secukinumab?
This is a human anti-il-17A mAb used to treat plaque psoriasis.
