Immunotherapy Flashcards
(37 cards)
What are the two immunomodulators called?
Immunosuppressants
Immunostimulants
What are the three biologics?
Antibodies
Cytokines
Cell Therapy
What are the differences between small molecules and biologics?
Small molecules
small size, stable, simple, non-specific, oral, high permeability, enzymes, oxidases(hepatic), hydrolases, conjugating enzymes, easily distrubuted in circulation and there is NO immunogenicity
Biologics
Large molecules, unstable, complex, specific, parenteral, invasive roye, low permeability, enzymes inc nucleases, peptidases, proteinases and hydrolases, limited distribution via circulation and lymphatics. there is immunogenicity
What are cytokines?
Cytokines are a family of small proteins used for communication in the immune system.
They play diverse roles in the regulation of an immune response: type, magnitude, location.
What are cytokines?
Cytokines are a family of small proteins used for communication in the immune system.
They play diverse roles in the regulation of an immune response: type, magnitude, location.
What do cytokines do?
Cytokines may drive inflammation, or dampen inflammation.
Cytokines are also important for the development or differentiation of immune cells.
Depending on the situation, we may wish to block or enhance a cytokine response.
(Note that classification of cytokines as pro- or anti-inflammatory will vary depending on the disease. Example shown is for rheumatoid arthritis.)
How are recombinant cytokines produced?
Uses recombinant DNA technology
Joining together of DNA from different sources.
Allows genes from one organism to be transferred to another for propagation or expression (protein product).
The human gene for the cytokine of interest is inserted into a vector (a DNA molecule used to carry the gene of interest into a cell and drive its expression. e.g. plasmid)
The vector + gene is introduced into a cell (e.g. E. coli) which produces the protein product.
What is the structure of antibodies like?
Composed of two heavy and two light chains.
Each chain has two regions: variable (one Ig domain) and constant (3-4 Ig domains).
Fc region: binds to cell surface receptors and complement proteins to mediate antibody functions.
Complementarity-determining regions (CDRs) are short, hyper-variable sequences of amino acids in the variable region of the antibody. They bind to antigen and determine antigen specificity.
What alters antibody functions?
Viruses, toxins, host proteins
Depend on Fc region: species mismatch will decrease function
ie blocking neutralisation, complement activation, ADCC, Opsonisation and phagocytosis
What is passive immunization?
Passive immunity is provided when a person is given antibodies to a disease rather than producing them through his or her own immune system
What is cell therapy?
Giving a patient new cells to:
Replace damaged cells
Change the function of existing cells
Kill tumour cells
Stem cells and/or immune cells most commonly used.
Allogeneic or Autologous
What is allogenic?
Taken from different individuals of the same species
What is autologous?
An autologous stem cell transplant uses healthy blood stem cells from your own body to replace your diseased or damaged bone marrow.
What are the advantages and disadvantages of autologous cell therapies?
ADV
Recognised as ‘self’ by the immune system - no rejection risk
No graft -vs- host disease
Can give multiple doses
DISADV
Expensive
delay in treatment
starting material may not have necessary characteristics
What are the adv and disadv of allogeneic cell therapies?
adv
can be manufactured at scale and banked
available immediatly
reproducibility - donors screened for desirable characteristics
disadv
immunogenic - risk of rejection
graft vs host disease
What are small molecule immune suppressants used for?
Broad inhibition of the immune response (non-specific)
Given prophylactically to prevent organ transplant rejection, or for the treatment of autoimmune disease.
(includes short peptides)
What is Azathioprine and what does it do?
Azathioprine is a prodrug.
It inhibits purine synthesis, purine are required to produce DNA and RNA by inhibiting by purine synthesis less DNA and RNA are produced for the sys thesis of WBC therefore immunosuppression
It is converted to the active metabolites 6-mercaptopurine (6-MP) and thioguanine (6-TGN).
Metabolites of azathioprine inhibit purine synthesis and halt DNA replication via incorporation into newly synthesised DNA (Remember! T and B cells are actively replicating cells)
6-thioguanine triphosphate inhibits activation of rac1 in T cells (downstream of CD28), inducing apoptosis.
Severe acute Crohn’s disease, severe SLE, non-responding rheumatoid arthritis, severe refractory eczema, suppression of transplant rejection, myasthenia gravis
Increases risk of cancer and infection, bone marrow depression (esp. in those with a genetic deficiency in thiopurine S-methyltransferase.), vomiting, pancreatitis, thrombocytopaenia.
Thiopurine S-methyltransferase methylates 6-mercaptopurine to methylmercaptopurine (inactive).
What is cyclosporine? and what does it do?
Cyclosporine is a calcineurin inhibitor, a cyp450, cyp3a4, p gycoprotein inhibitor. Inhibits synthesis of interleukins which are essential for the proliferation of T cells
Cyclic peptide of 11 amino acids.
Produced from a fungus, Tolypocladium inflatum
A calcineurin inhibitor.
Calcineurin would normally be activated by signalling through the T cell receptor, increasing production of the cytokine, IL-2.
IL-2 drives T cell differentiation.
Cyclosporine forms a complex with a cytosolic protein (cyclophilin) in lymphocytes.
The complex inhibits calcineurin, reducing synthesis of IL-2.
Severe acute ulcerative colitis, severe active rheumatoid arthritis, severe atopic dermatitis (short-term), severe psoriasis, organ transplantation, bone-marrow transplantation.
Decreases resistance to infection (live attenuated vaccines not advised).
Nausea, tiredness, hair growth, tremor, high blood pressure, kidney dysfunction.
May increase long term risk of cancer.
What is methotrexate and what does it do?
Inhibits dihydrofolate reductase (important for synthesis of purines and pyrimidines) when used as a chemotherapeutic agent.
Also used as an immunosuppressant in severe Crohn’s disease, moderate to severe active rheumatoid arthritis.
Broader mechanism of action in RA than in cancer.
Once a week dosing.
Cautions: bone marrow suppression (fall in WBC and platelet counts), GI, Liver and pulmonary toxicity
How does methotrexate work in rheumatoid arthirits?
Folate antagonism - blocks folate - folate causes proliferation of inflammatory cells - Folate metabolism is required for DNA synthesis
Adenosine Accumulation - Adenosine has anti-inflammatory effects on immune cells
Inflammatory signalling pathway - Downstream signalling of e.g. cytokine receptors
regulating - RANKL/RANK/OPG can cause bone erosion
Immune system - regulate CD4+T Alters ratio of Th17 to Treg cells
What is fingolimod? what does it do?
A sphingosine 1-phosphate receptor modulator used in Multiple Sclerosis.
Prevents egress of T cells from lymph nodes (reduces recirculation of autoreactive T cells to the CNS).
Increases proportion of Treg cells.
Can cause persistent bradycardia therefore not recommend in patients with pre-existing cardiac disorders.
Increased risk of skin cancers and lymphoma, congenital malformations, liver injury and herpes meningoencephalitis
Other examples
cladribine
sulfasalazine
tacrolimus
leflunomide
hydroxychloroquine
mycophenolate mofetil
sirolimus (rapamycin)
What are corticosteroids?
Steroid hormones produced in the adrenal cortex.
E.g. cortisol (glucocorticoid) and aldosterone (a mineralocorticoid).
Synthetic versions can be used to modify the immune response (anti-inflammatory at low doses, immunosuppressive at higher doses).
Dexamethasone
Prednisolone
Reduce migration on immune cells to sites of inflammation, inhibit NFkB (pro-inflammatory transcription factor), drive production of IL-10.
Commonly used to control acute inflammation.
Examples of immunosuppressant antibodies?
Muromonab
CD3
Kills T cells (e.g. ADCC)
acute transplant rejection
Basiliximab
CD25
Antagonist – stops IL-2 binding to its receptor and inhibits T cell activation
prophylaxis for kidney transplant rejection
Alemtuzumab
CD52
Depletes T and B cells (ADCC)
MS, B cell chronic lymphocytic leukaemia
