Immunomodulation Flashcards
What is the definition of immunomodulation?
The act of manipulating the immune system using immunomodulatory drugs to achieve a desired immune response
What may the therapeutic effects of immunomodulation lead to?
Immunopotentiation, immunosuppression or induction of immunological tolerance
it is used to turn down a part of the immune system that is causing harm, or to potentiate part of the immune system
What is the definition of biologic immunomodulators?
Medicinal products produced using molecular biology techniques including recombinant DNA technology
these complex molecules are similar/the same as proteins in the body
What are the main classes of biologic immunomodulators?
- Substances that are (nearly) identical to the body’s own key signalling proteins
- monoclonal antibodies
- fusion proteins
What are the differences in these anti-TNF drugs?
The immune system is more likely to react if there is a foreign murine component to the molecule
Adalimumab is a fully human monoclonal antibody so is less likely to cause an immune response
Etanercept is a fusion protein
What is meant by a “chimeric molecule”?
A chimeric molecule has a component that is from an animal origin
What are the 3 methods of immunopotentiation?
- Immunisation (active or passive)
- Replacement therapies
- Immune stimulants
What is the definition of passive immunisation?
The transfer of specific, high-titre antibody from a donor to a recipient
this provides immediate but transient protection
What are the types of passive immunisation?
What are the problems associated with this mechanism?
Types:
- pooled specific human immunoglobulin
- animal sera (containing antitoxins and antivenins)
Problems:
- risk of virus transmission
- serum sickness - type III hypersensitivity reaction
What are the uses of passive immunisation?
- Hepatitis B prophylaxis and treatment
- Botulism
- VZV in pregnancy
- Diptheria
- Snake bites
What is the definition of an active immunisation?
To stimulate the development of a protective immune response and immunological memory
this generates long lasting immune responses that provide long term protection
What immunological material can be used in an active immunisation?
- Weakened forms of pathogens
- killed inactivated pathogens
- purified materials (proteins, DNA)
- adjuvants
adjuvants are added to direct immune responses in certain directions
What are the problems associated with active immunisation?
- Allergy to any vaccine component
- Limited usefulness in immunocompromised patients
- There is a delay in achieving protection
What 4 methods are used in replacement therapies/immune stimulation?
- Pooled human immunoglobulin (IV or SC)
- G-CSF / GM-CSF
- Alpha-interferon
- Y-interferon
When is pooled human immunoglobulin used as a replacement therapy?
In patients with a diagnosis of antibody deficiency states
immunoglobulins are taken out of the serum of the donor
When is G-CSF / GM-CSF used?
Neutropenia
it acts on the bone marrow to increase the production of mature neutrophils
When are a-interferon and y-interferon used?
Alpha interferon:
- used in treatment of Hep C
y-interferon:
- used in treatment of intracellular infections (atypical mycobacteria)
- used in chronic granulomatous disease
- used in IL-12 deficiency
What are the 5 types of immunosuppressants?
- Corticosteroids
- Cytotoxic agents
- Anti-proliferative/activation agents
- DMARDs
- Biological DMARDs
When to corticosteroids tend to be used in treatment?
They are used to reduce the inflammatory response quickly
they affect all functions of the immune system so it is hard to target the use of steroids
they limit unintended damage during acute infection
What are the 6 actions of corticosteroids?
- Decreased neutrophil margination
- reduced production of inflammatory cytokines
- inhibition of phospholipase A2 - reduced arachidonic acid metabolites production
- lymphopenia
- decreased T cell proliferation
- reduced immunoglobulin production
What are the 5 main side effects of corticosteroids?
- Carbohydrate and lipid metabolism problems leading to diabetes and hyperlipidaemia
- reduced protein synthesis leading to poor wound healing
- osteoporosis
- glaucoma and cataracts
- psychiatric complications
In which conditions do corticosteroids tend to be used?
Autoimmune diseases:
- CTD
- vasculitis
- rheumatoid arthritis
inflammatory diseases:
- Crohn’s disease
- sarcoid
- GCA/polymyalgia rheumatica
malignancies:
- lymphoma
allograft rejection
Why are corticosteroids not used for long term therapy?
They are used to achieve a quick and profound immune response
other agents are used to maintain the immunosuppression after the corticosteroids have been administered
this is due to the side effects
Why are costimulatory molecules important in the immune response?
Which cytokine is secreted by T cells allowing for more activation?
Costimulatory molecules allow T cells to be fully stimulated
IL12 is secreted by T cells, which allows T cells to continue with the program of activation
What are the T cell costimulatory molecules?
Which drugs can be used at each stage?
What are the 4 categories of drugs used to target lymphocytes?
Antimetabolites:
- azathioprine (AZA)
- mycophenolate mofetil (MMF)
calcineurin inhibitors:
- cyclosporin a (CyA)
- tacrolimus
M-TOR inhibitors:
- sirolimus
IL-2 receptors mABs:
- basiliximab
- daclizumab
What is the difference in the way ciclosporin a and tacrolimus work?
CyA binds to intracellular protein cyclophilin
tacrolimus binds to intracellular protein FKBP-12
What is the mode of action of calcineurin inhibitors?
- They prevent activation of NFAT
- these are factors which stimulate cytokines (IL-2 and INFy)
- this prevents T cell activation
What are the T cell effects of calcineurin inhibitors?
There is reversible inhibition of T-cell activation, proliferation and clonal expansion
As the T cells are not killed, if the drugs are removed the immune system can be reactivated
What type of antibiotic is sirolimus (rapamycin)?
Macrolide antibiotic
it also binds to FKBP12 but has different effects
it inhibits the mammalian target of rapamycin (mTOR)
How does sirolimus work?
It inhibits the response to IL-2
this means that T cells are only partially activated and arrest at G1-S phase
they cannot achieve any further division and proliferation
What are the side effects associated with calcineurin/mTOR drugs?
- Hypertension
- hirsutism
- nephrotoxicity
- hepatotoxicity
- lymphomas
- opportunistic infections
- neurotoxicity
- multiple drug interactions - they induce P450
What can make someone more likely to suffer the side effects of calcineurin/mTOR drugs?
You are more likely to experience the side effects if the drugs are used for long term phases
modulate the amount of immunosuppression to try and reduce the risk of side effects
What are the clinical uses of calcineurin inhibitors/mTOR drugs?
- Transplantation - allograft rejection
- Autoimmune diseases
How do antimetabolites work?
They inhibit nucleotide (purine) synthesis
by preventing nucleotide incorporation within DNA, T cells cannot multiply as they are unable to replicate their DNA
What are the 2 types of antimetabolites drugs and how do they work?
Azathioprine:
- this is a guanine anti-metabolite
- it is rapidly converted into 6-mercaptopurine
mycophenolate mofetil (MMF):
- this prevents production of guanosine triphosphate
What are the effects of antimetabolites on T and B cells?
Impaired DNA production prevents the early stages of activated cells proliferation
they work better in autoreactive T and B cells as these drugs target rapidly dividing cells
What are 2 other antimetabolites and cytotoxic drugs and how do they work?
Methotrexate:
- this is a folate antagonist
- folate is needed for DNA synthesis
cyclophosphamide:
- this will cross-link DNA
- it is used in the treatment of autoimmune diseases and cancer as it targets rapidly dividing cells
What are the side effects of cytotoxic drugs?
All cytotoxic drugs:
- bone marrow suppression
- gastric upset
- hepatitis
- susceptibility to infections
cyclophosphamide:
- cystitis
methotrexate:
- pneumonitis
Why is the bone marrow suppressed in cytotoxic drug use?
What can this lead to?
The drugs target rapidly dividing tissues in the body with a high turnover of cells
this can lead to neutropenia, thrombocytopenia and anaemia
What are the clinical uses of cytotoxic drugs?
Azathioprine / MMF:
- autoimmune diseases - SLE, vasculitis, IBD
- allograft rejection
methotrexate:
- rheumatoid arthritis, PsA, polymyositis, vasculitis
cyclophosphamide:
- vasculitis (Wagner’s, CSS)
- SLE
what are the different categories of biologics?
- Anticytokines - TNF, IL-6 and IL-1
- Anti-B cell therapies
- Anti-T cell activation
- Anti-adhesion molecules
- Complement inhibitors
- Check point inhibitors
What are the benefits of using biologics?
They have much wider immunosuppression effects
You can pinpoint which part of the immune system needs to be targeted
Why are steroids not used in long term treatment of rheumatoid arthritis?
Steroids are effective for a period of time, but become less effective over time
they work to downregulate most of the pathways involved in RA
In which conditions is anti-TNF used?
What risk is associated with this?
They are used in rheumatoid arthritis and other inflammatory conditions
Crohn’s, psoriasis, ankylosis spondylitis
they increase the risk of TB
How does anti IL-6 (tocilizumab) work?
What conditions is it used in and what risks are associated?
It blocks the IL-6 receptor
it is used in therapy of rheumatoid arthritis and AOSD
it may cause problems with control of serum lipids
In which conditions is anti IL-1 used?
Used in treatment of AOSD and autoinflammatory syndromes
How does Rituximab work?
What conditions is it used in?
It is a chimeric monoclonal antibody against CD20 on B cell surface
it is used to treat:
- Lymphomas and leukaemias
- Transplant rejection
- Autoimmune disorders
How does Rituximab work?
It binds to the surface of B cells with CD20, but leaves the others intact
all the cells in the periphery will be expressing CD20
it wipes out the population of B cells
it does not affect the pre and pro B cells in the bone marrow
the B cells are then repopulated with a non-aggressive B cell population
What is meant by adoptive immunotherapy?
- Bone marrow transplant (BMT)
- stem cell transplant (SCT)
What are the uses of adoptive immunotherapy?
- Immunodeficiencies - SCID
- Lymphomas and leukaemias
- Inherited metabolic disorders (osteopetrosis)
- Autoimmune diseases
How do checkpoint inhibitors work?
Through interfering with the CD80/86 reaction
antigen presentation without costimulation means that most T cells become anergic
What therapies are shown here and how do they work?
Artificial CTLA antibodies cause T cells to start expressing PD1
after interacting with surrounding tissue, these T cells are deactivated
adding CTLA 4 antibody pushes all the T cells into activation
using anti-PDL1 takes the brakes off the immune system, leading to effective tumour recognition and killing
What are the 4 ways in which immunomodulators can be used in allergy?
- Immune suppressants
- Allergen specific immunotherapy
- Anti-IgE monoclonal therapy
- Anti IL-5 monoclonal treatment
What are the indications for allergen specific immunotherapy?
- Allergic rhinoconjunctivitis not controlled on maximum medical therapy
- Anaphylaxis to insect venoms
it involves the induction of tolerance through treatment with the allergen
By which mechanisms does allergen specific immunotherapy work for?
It switches the immune response from Th2 (allergic) to Th1 (non-allergic)
it leads to the development of T reg cells and tolerance
these will dampen down the immune response
Which routes can allergen specific immunotherapy be administered by?
Subcutaneous or sublingual for aeroallergens
What are the side effects of allergen specific immunotherapy?
Localised and systemic allergic reactions
What type of drug is Omalizumab?
When is it used and what are the risks?
- It is a monoclonal antibody against IgE
- it is used in asthma, chronic urticaria and angioedema
- it may cause severe systemic anaphylaxis
What type of drug is Mepolizumab?
When is it used and what are the risks?
- It is a monoclonal antibody against IL-5
- it prevents eosinophils recruitment and activation
- it is used in treatment of asthma
- it has no clinical efficacy in hypereosinophilic syndrome
