Immune modulating therapies 2 Flashcards
- List some approaches to suppressing the immune system.
Steroids Anti-proliferative agents Plasmapheresis Inhibitors of cell signalling Agents directed against cell surface antigens Agents directed at cytokines
- How much endogenous steroid does the body produce per day?
Equivalent to 5-7.5 mg of prednisolone
- Describe the effects of steroids on:
a. Prostaglandins
b. Phagocytes
c. Lymphocyte Function
a. Prostaglandins
Inhibits phospholipase A2
Phospholipase A2 is responsible for the conversion of phospholipids into arachidonic acid (which will then be converted to eicosanoids by COX)
Inhibiting phospholipase A2 leads to a reduction in arachidonic acid and prostaglandin formation and, hence, a reduction in inflammation
b. Phagocytes
Decrease traffic of phagocytes to inflamed tissue (reduces the expression of adhesion molecules on the endothelium)
This leads to a transient increase in neutrophil count
Decreased phagocytosis
Decreases proteolytic enzymes
c. Lymphocyte Function Lymphopaenia (sequestration in lymphoid tissue) Blocks cytokine gene expression Decreased antibody production Promotes apoptosis
- List some side-effects of corticosteroids.
Central obesity Moon face Easy bruising Thin skin Osteoporosis Diabetes Cataracts Glaucoma Peptic ulceration Immunosuppression
- List some examples of anti-proliferative agents.
Cyclophosphamide
Mycophenolate
Azathioprine
Methotrexate
- What is the mechanism of action of cyclophosphamide?
Alkylates the guanine base of DNA which damages the DNA and prevents replication (affects B cells more than T cells)
used in
Multisystem connective tissue disease
Vasculitis
Anti-cancer
- List some side-effects of cyclophosphamide.
Toxic to proliferating cells – bone marrow suppression, sterility (mainly males), hair loss
Haemorrhagic cystitis – due to toxic metabolic (acrolein) in the urine
Malignancy – bladder cancer, haematological malignancy, non-melanoma skin cancer
Teratogenic
Infection (e.g. PCP)
- Outline the mechanism of action of azathioprine.
Metabolised by the liver to 6-mercaptopurine
Blocks de novo purine synthesis (e.g. adenine and guanine)
Prevents DNA replication
Preferentially inhibits T cell activation and proliferation
- List some indications for azathioprine.
Transplantation
Autoimmune
Autoinflammatory (e.g. Crohn’s)
- List some side-effects of azathioprine.
Bone marrow suppression
Hepatoxicity
Infection
- Which precaution must you take before starting a patient on azathioprine?
Check TPMT activity – 1 in 300 individuals have a TPMT polymorphism which means that they are unable to metabolise azathioprine leading to bone marrow suppression
- Outline the mechanism of action of mycophenolate mofetil.
Blocks de novo nucleotide synthesis
Prevents replication of DNA
Affects T cell proliferation more than B cells
- List some indications for mycophenolate mofetil.
Transplantation
Autoimmune disease
Vasculitis
- List some side-effects of mycophenolate mofetil.
Bone marrow suppression
Teratogenic
Infection (particularly HSV reactivation and PML (JC virus))
- Describe how plasmapheresis works.
The patient’s blood is passed through a separator where the pathogenic immunoglobulins are removed and the plasma is reinfused
- What is the main issue with plasmapheresis?
Rebound antibody production – although antibodies have been removed, the plasma cells are still there
NOTE: therefore, anti-proliferative agents are often given alongside plasmapheresis
- List some indications for plasmapheresis.
Severe antibody-mediated disease (e.g. Goodpasture’s, acute myasthenia gravis, severe transplant rejection)
- Describe the mechanism of action of calcineurin inhibitors.
Normally, TCR engagement leads to increased cytoplasmic calcium which binds to calmodulin leading to the activation of calcineurin
Calcineurin then activates NFATc resulting in the upregulation of IL2
Calcineurin inhibitors block this pathway, thereby blocking IL2 production
- Give two examples of calcineurin inhibitors.
Ciclosporin
Tacrolimus
- What are the main side-effects of calcineurin inhibitors?
Hypertension and nephrotoxicity (also diabetes, nephrotoxic)
- Describe how mTOR inhibitors work and give and example
Inhibit proliferation of T cells e.g. rapamycin (used in transplantation)
- Describe the mechanism of action of JAK inhibitors.
Interferes with the JAK-STAT pathway which is important in transducing signals from cytokine binding
This influences gene transcription and reduces the production of inflammatory mediators
Effective in rheumatoid arthritis
- Describe the mechanism of action of PDE4 inhibitors.
PDE4 is important in the metabolism of cAMP
PDE4 inhibitors result in increased levels of cAMP which activates PKA and prevents the activation of transcription factors
This leads to a decrease in cytokine production
Effective in psoriasis and psoriatic arthritis
- Give an example of a PDE4 inhibitor.
Apremilast
- For each of the following monoclonal antibodies, state the antigen that they are targeting:
a. Basiliximab
b. Abatacept
c. Rituximab
d. Vendolizumab
e. Tocilizumab
a. Basiliximab Anti-CD25 b. Abatacept CTLA4-Ig c. Rituximab Anti-CD20 d. Vendolizumab Anti-alpha4b7 integrin e. Tocilizumab Anti-IL6 receptor
- Describe how anti-thymocyte globulin is made. What is it used for?
Human thymocytes (lymphocytes from the thymus gland) are sampled and injected into a rabbit which produces a variety of antibodies against thymocytes This is injected into patients and it is very effective at targeting T cells (but it is not very specific) This leads to T cell depletion and it is effective in allograft rejection
- List some side-effects of anti-thymocyte globulin.
Infusion reactions
Leukopaenia
Infection
Malignancy
- Describe the mechanism of action and the use of basiliximab.
Targets IL2 receptor alpha chain (aka CD25)
This part of the receptor is specific for IL2 receptors
Results in inhibition of T cell proliferation
- Describe the mechanism of action of abatacept.
It is made from the fusion of CTLA4 and IgG Fc
APCs bind to CTLA4 (inhibitory) and CD28 via CD80 and CD86 receptors
Abatacept binds to CD80 and CD86 receptors and prevents engagement with T cells thereby reducing T cell activation
It is effective in rheumatoid arthritis
- Describe the mechanism of action of rituximab.
Targets CD20 which is found on mature B cells
This results in depletion of mature B cells
- List some indications for rituximab.
Lymphoma
Rheumatoid arthritis
SLE
- Describe the mechanism of action of vendollizumab.
Antibody against alpha-4b7 integrin
Alpha-4 integrin is expressed with beta-1 or beta-7
This complex binds to MadCAM1 to mediate rolling and arrest of leukocytes
Blocking this integrin inhibits leukocyte migration
- What is the main indication of vendollizumab?
IBD
- Describe the mechanism of action of tocilizumab.
Antibody against IL6 receptor
Results in reduced activation of macrophages, T cells, B cells and neutrophils
- What are the main indications of tocilizumab?
Castleman’s disease (IL6-producing tumour)
Rheumatoid arthritis
- List three types of anti-TNFalpha antibodies.
Infliximab
Adalimumab
Certolizumab
Golimumab
- List some uses of anti-TNF alpha antibodies.
Rheumatoid arthritis
Ankylosing spondylitis
Psoriasis
IBD
- List some side-effects of anti-TNF alpha antibodies.
Infusion reactions Infection Lupus-like conditions Demyelination Malignancy
- Describe the mechanism of action of etanercept.
TNF alpha antagonist
It is a decoy receptor that mops up TNF alpha thereby inhibiting its action
- What is the mechanism of action of guselkumab and what is it used for?
Antibody that binds to the p19 alpha subunit of IL23. Used for psoriasis or psoriatic arthritis
- Which interleukins can be blocked in severe asthma or eczema?
Anti IL13/4 – asthma and eczema
Anti IL13 – eczema
Anti IL5 – eosinophilic asthma
- Describe the mechanism of action of denosumab.
RANKL is produced by osteoblasts and it acts on RANK receptors on osteoclasts
It promotes osteoclast differentiation and function, thereby leading to increased bone resorption
Denosumab binds to RANKL and reduces osteoclast differentiation and function
NOTE: it is used for osteoporosis and is administered as SC injections every 6 months
- List some side-effects of denosumab.
Injection site reactions
Infection
Avascular necrosis of the jaw
