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
