Immuno: 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
What is the difference between prednisolone and prednisone?
Prednisone is mainly used in the US - it is metabolised to prednisolone in the liver
what is a steroid and what actions do they exert?
synthetic glucocorticoid, no mineralocorticoid activity
How much endogenous steroid does the body produce per day?
Equivalent to 3-4 mg of prednisolone
Describe the effects of steroids on:
- Prostaglandins
- Phagocytes
- Lymphocyte Function
- Prostaglandins
- Inhibits phospholipase A2
- Phospholipase A2 is responsible for the conversion of phospholipids into arachidonic acid (which will then be converted to eicosanoids- leukotrienes/prostaglandins by COX)
- Inhibiting phospholipase A2 leads to a reduction in arachidonic acid and prostaglandin formation and, hence, a reduction in inflammation
- 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
- 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
- Pancratitis
- Avascular necrosis
- Infection
- Immunosuppression
What should be given with steroids to prevent PCP?
co-trimoxazole >20mg
examples of antiproliferative immunosuppressants
cyclophosphamide
mycophenolate
azathioprine
complications of immunosuppressive antiproliferative drugs
- BM suppression
- infeciton
- malignancy
- teratogenic
inhibit DNA synthesis, affecting cells with rapid turmover
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)
List some indications of cycolphosphamide.
- 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
- Preferntially 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 TPMT polymorphism which means that they are unable to metabolise azathioprine leading to bone marrow suppression.
Outline the mechanism of action of mycophenolate mofetil.
- Blocking 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 nephrotoxicty (also diabetes, neurotoxic and dysmporphic facies)
Give an example of a JAK inhibitor.
Tofacitinib (JAK1 and JAK2 inhibitor)
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
Give an example of a PDE4 inhibitor.
Apremilast
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
For each of the following monoclonal antibodies, state the antigen that they are targeting:
- Basiliximab
- Abatacept
- Rituximab
- Natalizumab
- Tocilizumab
- Basiliximab = anti-CD25
- Abatacept = CLTA4-Ig
- Rituximab = anti-CD20
- Natalizumab = anti-α4 integrin
- Tocilizumab = anti-IL6 receptor
What does the suffix (-cept) mean?
It is made up of a receptor at the end of an IgG Fc portion
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 receptors alpha chain (aka CD25)
- This part of the receptor is specific for IL2-2Ra chain
- Results in inhibition of T cell proliferation
basiliximab uses
Prophylaxis of allograft rejection
IV given before + after transplant
basiliximab side effects
infusion related
infection
malignancy
Describe the mechanism of action of abatacept.
- It is made from the fusion of CTLA4 and IgG Fc
- APCs bind to CTLA4 (inhibitor) 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
- reduces co-stimulation with CD28
abatacept uses
rheumatoid arthritis
IV 4/weekly
SC weekly
abatacept toxicity CTLA4-Ig
infusion reactions
infection- TB, HBV, HCV
caution with malignancy
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
NOTE: it is given as two IV doses every 6-12 months
toxicity of rituximab
infusion reactions
infection PML
exacerbation CV disease
Describe the mechanism of action of natalizumab.
- Antibody against alpha-4 integrin
- Alpha-4 integrin is expressed with beta-1 or beta-7
- This complex binds to VCAM1 or MadCAM1 to mediate rolling and arrest of leukocytes
- Blocking this integrin inhibits leukocyte migration
What is the main indication of natalizumab?
Multiple sclerosis
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-TNFα antibodies.
- Infliximab
- Adalimumab
- Certolizumab
- Golimumab
Which antigens are targeted by the following monoclonal antibodies:
- Ustekinumab
- Secukinumab
- Denosumab
- Ustekinumab
- IL12
- IL23
- Secukinumab
- IL17
- Denosumab
- RANKL
What is TNF-alpha?
It is a critical molecule in the cytokine cascade responsible for the inflammatory response in inflammatory conditions
infliximab IV/ SC, adalimumab, certolizumab, golimumab
List some uses of anti-TNFα antibodies.
- Rheumatoid arthritis
- Ankylosing spondylitis
- Psoriasis
- IBD
- familial mediterranean fever
List some side-effects of anti-TNFα antibodies.
- Infusion reactions
- Infection TB, hbv, hcv
- Lupus-like conditions
- Demyelination
- Malignancy
can develop antibodies against these agents!
Describe the mechanism of action of etanercept.
- It is a decoy receptor that mops up TNFα thereby inhibiting its action
- NOTE: it is given as a SC injection
- Used in rheumatoid arthritis, psoriasis and ankylosing spondylitis
Describe the mechanism of action of ustekinumab.
- Antibody against the p40 subunit that is found in IL12 and IL23
- These cytokines mainly act on NK cells and T cells thereby modulating their activity
- Used in psoriasis and Crohn’s disease
Describe the mechanism of action and uses of secukinumab.
- Antibody to IL17A thereby inhibiting its effect
- Indications include psoriasis and ankylosing spondylitis
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
- Osteoprotegrin is a natural decoy receptor for RANKL which regulates the system
- Denosumab binds to RANKL and reduces osteoclast differentiation and function
NOTE: it is used for osetoporosis and is administered as SC injections every 6 months
List some side-effects of denosumab.
- Injection site reactions
- Infection
- Avascular necrosis of the jaw
List some types of infusion reaction.
- Urticaria
- Hypotension
- Tachycardia
- Wheeze
- Headache
- Fever
- Myalgia
