Immuno: Immune modulating therapies 2 Flashcards
1
Q
List some approaches to suppressing the immune system.
A
- Steroids
- Anti-proliferative agents
- Plasmapheresis
- Inhibitors of cell signalling
- Agents directed against cell surface antigens
- Agents directed at cytokines
2
Q
What is the difference between prednisolone and prednisone?
A
Prednisone is mainly used in the US - it is metabolised to prednisolone in the liver
3
Q
How much endogenous steroid does the body produce per day?
A
Equivalent to 5-7.5 mg of prednisolone
4
Q
Describe the effects of steroids on:
- Prostaglandins
- Phagocytes
- 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
- 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
5
Q
List some side-effects of corticosteroids.
A
- Central obesity
- Moon face
- Easy bruising
- Thin skin
- Osteoporosis
- Diabetes
- Cataracts
- Glaucoma
- Peptic ulceration
- Immunosuppression
6
Q
List some examples of anti-proliferative agents.
A
- Cycophosphamide
- Mycophenolate
- Azathioprine
- Methotrexate
7
Q
What is the mechanism of action of cyclophosphamide?
A
- Alkylates the guanine base of DNA which damages the DNA and prevents replication (affects B cells more than T cells)
8
Q
List some indications of cycolphosphamide.
A
- Multisystem connective tissue disease
- Vasculitis
- Anti-cancer
9
Q
List some side-effects of cyclophosphamide.
A
- 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)
10
Q
Outline the mechanism of action of azathioprine.
A
- 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
11
Q
List some indications for azathioprine.
A
- Transplantation
- Autoimmune
- Autoinflammatory (e.g. Crohn’s)
12
Q
List some side-effects of azathioprine.
A
- Bone marrow suppression
- Hepatoxicity
- Infection
13
Q
Which precaution must you take before starting a patient on azathioprine?
A
Check TPMT activity - 1 in 300 individuals have TPMT polymorphism which means that they are unable to metabolise azathioprine leading to bone marrow suppression.
14
Q
Outline the mechanism of action of mycophenolate mofetil.
A
- Blocking de novo nucleotide synthesis
- Prevents replication of DNA
- Affects T cell proliferation more than B cells
15
Q
List some indications for mycophenolate mofetil.
A
- Transplantation
- Autoimmune disease
- Vasculitis
16
Q
List some side-effects of mycophenolate mofetil.
A
- Bone marrow suppression
- Teratogenic
- Infection (particularly HSV reactivation and PML (JC virus))
17
Q
Describe how plasmapheresis works.
A
- The patient’s blood is passed through a separator where the pathogenic immunoglobulins are removed and the plasma is reinfused
18
Q
What is the main issue with plasmapheresis?
A
- Rebound antibody production - although antibodies have been removed, the plasma cells are still there
NOTE: therefore, anti-proliferative agents are often given alongside plasmapheresis
19
Q
List some indications for plasmapheresis.
A
- Severe antibody-mediated disease (e.g. Goodpasture’s, acute myasthenia gravis, severe transplant rejection)
20
Q
Describe the mechanism of action of calcineurin inhibitors.
A
- 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
21
Q
Give two examples of calcineurin inhibitors.
A
- Ciclosporin
- Tacrolimus
22
Q
What are the main side-effects of calcineurin inhibitors?
A
Hypertension and nephrotoxicty (also diabetes, neurotoxic and dysmporphic facies)
23
Q
Give an example of a JAK inhibitor.
A
Tofacitinib (JAK1 and JAK2 inhibitor)
24
Q
Describe the mechanism of action of JAK inhibitors.
A
- 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
25
Give an example of a PDE4 inhibitor.
Apremilast
26
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
27
For each of the following monoclonal antibodies, state the antigen that they are targeting:
1. Basiliximab
2. Abatacept
3. Rituximab
4. Natalizumab
5. Tocilizumab
1. Basiliximab = anti-CD25
2. Abatacept = CLTA4-Ig
3. Rituximab = anti-CD20
4. Natalizumab = anti-α4 integrin
5. Tocilizumab = anti-IL6 receptor
28
What does the suffix (-cept) mean?
It is made up of a receptor at the end of an IgG Fc portion
29
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
30
List some side-effects of anti-thymocyte globulin.
* Infusion reactions
* Leukopaenia
* Infection
* Malignancy
31
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
* Results in inhibition of T cell proliferation
32
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
* It is effective in rhumatoid arthritis
33
Describe the mechanism of action of rituximab.
* Targets CD20 which is found on mature B cells
* This results in depletion of mature B cells
34
List some indications for rituximab.
* Lymphoma
* Rheumatoid arthritis
* SLE
NOTE: it is given as two IV doses every 6-12 months
35
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
36
What is the main indication of natalizumab?
Multiple sclerosis
37
Describe the mechanism of action of tocilizumab.
* Antibody against IL6 receptor
* Results in reduced activation of macrophages, T cells, B cells and neutrophils
38
What are the main indications of tocilizumab?
* Castleman's disease (IL6-producing tumour)
* Rheumatoid arthritis
39
List three types of anti-TNFα antibodies.
* Infliximab
* Adalimumab
* Certolizumab
* Golimumab
40
Which antigens are targeted by the following monoclonal antibodies:
1. Ustekinumab
2. Secukinumab
3. Denosumab
1. Ustekinumab
* IL12
* IL23
2. Secukinumab
* IL17
3. Denosumab
* RANKL
41
What is TNF-alpha?
It is a critical molecule in the cytokine cascade responsible for the inflammatory response in inflammatory conditions
42
List some uses of anti-TNFα antibodies.
* Rheumatoid arthritis
* Ankylosing spondylitis
* Psoriasis
* IBD
43
List some side-effects of anti-TNFα antibodies.
* Infusion reactions
* Infection
* Lupus-like conditions
* Demyelination
* Malignancy
44
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
45
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
46
Describe the mechanism of action and uses of secukinumab.
* Antibody to IL17A thereby inhibiting its effect
* Indications include psoriasis and ankylosing spondylitis
47
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
48
List some side-effects of denosumab.
* Injection site reactions
* Infection
* Avascular necrosis of the jaw
49
List some types of infusion reaction.
* Urticaria
* Hypotension
* Tachycardia
* Wheeze
* Headache
* Fever
* Myalgia
