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 prednisolone
synthetic glucocorticoid
What is the difference between prednisolone and prednisone?
Prednisone is mainly used in the US - it is metabolised to prednisolone in the liver
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 by COX)
- Inhibiting phospholipase A2 leads to a reduction in arachidonic acid and prostaglandin formation and, hence, a reduction in inflammation
- (same pathway as NSAIDS)
- Phagocytes - innate immunity
- 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 - adaptive imunity
- Lymphopaenia (sequestration in lymphoid tissue)
- Blocks cytokine gene expression
- Decreased antibody production
- Promotes apoptosis
effect of steroids on WBC
neutrophilia
leukoapenia
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.
- Cycophosphamide
- 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)
Most toxic - antiproliferative
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)
Fertility consideration with cyclophosphamide
sperm and egg freezing
Abx prophylaxis with cyclophosphamide, or long-term steroids
Co-trimoxazole
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
Toxic to proliferating cells
List some indications for azathioprine.
- Transplantation - prevent graft rejection
- 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.
Also check blood count after starting therapy
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 Progressive multifocal leukoencephalopthy caused by 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 - Type II hypersensitivity
(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, ABD, atopic eczema
Can be taken orally (unlike monclonal anitbodies)
But are less specific than monoclonal a tibodies –> more side effects
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
Don’t need to remember the names
what monoclonal antibody is safe to use in patients with history of malignancy
Rtiuximab - anti-CD20
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
- 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 (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
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
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
List some uses of anti-TNFα antibodies.
- Rheumatoid arthritis
- Ankylosing spondylitis
- Psoriasis
- IBD
List some side-effects of anti-TNFα antibodies.
- Infusion reactions
- Infection
- Lupus-like conditions
- Demyelination
- Malignancy
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 –> 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
(IgE-mediated- type 1 hypersensitivity) - Headache
- Fever
- Myalgia
**
What interleukins are relevant to atopy
IL4, 5, 13
Good antibody targets in management
What infections are screened prior to starting immunosuppressive treatment
TB - history, CXR, TB interferon gamma for previous exposure, latent TB needs treatment
Hep B, Hep C - Hep B core antibody, Hep C antibody –> further investigation for virus infectino if +ve
HIV - check serology
John Cunningham Virus (JCV) - common polyomavirus can reactive in brean –> infects + destroys oligodendrocytes –> Progressive multifocal leukomalacia
What malignancies are you potentially at increased risk of with immunosuppression
melanoma
EBV reactivation –> lymphoma
