Immu 4: Immuno Modulating Therapies 2 Flashcards
How do Corticosteroids inhibit Prostaglandins and hence have an anti-inflammatory effect ?
Corticosteroids INHIBIT Phospholipase A2
(Normaly)
Phospholipase A2 converts phospholipids into Arachidonic acid
Arachidonic acid is converted to Prostaglandins or leukotrienes by COX enzymes.
Prostaglandins cause Inflammation
So less phospholipase A2 = less Arachidonic acid = less Prostaglandins or leukotrienes = less inflammation
Give 2 examples of Eicosanoids ?
Prostaglandins
Leukotrienes
Side effects of corticosteroids
- Diabetes
- central obesity
- moon face
- lipid abnormalities
- osteoporosis
- hirsutism
- adrenal suppression
- Cataracts
- glaucoma
- peptic ulceration
- pancreatitis
- avascular necrosis of hip and knee
Give 3 examples of immune modulating functions of corticosteroids ?
- Phospholipase A2: Inhibit Prostaglandin synthesis
- Phagocytes: Inhibit Phagocyte entry into inflamed tissues, decreased phagocytosis, Phagocytes also release LESS proteolytic enzymes
- Lymphocytes: Causes lymphopenia (Lymphocytes sequester in lymphoid tissues), Cytokine gene expression is BLOCKED by corticosteroids, promote apoptosis of lymphocytes
Give 3 examples of Anti-proliferative agents (stop cells proliferating by blocking DNA synthesis)?
- Cyclophosphamide
- Mycophenolate
- Azathioprine
- Methotrexate
What is the mechanism by which cyclophosphamide inhibits lymphocyte proliferation?
Which lymphocyte does this affect more?
- alkylates guanine bases on DNA - damages DNA
- Prevents cell replication particularly in rapidly dividing cells (cancer, lymphocytes)
- Affects B > T cells
Give 3 examples of diseases in which Cyclophosphamide is indicated ?
- SLE
- GPA (granulomatosis with polyangitis) (wegner’s granulomatosis)
- Cancers- Hodgkin’s lymphoma
Suggest 4 side effects of cyclophosphamide ?
What do these side effects mean for how the drug is used?
Toxic to proliferating cells
- Hair loss
- Sterility
- Bone marrow suppression
Haemorrhagic cystitis - toxic to the bladder since toxic metabolite is excreted in the urine
Malignancy
- bladder cancer
- haem malignancies
- non-melanoma skin cancer
Infection eg P. jirovecii
Given the side effects, this is why you would not use cyclophosphamide for long periods of time - Often started and induce remission with it. Then put onto azathioprine or mycophenolate
Describe the mechanism by which azathioprine inhibits DNA replication ?
Which lymphocyte does this target more?
- Metabolised to 6-mercaptopurine which is a purine analogue, thus interferes with DNA production and inhibits proliferating cells
- prevents DNA replication
- preferentially inhibits T cell activation and proliferation
Affects T > B cells
Give 3 indications for azathioprine ?
Transplantation
auto-immune diseases
Crohn’s and UC
Which genetic polymorphism contraindicates the use of azathioprine because of risk of bone marrow suppression ?
- Thiopurine methyl transferase (TPMT)
- check for TPMT activity or gene variants before treatment is started
Side effects of azathioprine (3)
- bone marrow suppression
- hepatotoxicity
- infection
What is an alternative to azathioprine used in transplantation ?
Mycophenolate Mofetil
mechanisms of mycophenolate mofetil
Which lymphocyte does this affect more?
- blocks de novo nucleotide synthesis
- prevents replication of DNA
prevents B > T cell proliferation
Which particular virus are pts on Mycophenolate mofetil more at risk of? (2)
- herpes virus reactivation
- JC virus (this can then cause Progressive multifocal leukoencephalopathy)
indications for mycophenolate mofetil use (2)
transplantation
AI diseases and vasculitis
Which virus can cause Multifocal leukoencephalopathy infection in the immunocompromised patient ?
JC virus
How does plasmapheresis work ?
Patients blood is separated and the plasma is treated to remove immunoglobulins and is then re-infused
When is Plasmaphoresis indicated ?
In Severe antibody-mediated disease where the known pathogenic antibodies can be removed
- Severe transplant rejection (antibodies against donor HLA)
- Severe acute myasthenia gravis (anti-AChR antibodies)
- Goodpasture’s syndrome (anti-glomerular basement membrane antibodies)
Downside of plasmaphoresis
- The problem with taking the antibody out is that there are still B and T cells, so they will still go on to produce the antibody. Rebound antibody production limits the efficacy
- Therefore, it is usually given with an anti-proliferative agent
What is the role of IL2 in the T cell response ?
IL2 causes T cell proliferation
How does ciclosporin or tacrolimus inhibit T cell proliferation ?
- Cyclosporin is a calcineurin inhibitor.
- It blocks IL2 production
- Thereby inhibiting T cell proliferation
Downside of tacrolimus or ciclosporin
they are nephrotoxic and induce hypertension (issue in kidney transplants)
How do Anti-thymocyte globulins cause T cell depletion ?
Downside to them
- Thymocytes (lymphocytes from human thymus) are injected into rabbits
- Rabbits produced antibodies to the thymocytes
- The antibodies are retrieved and injected into humans to cause a non-specific immune response against T cells
Downside: very non-specific
Which cells are affected by Rituximab ?
B cells (depletes mature B cells - NB plasma cells will be retained and so can produce antibodies)
Rituximab targets CD20 a B cell marker
Which disease is characterised by a IL6 producing tumour
What drug can therefore be used for this?
Castleman’s disease
Tocilizumab, Sarlimumab (blocks IL-6 receptor)
List 4 diseases in which anti-TNF alpha antibodies (infliximab) is indicated ?
- Rheumatoid arthritis
- Ankylosing spondylitis
- Psoriasis/psoriatic arthritis
- IBD
Explain what effect RANK L binding to RANK receptors has on bone ?
- RANKL produced by Osteoblasts binds to RANK receptor on osteoclast precursors causing them to differentiate into Osteoclasts.
- This causes increased bone resorption
What is Osteoprotegrin (OPG) and what role does it have in controlling bone resorption ?
- OPG is secreted by Osteoblasts and is a decoy receptor for RANKL to reduce activation and differentiation of Osteoclasts.
- Hence inhibiting bone resorption
- Regulator for RANKL pathway
What is the mechanism by which Denosumab works in Osteoporosis treatment ?
- Monoclonal antibody to RANKL so that it cant bind to RANK receptor on osteoclast precursors.
- This reduces Osteoclast resorption of bone
What is a complication of osteoporosis treatment with denosumab ?
Avascular necrosis of the jaw
Name a drug that prevents DNA replication especially of T cells
When is this drug used?
Mycofenylate mofetil
Used as alternative to azothioprine in transplantation suppression
Which immuno modulating drug causes a transient increase in neutrophil count ?
Prednisolone
Which immuno modulating drug can cause gingival hypertrophy as a side effect?
Ciclopsporin
List 3 side effects of methotrexate ?
Pneumonitis
pulmonary fibrosis
cirrhosis
A patient with signs of severe myasthenia gravis requires ventilation. Which one of the following would be the most suitable treatment ?
A) Corticosteroids
B) Ciclosporin
C) Tacrolimus
D) Plasmapheresis
D) Plasmapherisis
can remove the Ach receptor antibodies in the blood so is useful initially. Later needs acetylcholinesterase inhibitors.
Name a monoclonal antibody drug that targets IL-2 to prevent T cell proliferation. This drug is used prophylactically in allograft transplant.
Basiliximab
Targets CD25 on the alpha chain of IL-2 which stops T-cell proliferation if they are presented with donor HLA.
Name a drug that is a CTLA4- IgG fusion protein and is used in the treatment of rheumatoid arthritis resistant to DMARDs ?
What condition can this be used for?
Abatacept
- A fusion protein between CTLA4 and Immunoglobulin IgG.
- Binds to CD80 and CD86, which prevents CTLA4 or CD28 on T cells from binding to CD80 and CD86
- Binds to APCs to prevent them from stimulating and activating T cells.
Can be used for rheumatoid arthritis
Name 2 drugs used to treat malignant melanoma ?
Ipilimumab (Antibody specific for CTLA4)
Pembrolizumab (Antibodies specific for PD-1)
Which drug works by inhibiting phospholipase A2 ?
Prednisolone
Which mutation if present can cause severe neutropenia with azathioprine treatment ?
TPMT
(can’t metabolise azathioprine)
Which 2 drugs, other than steroids, can be used in transplant rejection?
- OKT3 Muromonab (CD3 inhibitor mouse monoclonal antibody)
- ATG (anti thymocyte globulin)
(can also do plasmapheresis if antibody mediated rejection or IVIG - NB the above is for cellular rejection)
List 2 drugs that can be given before transplant (induction)
3 drugs for baseline suppression
- Basiliximab (anti-CD25)
- Alemtuzumab (anti CD52)
- Calcineurin inhibitor (tacrolimus, ciclosporin)
- PLUS mycophenolate mofetil OR azathioprine
- PLUS steroids (prednisolone)
What is Ustekinumab used for ?
Psoriasis and Crohn’s
-Targets IL12 and IL23
what are the effects of steroids on phagocytes (4)
- decreased traffic of phagocytes into inflamed tissue
- reduce the expression of adhesion molecules on the endothelium –> transient increase in neutrophil count
- decreased phagocytosis
- decreased release of proteolytic enzymes
what are the effects of steroids on lymphocyte function (4)
- lymphopaenia - sequestration of lymphocytes into lymphoid tissue
- blocks cytokine gene expression
- decreased antibody production
- promotes apoptosis
what is the role of calcineurin inhibitors
- eg ciclosporin and tacrolimus
- prevent T cell signalling
- IL2 acts on T cells and prevents T cell activation and proliferation
- side effects = nephrotoxicity, hypertension, neurotoxicity, diabetogenic, dysmorphic features
What is an example of JAK inhibitor?
what is the role of JAK inhibitors?
2 conditions they can be used in?
Example: Tofacitinib
- interferes with JAK-STAT signalling
- inhibits the production of inflammatory molecules in response to cytokines
- Condition: rheumatoid arthritis, psoriatic arhtritis
What is an example of PDE4 inhibitor?
what is the role of PDE4 inhibitors
Apremilast
- PDE4 important for the metabolism of cAMP
- So apremilast leads to increase in cAMP
- cAMP activates Protein Kinase A pathway which prevents activation of transcription factors
- leads to decrease in cytokine production
- used in psoriasis and psoriatic arthritis
what is the role of basiliximab
- antibody directed against CD25
- prophylaxis of allograft rejection
- targets IL2 receptor
- inhibits T cell proliferation
What drug can you use before and after transplant surgery?
How does this help?
Basiliximab (anti CD-25)
BLOCKS the action of T cells, so T cells cannot proliferate well in response to antigen exposure - prophylaxis for allograft rejection
what is the role of abatacept
- receptor made form a fusion of CTLA4 + IgG Fc component
- binds CD80 and CD86 - reduced T cell activation
- used for rheumatoid arthritis
what is natalizumab
antibody against alpha 4 integrin
inhibits leukocyte migration
used in MS
what is tocilizumab / Sarlimumab
Conditions it can be used for (2)
- antibody against IL6 receptor
- reduced activation of macrophages, T cells, B cells and neutrophils
Castleman’s disease, rheumatoid arthritis
list agesnts that target cytokines (4)
- ustekinumab - antibody to p40 subunit of IL12 and IL23
- secukinumab - antibody to IL17A
- Guselkumab - Antibody against p19a subunit of IL-23
- denosumab - antbody against RANKL (osteoporosis)
which vaccines should not be given to immunosuppressed people (4)
polio
measles (MMR)
BCG
yellow fever
What drug can be used for prophylaxis for allograft rejection?
Basiliximab- anti-CD25
NB CD25 is a chain in the IL-2 recetor on T cells (this receptor very important for T cell clonal expansion)
4 examples of Anti-TNFalpha Antibodies
Infliximab, Adalimumab, Certolizumab, Golimumab
2 groups of drugs that target anti-TNFalpha
3 conditions these are effective against
- anti-TNFalpha antibodies: Infliximab, Adalimumab, Certolizumab, Golimumab
- TNFalpha antagonist: Etanercept
- Rheumatoid arthritis
- Ankylosing spondylitis
- Psoriasis and psoriatic arthritis
Which cytokine is pivotal in inflammation?
TNF-alpha (blocking it has very therapeutic effects in inflammatory conditions)
Tx options for psoriasis (6)
- anti-TNFalpha ABx: Infliximab, Adalimumab, Certolizumab, Golimumab
- TNFalpha antagonist: Etanercept
- IL-12 and IL-23 antibody: Ustekinumab
- Antibody to IL-17alpha: Secukinumab
- calcineurin inhibitor: ciclosporin
- PD4 blocker: Apremilast
2 groups of drugs to target T cell surface markers
- Rabbit anti-thymocyte globulin
- Basiliximab (anti-CD25)
1 group of drug to target B cells
Rituximab (anti-CD20)
1 drug for Lymphocyte migration
- Vedolizumab (anti-a4b7 integrin)
1 group of drug to block Monocytes, neutrophils, B cells and T cells
- Tocilizumab, Sarlimumab (anti IL-6 receptor)
Role of Vedolizumab
What does it target
Condition it can be used for
- Target cell migration of lymphocyes
- Antibody specific for a4b7 integrin - Vedolizumab inhibits T cell (and leukocytes in general) migration by inhibiting the action of a4b7
- Condition: IBD
What lymphocyte targetting drug can you take to treat IBD?
Which drug targeting cytokines can you take to treat Crohn’s specifically?
- Vedolizumab- Antibody specific for a4b7 integrin
- inhibits T cell (and leukocytes in general) migration by inhibiting the action of a4b7
- Ustekinumab- Antibody against the p40 subunit of IL-12 and IL-23
1 group of drug to target TNFalpha cytokine
Anti-TNFa Antibodies: Infliximab, Adalimumab, Certolizumab, Golimumab
1 drug to target TNFalpha receptor (TNF antagonist)
Etanercept
Drug to target IL-12 and IL-23 cytokines
Ustekinumab
Drug to target IL-23 cytokine
Guselkumab
Drug to target IL17 cytokine
Secukinumab
Which immunosuppressive drug in particular can increase R of TB infection?
TNFalpha antagonist (Etanercept) and anti-TNFalpha antibodies (Infliximab, Adalimumab, Certolizumab, Golimumab)
