Immuno 10: 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
Give 2 examples of Eicosanoids ?
Prostaglandins
Leukotrienes
Give 3 examples of immune modulating functions of corticosteroids ?
Inhibit Prostaglandin synthesis Inhibit Phagocyte entry into inflamed tissues Causes lymphopenia (Lymphocytes sequester in lymphoid tissues)
Give 3 examples of Anti-proliferative agents ?
Cyclophosphamide
Mycophenolate
Azathioprine
Methotrexate
What is the mechanism by which cyclophosphamide inhibits lymphocyte proliferation?
Cyclophosphamide alkylates guanine bases on 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 3 side effects of cyclophosphamide ?
Hair loss Sterility Haemorrhagic cystitis toxic metabolite is excreted in the urine bladder cancer haem malignancies non-melanoma skin cancer infection eg P. jirovecii
Describe the mechanism by which azathioprine inhibits DNA replication ?
Metabolised to 6-mercaptopurine which blocks synthesis of adenine and guanine
prevents DNA replication
preferentially inhibits T cell activation and proliferation
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
What is an alternative to azathioprine used in transplantation ?
Mycophenolate Mofetil
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 ?
Severe transplant rejection (antibodies against donor HLA)
Severe acute myasthenia gravis
Goodpasture’s syndrome
What is the role of IL2 in the T cell response ?
IL2 causes T cell proliferation
How does cyclosporin inhibit T cell proliferation?
Cyclosporin is a calcineurin inhibitor.
It blocks IL2 production
Thereby inhibiting T cell proliferation
How do Anti-thymocyte globulins cause T cell depletion ?
Thymocytes (lymphocytes from human thymus) were 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
Which cells are affected by Rituximab ?
B cells
Rituximab targets CD20 a B cell marker
Name a drug that inhibits leukocyte binding to VCAM1 and is used to treat relapsing-remitting Multiple sclerosis ?
Natalizumab
Which disease is characterised by a IL6 producing tumour
Castleman’s disease
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
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
Mycofenylate mofetil
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 ?
Abatacept
A fusion protein between CTLA4 and Immunoglobulin IgG.
Binds to APCs to prevent them from stimulating T cells.
Name 2 drugs used to treat malignant melanoma?
Ipilimumab
Pembrolizumab
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 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)
List 2 drugs that can be given before transplant
- Basiliximab
- Alemtuzumab (anti CD52)
What is Ustekinumab used for ?
Psoriasis
-Targets IL12 and IL23
List 4 drugs given as maintenance therapy post transplantation ?
- Cyclosporin
- Mycofenolate mofetil
- Azathioprene
- Prednisolone
what are the effects of steroids on phagocytes
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
lymphopaenia - sequestration of lymphocytes into lymphoid tissue
blocks cytokine gene expression
decreased antibody production
promotes apoptosis
mechanisms of mycophenolate mofetil
blocks de novo nucleotide synthesis
prevents replication of DNA
prevents B > T cell proliferation
indications for mycophenolate mofetil use
transplantation
AI diseases and vasculitis
side effects of mycophenolate mofetil
BM suppression
teratogenic
infection - HSV reactivation, progresisve multifocal leukoencephalotahy (JC virus)
what is plasmapheresis
patient blood passed through a separator
cellular contents reinfused
plasma treated to remove antibodies and reinfused
can get rebound antibody production
indications for plasmaphoresis
severe antibody-mediated disease eg:
goodpastires syndrome
severe acute myasthenia gravis
severe transplant rejection
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 the role of JAK inhibitors
eg tofacitinib (JAK1+ JAK 3 inhibitor) interferes with JAK-STAT signalling influences gene transcription inhibits the production of inflammatory molecules effective in rheumatoid arthritis
what is the role of PDE4 inhibitors
eg apremilast
PDE4 important for the metabolism of cAMP
leads to increase in cAMP
cAMP activates PKA which prevents activation of TF
leads to decrease in cytokine production
used in psoriasis and psoriatic arthritis
what is the role of anti-thymocyte globulin
thymocytes from humans injected into rabbits
take antibodies they make against the thymocytes
serum taken an injected into patient
causes T cell depletion
useful in allograft rejection
S/E - infusion reactions, leukopenia, infection, malignancy
what is the role of basiliximab
antibody directed against CD25
prophylaxis of allograft rejection
targets IL2 receptor
inhibits T cell proliferation
what is the role of abartacept
receptor made form a fusion of CTLA4 + IgG Fc component
binds CD80 and CD86 - reduced T cell activation
what is rituximab
anti-CD20 antibodies
expressed on mature B cells but not plasma cells
depletion of mature B cells
used in lymphoma, rheumatoid arthritis, SLE
2 IV doses every 6-12 months
what is natalizumab
antibody against alpha 4 integrin
inhibits leukocyte migration
used in MS
what is tocilizumab
antibody against IL6 receptor
reduced activation of macrophages, T cells, B cells and neutrophils
rheumatoid arthritis
which agents target TNF alpha
infliximab, adalimumab, certolizumab, golimumab
used in: rheumatid arthritis, ankylosing spondylitis, psoriasis, IBD
etanercpt - TNF alpha antagonist
list other agesnts that target cytokines
ustekinumab - antibody to p40 subunit of IL12 and IL23
secukinumab - antibody to IL17A
denosumab - antbody against RANKL (osteoporosis)
which vaccines should not be given to immunosuppressed people
polio
measles
BCG
yellow fever
