Immuno 10: Immuno Modulating Therapies 2 Flashcards by Dev Gakhar

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

How well did you know this?

Not at all

Perfectly

Give 2 examples of Eicosanoids ?

Prostaglandins

Leukotrienes

How well did you know this?

Not at all

Perfectly

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)

How well did you know this?

Not at all

Perfectly

Give 3 examples of Anti-proliferative agents ?

Cyclophosphamide
Mycophenolate
Azathioprine
Methotrexate

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

Give 3 examples of diseases in which Cyclophosphamide is indicated ?

SLE
GPA (granulomatosis with polyangitis) (wegner’s granulomatosis)
Cancers- Hodgkin’s lymphoma

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

Give 3 indications for azathioprine ?

Transplantation
auto-immune diseases
Crohn’s and UC

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

What is an alternative to azathioprine used in transplantation ?

Mycophenolate Mofetil

How well did you know this?

Not at all

Perfectly

Which virus can cause Multifocal leukoencephalopathy infection in the immunocompromised patient ?

JC virus

How well did you know this?

Not at all

Perfectly

How does plasmapheresis work ?

Patients blood is separated and the plasma is treated to remove immunoglobulins and is then re-infused

How well did you know this?

Not at all

Perfectly

When is Plasmaphoresis indicated ?

Severe transplant rejection (antibodies against donor HLA)
Severe acute myasthenia gravis
Goodpasture’s syndrome

How well did you know this?

Not at all

Perfectly

What is the role of IL2 in the T cell response ?

IL2 causes T cell proliferation

How well did you know this?

Not at all

Perfectly

How does cyclosporin inhibit T cell proliferation?

Cyclosporin is a calcineurin inhibitor.
It blocks IL2 production
Thereby inhibiting T cell proliferation

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

Which cells are affected by Rituximab ?

B cells

Rituximab targets CD20 a B cell marker

How well did you know this?

Not at all

Perfectly

Name a drug that inhibits leukocyte binding to VCAM1 and is used to treat relapsing-remitting Multiple sclerosis ?

Natalizumab

How well did you know this?

Not at all

Perfectly

Which disease is characterised by a IL6 producing tumour

Castleman’s disease

How well did you know this?

Not at all

Perfectly

List 4 diseases in which anti-TNF alpha antibodies (infliximab) is indicated ?

Rheumatoid arthritis
Ankylosing spondylitis
Psoriasis/psoriatic arthritis
IBD

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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