Immuno: Immune modulating therapies Pt.3

Question 1

List some approaches to suppressing the immune system.

Answer 1

• Steroids
• Anti-proliferative agents
• Plasmapheresis
• Inhibitors of cell signalling
• Agents directed against cell surface antigens
• Agents directed at cytokines

Question 2

What is daily endogenous steroid secretion equivalent to in prednisolone?

Answer 2

Equivalent to 3-4 mg prednisolone

Question 3

What is the effect of steroids on prostaglandins?

Answer 3

Corticosteroids inhibit phospholipase A2

• Phospholipase A2 converts phospholipids into arachidonic acid which is subsequently converted into prostaglandins and leukotrienes by cyclo-oxygenases

Question 4

What is the effect of steroids on macrophages?

Answer 4

• Decreases macrocyte trafficking to site of inflammation
• Decreased endothelial adhesion molecule expression (results in transient neutrophilia)
• Decreases phagocytosis
• Decreases release of proteolytic enzymes

Question 5

What is the effect of steroids on lymphocytes?

Answer 5

• Lymphopenia
• Blocks cytokine gene expression
• Decreases antibody production
• Promotes apoptosis

Question 6

List some adverse-effects of corticosteroids.

Answer 6

• Metabolic: diabetes, central obesity, moon face, lipid abnormalities, osteoporosis, hirsuitism, adrenal suppression
• Other: cataracts, glaucoma, peptic ulceration, pancreatitis, avascular necrosis
• Immunosuppression: infection

Question 7

List some examples of anti-proliferative agents.

Answer 7

• Cyclophosphamide
• Mycophenolate
• Azathioprine
• Methotrexate

Question 8

What is the mechanism of action of cyclophosphamide?

Answer 8

Alkylates the guanine base of DNA which inhibits replication

Affects B cells more than T cells

Question 9

List some indications of cyclophosphamide.

Answer 9

• Multisystem connective tissue disease (e.g. lupus)
• Vasculitis
• Anti-cancer (NHL)

Question 10

List some adverse-effects of cyclophosphamide.

Answer 10

• Toxic to proliferating cells - bone marrow suppression, sterility (mainly males), hair loss
• Haemorrhagic cystitis - due to toxic metabolite (acrolein) in the urine
• Malignancy - bladder cancer, haematological malignancy, non-melanoma skin cancer
• Infection (e.g. PCP)

Most toxic antiproliferative

Question 11

Outline the mechanism of action of azathioprine.

Answer 11

• Metabolised by the liver to 6-mercaptopurine
• Blocks de novo purine synthesis by inhibiting HGPRT

Hypoxanthine-guanine phosphoribosyltransferase

Preferentially inhibits T cell activation and proliferation

Question 12

List some indications for azathioprine.

Answer 12

• Transplantation
• Autoimmune disease (e.g. RA)
• Autoinflammatory disease (e.g. Crohn’s)

Question 13

List some adverse-effects of azathioprine.

Answer 13

• Bone marrow suppression
• Hepatoxicity (indiosyncratic and uncommon)
• Infection (less so than cyclophosphamide)

Question 14

Which precaution must you take before starting a patient on azathioprine?

Answer 14

Check TPMT activity

• TPMT required for azathioprine inactivation and metabolism
• 1 in 300 individuals have TPMT polymorphism which means that they are unable to metabolise azathioprine leading to severe bone marrow suppression

TPMT - thiopurine methyltransferase

Question 15

What drug interacts dangerously with azathioprine?

Answer 15

Allopurinol - inhibits xanthine oxidase

Question 16

Outline the mechanism of action of mycophenolate mofetil.

Answer 16

Blocking de novo purine nucleotide synthesis by inhibiting IMPDH thus preventing DNA replication (thus inhibiting proliferation of T and B lymphocytes)

Inosine-5′-monophosphate dehydrogenase

Affects T cell proliferation more than B cells

Question 17

List the indication for mycophenolate mofetil.

Answer 17

Transplant immunosuppression

Question 18

List some adverse-effects of mycophenolate mofetil.

Answer 18

Bone marrow suppression

Infection

• Herpes virus reactivation
• Progressive multifocal leukoencephalopathy (JC virus)

Question 19

Describe how plasmapheresis works.

Answer 19

The patient’s blood is passed through a cell separator where the autoreactive immunoglobulins are removed and cells and plasma are reinfused

Question 20

What is the main issue with plasmapheresis?

Answer 20

Rebound antibody production - although antibodies have been removed, the plasma cells are still there

Therefore, anti-proliferative agents are often given alongside plasmapheresis