immunosuppressants

Question 1

what is the main use-case for immunosuppressants?

Answer 1

organ transplant, to prevent rejection (type IV hypersensitivity reaction)

Question 2

A very large (~1200Da) T-cell selective immunosuppressant via calcineurin inhibition (calcineurin complex is needed for calmodulin signalling to activate NFATc via dephosphorylation –> expression of inflammatory cytokines)

Answer 2

ciclosporin: forms a complex cyclophilin, this complex inhibits calcineurin, meaning NFATc remains phosphorylated and inactive, inhibiting T cell activation and downstream T/B cell proliferation

Question 3

This is an mTOR inhibitor immunosuppressant. mTOR is an important mediator in downstream IL2 receptor signalling, promoting proliferation of activated lymphocytes

Answer 3

Sirolimus, binds to FKBP12 forming a complex which inhibits mTOR’s kinase activity, no activation of p70S6K, allows repressive activity of 4EBP-1 to continue, inhibiting proliferation and causing cell cycle arrest at G1 phase.

Question 4

These two immunosuppressants are often used as a potent combination

Answer 4

ciclosporin (calcineurin inhibitor) and sirolimus

Question 5

This is a cytotoxic immunosuppressant which is metabolised into 6-thioguanine, inhibiting nucleic acid synthesis

Answer 5

azathioprine, not really used much any more

Question 6

This is a newer cytotoxic immunosuppressant which is converted into mycophenolic acid, an inhibitor of de novo purine biosynthesis by inhibiting IMPDH

Answer 6

mycophenolate mofetil. Preferentially inhibits the inducible isoform of IMPDH, meaning it effectively targets highly proliferative cell lineages such as activated T/B lymphocytes

Question 7

This is a sphingosine-1-phosphate (S-1-P) receptor agonist used in the treatment of multiple sclerosis, an autoimmune disorder targeting neurons. Activation of the receptor leads to rapid downregulation –> internalisation. Receptor is necessary for T cell migration out of lymphoid organs

Answer 7

fingolimod. common side effect is first-dose bradycardia

Question 8

Side effect associated with first dose of polyclonal rabbit/horse antibodies against human thymocytes/lymphocytes respectively

Answer 8

first-dose cytokine storm

Question 9

This is a monoclonal antibody immunosuppressant

Answer 9

anti-IL2Ralpha, blocks IL-2 signalling, which is vital in clonal expansion