Immunosuppressants

Question 1

List TWO examples of immunosuppressant calcineurin inhibitors

Answer 1

Ciclosporin, tacrolimus

Question 2

List TWO examples of immunosuppressant cytotoxic antimetabolites

Answer 2

Azathioprine, mycophenolate

Question 3

Name an example of an immunosuppressant mTor inhibitor

Answer 3

Sirolimus

Question 4

Name an example of a polyclonal antibody used for immunosuppression

Answer 4

Rabbit anti-thymocyte globulin

Question 5

Name an example of a monoclonal antibody targetting the IL-2 receptor that suppresses T cell proliferation

Answer 5

Daclizumab

Question 6

Name an anti-cytokine signalling monoclonal antibody targetting IL-2 receptors

Answer 6

Daclizumab

Question 7

Name an immunosuppressant drug targetting S1P receptors

Answer 7

Fingolimod

Question 8

Describe the mechanism of action of fingolimod

Answer 8

> Phosphorylated to active metabolite fingolimod‐P
Structurally similar to sphingosine1‐phosphate (S1P)
Potent S1P receptor agonist
Functional antagonist (likely through desensitizing S1P receptors or disrupting S1P signalling gradients)
Reduces lymphocyte egress from lymph nodes
Disrupts cytokine-mediate lymphocyte homing
Reduces circulating lymphocytes

Question 9

What is the half-life of fingolimod?

Answer 9

Approximately 8 days

Question 10

What is the major adverse effect of fingolimod?

Answer 10

“First-dose” negative cardiac chronotropic effects due to S1P1 and S1P3 activation in sinoatrial cells

Question 11

Name an immunosuppressant drug derived from from Isaria sinclarii (cordyceps)

Answer 11

Fingolimod

Question 12

What is the primary indication for fingolimod?

Answer 12

Multiple sclerosis

Question 13

To which immunophilin does ciclosporin bind?

Answer 13

Cyclophilin

Question 14

To which immunophilin do tacrolimus and sirolimus bind?

Answer 14

FKBP12

Question 15

Explain the mechanism of action of sirolimus

Answer 15

> Binds the immunophilin FKBP12
Complex with FKBP12 inhibits mTor
Arrests cell cycle from G1 to S phase
Reduces cytokine‐mediated proliferation of T & B cells

Question 16

Which is more potent, ciclosporin or tacrolimus?

Answer 16

Tacrolimus is 10x to 100x more potent that ciclosporin

Question 17

Explain the mechanisms of action of ciclosporin and tacrolimus

Answer 17

> Ciclosporin and tacrolimus bind immunophilins (cyclophilin and FKBP12, respectively)
Complex with immunophilin inhibits calcineurin (activated by T cell receptors)
Prevents dephosphorylation and nuclear translocation of NFAT
Prevents nuclear transcription of cytokine genes (e.g., IL-2, TNFalpha and IFNgamma)
Inhibits T cell proliferation (also proliferation of B cells and cytotoxic T-lymphocytes)

Question 18

List FOUR major adverse effects of cytotoxic antimetabolite immunosuppresant drugs

Answer 18

bonemarrow depression: leukopenia, anaemia,

thrombocytopenia, bleeding, GI toxicity, lymphoma, neoplasia

Question 19

List at least THREE targets of rabbit anti‐thymocyte globulin polyclonal antibody used as an immunosuppressant drug

Answer 19

Non‐selective purified IgG targeting T and B lymphocytes, NK cells, and MHC class I and II antigens, co‐stimulator molecules

Question 20

List FOUR mechanisms of action of rabbit anti‐thymocyte globulin polyclonal antibody used as an immunosuppressant drug

Answer 20

Mechanisms of action:
• opsonization and complement‐dependent cytotoxicity
• antibody‐dependent cell‐mediated cytotoxicity
• depletion of T lymphocytes
• cross‐link TCR leading to T cell anergy induction

Question 21

List FOUR side effects of rabbit anti‐thymocyte globulin polyclonal antibody used as an immunosuppressant drug

Answer 21

Side effects:
• first dose effect: cytokine release syndrome (fever, chill, hypotension)
• thrombocytopenia/ leukopenia/serum sickness
• development of anti‐foreign IgG antibodies
• histiocytic lymphoma at site of injection