Immunopharmacology

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 immunosuppressant drug targetting S1P receptors

Answer 6

Fingolimod

Question 7

Explain the mechanisms of action of ciclosporin and tacrolimus

Answer 7

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

Question 8

Which is more potent, ciclosporin or tacrolimus?

Answer 8

Tacrolimus is 10x to 100x more potent that ciclosporin

Question 9

What are the clinical uses of Ciclosporin and tacrolimus?

Answer 9

kidney, pancreas, liver and cardiac transplants,rhumatoid arthritis, psoriasis (a rash with itchy, scaly patches, most commonly on the knees, elbows, trunk and scalp)

Question 10

Explain the mechanism of action of sirolimus

Answer 10

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

Question 11

To which immunophilin does ciclosporin bind?

Answer 11

Cyclophilin

Question 12

To which immunophilin do tacrolimus and sirolimus bind?

Answer 12

FKBP12

Question 13

Describe the mechanism of cytotoxic antimetabolites, Azathioprine

Answer 13

1. Azathioprine converted to 6-MP

2.impedes DNA synthesis and de novo purine synthesis which decrease proliferation of lymphocytes

Question 14

Describe the mechanism of cytotoxic antimetabolites, Mycophenolate

Answer 14

Inhibits De novo purine synthesis by inhibiting IMPDH

More selective anti-proliferative effects for T/B cells

Question 15

List FOUR major adverse effects of cytotoxic antimetabolite immunosuppresant drugs

Answer 15

1. bonemarrow depression: leukopenia, anaemia,
2. thrombocytopenia
3. GI toxicity
4. lymphoma
5. neoplasia
6. bleeding

Question 16

Describe the mechanism of action of fingolimod

Answer 16

1. Phosphorylated to active metabolite fingolimod‐P
2. Potent S1P receptor agonist
   BUT Functional antagonist
3. Reduces lymphocyte egress from lymph nodes; Disrupts cytokine-mediate lymphocyte homing & Reduces circulating lymphocytes

Derived from cordyceps

Question 17

What is the half-life of fingolimod?

Answer 17

Approximately 8 days

Question 18

What is the primary indication for fingolimod?

Answer 18

Multiple sclerosis

Question 19

What is the major adverse effect of fingolimod?

Answer 19

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

Question 20

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

Answer 20

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

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

Question 22

Describe the mechanism of action of monoclonal antibodies, daclizumab

Answer 22

targets the IL-2 receptor that suppresses T cell proliferation

Question 23

WHat is the clinical use ofdaclizumab?

Answer 23

Suppression of transplant rejection