Immunopharmacology

Question 1

What are 6 types of immune suppressants?

Answer 1

1) Calcineurin inhibitors
2) mTOR inhibitors
3) Cytotoxic antimetabolites
4) S1P Receptor agonists
5) pAbs
6) mAbs

Question 2

What are 2 calcineurin inhibitors?

Answer 2

Ciclosporin
Tacrolimus

Question 3

What are the differences between ciclosporin and tacrolimus?

Answer 3

• Calcineurin binds to cyclophilin to inhibit calcineurin, Tacrolimus binds to FKBP12
• Tacrolimus is 10-100x>potent than Ciclosporin
• Both can be given Oral/IV Calcineurin can be given as ophthalmic solution, tacrolimus can be given topical
• Ciclosporin can cause gum hyperplasia

Question 4

How do calcineurin inhibitors like ciclosporin and tacrolimus lead to immune suppression?

Answer 4

By binding to other molecules and inhibiting calcineurin, they prevent the dephosphorylation (activation) and nuclear translocation of NFAT (transcription factor of activated T cells).
→ inhibit cytokine gene transcription (eg. IL-2/3/4/6, TNFα, IFNy)
→ inhibits primary T cell proliferation

Question 5

What are some clinical indications of calcineurin inhibitors?

Answer 5

1) Kidney, pancreas, liver, cardiac transplants
2) Uveitis
3) RA
4) Psoriasis

Question 6

What are some adverse effects of calcineurin inhibitors?

Answer 6

1) Hyperglycemia
2) Hyperlipidemia
3) Hypertension
4) Neurotoxicity
5) Nephrotoxicity
6) Gum hyperplasia (Ciclosporin only)

Question 7

Give an example of a mTOR inhibitor

Answer 7

Sirolimus (Rapamycin)

Question 8

How does an mTOR inhibitor like sirolimus lead to immune suppression?

Answer 8

It binds to FKBP12 and inhibits mTOR
→ maintains the repressor activity of 4E-BP1
→ growth arrest from G1 to S
→ inhibit cytokine-mediated proliferation of T and B cells

Question 9

What is a drug commonly used with sirolimus?

Answer 9

ciclosporin (useful but ↓renal f(x))

Question 10

Why are Sirolimus-eluting coronary stent used?

Answer 10

Sirolimus inhibits T/B cell proliferation and has anti-proliferative and anti-angiogenic properties → prevent arterial stenosis/re-narrowing of artery

Question 11

What are some clinical indications of mTOR inhibitors?

Answer 11

Sirolimus-eluting coronary stents

Question 12

What are some adverse effects of mTOR inhibitors?

Answer 12

1) Hyperlipidemia
2) Hyperglycemia
3) Hypertension
4) Thrombocytopenia

Question 13

Give 2 examples of cytotoxic metabolites.

Answer 13

Azathioprine, Mycophenolate
also Cyclophosphamide (alkylating agent), methotrexate (DHR inhibitor)

Question 14

How do anti-metabolites lead to immune suppression?

Answer 14

They misincorporate into DNA and impede lymphocyte proliferation

Question 15

What is the MOA of Azathioprine?

Answer 15

1) 6-MP→ 6-TG (guanine analogue) → impedes DNA synthesis → ↓lymphocyte proliferation

Question 16

What is the triple therapy used with Azathioprine and when is it clinically indicated?

Answer 16

Calcineurin inhibitor + Corticosteroid + Azathioprine
- for renal transplant and autoimmune disorders

Question 17

What are some adverse effects of Azathioprine

Answer 17

1) Bone marrow suppression
2) Bleeding
3) GI toxicity
4) Lymphoma
5) Neoplasia

Question 18

What is the MOA of Mycophenolate?

Answer 18

1) MMF/MPS converted to → MPA (mycophenolic acid) (active metabolite)
2) MPA inhibits IMPDH → inhibits purine synthesis
- preferentially inhibits Type 2 (inducible) > 1 (resting) IMPDH
3) impedes DNA synthesis → ↓lymphocyte proliferation

Question 19

What are the differences between Mycophenolate and Azathioprine?

Answer 19

Mycophenolate
- > anti-proliferative effects
- < bone marrow depressions and GI toxicity
- but results in neutropenia (↑risk of opportunistic viral/fungal infections) and Hypertension

Question 20

What is an example of a S1P Receptor agonist?

Answer 20

Fingolimod

Question 21

What is the MOA of Fingolimod?

Answer 21

1) Phosphorylated to Fingolimod-P (analogue of S1P)
2) competitively inhibits S1PR and activates it
3) Functional antagonist (likely through desensitizing S1P receptors or disrupting S1P signalling gradients)
4) prevents lymphocyte egress from lymph nodes and chemokine-gradient-mediated homing
5) ↓ circulating lymphocytes

Question 22

When is fingolimod clinically indicated?

Answer 22

Multiple sclerosis

Question 23

What is the main adverse effect of fingolimod?

Answer 23

1st dose negative cardiac chronotropic effects
(due to S1P1/3 activation in sinoatrial cells)

Question 24

What is the half life of fingolimod?

Answer 24

T1/2~8hrs

Question 25

What kind of polyclonal Abs are used in immune suppression?

Answer 25

Thymoglobulin (Rabbit anti-thymocyte globulin)
- targets lymphocytes, NK cells, MHC1/2 Ags, co-simulator molecules, etc.

Question 26

What is the MOA of Thymoglobulin?

Answer 26

Being a non-selective polyclonal IgG, it:
1) opsonisation and CDC
2) ADCC
3) T cell depletion
4) TCR crosslinking → anergy induction

Question 27

What are some adverse effects of thymoglobulin?

Answer 27

1) 1st dose effect (cytokine release syndrome): fever, chills, hypotension
2) thrombocytopenia, leukopenia, serum sickness
3) developing anti-foreign IgG Ab
4) Histiocytic lymphoma @ injection site

Question 28

What kind of monoclonal Abs are used in immune suppression?

Answer 28

anti-IL-2 receptor mAbs

Question 29

What is an example of a monoclonal Ab used in immune suppression?

Answer 29

Daclizumab (immunomodulatory, humanised)
- anti-IL-2Rα → inhibits mTOR

Question 30

What is the main clinical indication of daclizumab?

Answer 30

transplant rejection suppression

Question 31

What are some adverse effects of daclizumab and how do they change on continuous use?

Answer 31

The risks generally decrease on continuous use
1) Anaphylaxis and serum sickness
2) 1st dose “flu-like” syndrome: fever, headache, cytokine storm
3) ↑risk of infection/malignancies