Immunosuppressive Drugs (Zheng)

Question 1

Dacluzimab

Answer 1

• Immunosuppressive drug

- anti- IL-2 receptor, prevents IL-2 binding to thymocytes, preventing T-cell maturation

Question 2

Calcineurin Inhibitors

Answer 2

• Cyclosporine

- Tacrolimus

Question 3

Cytotoxic Drugs

Answer 3

• Azathioprine

- Mycophenolate Mofetil

Question 4

mTOR Inhibitors

Answer 4

• Sirolimus (Rapamycin)

- Everolimus

Question 5

Biologics (Antibodies)

Answer 5

• Antithymocyte Globulin
• Muromonab-CD3
• Daclizumab antibody

Question 6

Cyclosporine + Tacrolimus

Answer 6

• Bind calcineurin, preventing dephosphorylation of NFAT, preventing IL-2 transcription and T-cell maturation.
• Tacrolimus is same mechanism but more potent
• Risks: renal toxicity, infections (since inhibiting T-cells), drug interactions (CYP overlap)–>grapefruit juice.

Question 7

Sirolimus + Everolimus

Answer 7

• Bind mTOR (part of IL-2 pathway activating growth of T-cells), inhibits
• Also used as anticancer, in drug-eluting stents
• Risks: drug interaction (CYP overlap), particularly with calcineurin inhibitors (can cause renal toxicity)

Question 8

Azathioprine

Answer 8

• purine analog, incorporated to cell DNA/RNA and messes up proliferating cells (like lymphocytes)
• Risks of infection, bone marrow suppression. Drug interaction with allopurinol (both metabolized by xanthine oxidase, but allopurinol inhibits XO)

Question 9

Mycophenolate Mofetil

Answer 9

• Inhibits inisotol monophosphate dehydrogenase (purine de novo synthesis). Selectively inhibits lymphocytes since they lack salvage pathway, other cells have it so they’re fine.
• Risks: GI toxicity (also a proliferating tissue, inhibition disturbs)

Question 10

Antithymyocyte Globulin

Answer 10

• antibodies vs. human thymocytes. Deplete thymocytes and lymphocytes dependent on thymocytes for activation
• Used for bone marrow transplant

Question 11

Daclizumab

Answer 11

• Monoclonal antibody
• Binds CD-25 - IL-2 receptor on activated T-cells, antagonist
• Used vs. acute graft rejection

Question 12

Muromonab-CD3

Answer 12

• Monoclonal antibody vs. CD3 subunit of TCR, causing T-cell destruction
• Used in acute graft rejection, bone marrow transplant
• Risk: massive cytokine release from dying T-cells, so give glucocorticoids first

Question 13

Glucocorticoids

Answer 13

• natural and synthetic analogs act to inhibit expression of cytokine genes (IL-1, 2, 6, IFN, TNF-å), inhibiting T-cell proliferation and inflammation
• Used prophylactically vs. transplant rejection, autoimmune disorders, allergies, cancers
• Risks: many side effects, including “moon face”

Question 14

Muromonab

Answer 14

• Immunosuppressive drug

- CD3 monoclonal antibody (binds CD3 receptor on T-cells, preventing activation