Immunosuppressants

• What is the mechanism of action of mycophenolate mofetil?

  Mycophenolate mofetil reversibly inhibits inosine monophosphate (IMP) dehydrogenase, preventing purine synthesis in T and B cells
• What is the mechanism of action of tacrolimus (FK506)?

  FK506 binds to FK506 binding protein (FKBP) and inhibits calcineurin, thereby preventing interleukin (IL)-2 transcription and thus inhibiting T cell activation
• What is the mechanism of action of cyclosporine?

  Cyclosporine inhibits calcineurin and binds cyclophilin, preventing interleukin (IL)-2 transcription and thus blocking T cell activation
• What is the mechanism of action of sirolimus (rapamycin)?

  Rapamycin inhibits mTOR (binds FKBP), blocking T cell activation and B cell differentiation by inhibiting the cellular response to interleukin (IL)-2
• How does the inhibition of nuclear factor (NF)-κB by steroids lead to immune system suppression?

  NF-κB inhibition decreases cytokine transcription by suppressing B and T cell function and inducing T cell apoptosis
• Which immunosuppressant drug class can cause a buffalo hump, hyperglycemia, striae, and acne?

  Glucocorticoids (Cushing syndrome)
• What are three toxicities associated with basiliximab?

  Edema, hypertension, tremor
• What immunosuppressant is associated with increased toxicity when combined with allopurinol?

  Azathioprine
• What are the three main clinical indications for azathioprine, apart from transplant rejection prophylaxis?

  Rheumatoid arthritis, glomerulonephritis, and Crohn disease
• What antimetabolite is azathioprine a precursor for?

  6-Mercaptopurine (interferes with nucleic acid synthesis)
• What immunosuppressant is often found in drug-eluting stents?

  Sirolimus (rapamycin)
• Which three toxicities are associated with sirolimus (rapamycin)?

  Pancytopenia, insulin resistance, hyperlipidemia (sirolimus causes "pansirtopenia")
• What immunosuppressant medication is synergistic with cyclosporine?

  Sirolimus (rapamycin)
• What two immunosuppressants are specifically preferred for kidney transplant rejection prophylaxis?

  Sirolimus and Basiliximab (think Sir Basil's kidney transplant)
• What immunosuppressant that is used for psoriasis can cause gingival hyperplasia and hirsutism?

  Cyclosporine
• What two immunosuppressants are commonly associated with drug-induced kidney failure?

  Cyclosporine and tacrolimus
• What are the two main clinical indications for cyclosporine, apart from transplant rejection?

  Rheumatoid arthritis and psoriasis
• What two conditions are more common due to long-term use of immunosuppressants?

  Cancers and infections
• What is the clinical advantage of combining different immunosuppressants?

  It increases their net efficacy while minimizing their individual toxicities
• What is an important adverse effect of cyclosporine?

  Nephrotoxicity
• What are the two adverse effects that are more commonly associated with tacrolimus than with cyclosporine?

  Diabetes (metabolic side effects) and neurotoxicity
• What is beneficial about the side-effect profile of mycophenolate mofetil?

  Less nephrotoxic and neurotoxic than other immunosuppressants
• What viral infection is associated with mycophenolate mofetil?

  Cytomegalovirus (CMV)
• What two hematologic malignancies are glucocorticoids often used to treat?

  Non-Hodgkin lymphoma and chronic lymphocytic leukemia
• What mechanism causes artificial leukocytosis in patients taking glucocorticoids?

  Glucocorticoids cause demargination of WBCs in the vasculature, producing an apparent (artificial) leukocytosis on blood testing
• What two types of gene transcription are inhibited by glucocorticoids?


  Inflammatory cytokine genes and nuclear factor (NF)-κB
• What types of gene transcription is mammalian target of rapamycin (mTOR) responsible for?

  Proliferation genes
• What type of nucleotides do both mycophenolate mofetil and azathioprine inhibit?

  Purines (adenine, guanine)
• What complication can result if a patient abruptly stops taking a glucocorticoid after long-term use?


  Adrenal insufficiency
• What two factors can amplify the nephrotoxicity of calcineurin inhibitors?

  Higher doses and poor renal function
• What downstream messenger is activated by interleukin (IL)-2R signaling?

  Mammalian target of rapamycin (mTOR)