1. Four classes of current immunosuppressive drugs.
    • Glucocorticoids
    • Signal Transduction Inhibitors
    • Purine Synthesis Inhibitors
    • Immunosuppressive Antibodies
  2. General effects that current immunosuppressive drugs induce.
    • Inhibition of gene expression
    • T cell depletion
    • Deplete specific immune cells (via antibodies)
    • Neutralize cytokines
    • Inhibit lymphocyte signaling
  3. What is generally dose limiting for current immunosuppressive drugs?
    Dose-related toxicity not related to immunosuppression itself.
  4. Describe complications of chronic immunosuppressive drugs usage.
    High doses and long-term therapy can suppress HPA system (prednisone).  Avoid abrupt DC.
  5. Contrast immunosuppressive drugs that affect T-cell activation v. proliferation?
    Inactivators (cyclosporine, tacrolimus) inhibit calcineurin, non-proliferator (sirolimus) inhibits mTOR.
  6. Describe the effect that cyclosporine has had on transplantation success?
    Improved 5-year survival rate since introduction in 1983.
  7. Similarities and differences among cyclosporine, tacrollimus, and sirolimus?
    • Cyclosporine & Tacrolimus: (calcineuron inhibitors) - cyp3A4, nephrotoxicity, administered PO or IV, both can cause hyperglycemia (much higher in Tacrolimus).  Cyclosporine forms complex with cyclophilin. Tacrolimus forms complex with FKBP - both inhibit calcineuron preventing IL-2.
    • Sirolimus: Binds to FKBP, but inhibits mTOR preventing T cell proliferation. Nephrotoxicity concern. CYP3A4. Used primarily in kidney transplants.
  8. Why are anti-metabolites effective against proliferating lymphocytes?
    • Purine needed for DNA (A and G backbone)
    • Inhibits proliferation of fast-growing T & B
  9. Why are certain antibodies useful for immunosuppression?
    Antibodies bind to and inhibit important immunological cells/signalers: muromonab (CD3), Basiliximab (IL-2 receptor antagonist, CD25), Adalimumab (TNF-α).
  10. Prednisone
    • Glucocorticoid
    • Repress COX-2, decrease cytokine production
    • Avoid abrupt DC (suppresses HPA)
  11. Cyclosporine
    • Signal Transduction Inhibitor
    • CNI (decrease IL-2)
    • Binds to cylcophilin, inhibits calcineuron
    • CYP3A4
    • Nephrotoxicity
  12. Tacrolimus
    • Signal Transduction Inhibitor
    • CNI (decrease IL-2)
    • Binds to FKBP, inhibits calcineuron
    • CYP3A4
    • Nephrotoxicity
    • Risk of hyperglycemia higher than cyclosporin
  13. Sirolimus
    • Signal Transduction Inhibitor
    • mTOR inhibitor
    • Binds to FKBP, inhibits mTOR
    • (IL-2 released, but not allowed to work)
    • CYP3A4
    • Nephrotoxicity
    • Used in kidney transplants
  14. Azathioprine
    • Purine synthesis inhibitor
    • Kidney transplants
    • Depletes purine nucleotides, ATP, GTP, glycoprotiens.
    • Incorporates into DNA
    • Inhibits de novo purine synthesis
    • Category D
    • Enhanced toxicity with allopurinol
  15. Mycophenolate mofetil
    • Purine synthesis inhibitor
    • Prodrug
    • Prevents organ rejection
    • Less bone marrow suppression than azothioprine
    • Reversible inhibitor of IMD
    • Inhibits de novo guanosine, resulting in less T and B
    • Complete bioavailability
    • Beware of chronic renal insufficiency
    • Category D
  16. Muromonab-CD3
    • Immunosuppressive antibody
    • Directed against CD3
    • Blocks acute rejection (only given in initial phase)
    • Depletion of T cells
    • Flu-like symptoms possible first day
    • Allergy to mouse proteins (if umab - no mouse proteins)
  17. Basiliximab
    • Immunosuppressive antibody
    • Directed against CD25 (IL-2 receptor-CD25 complex)
    • Only against ACTIVATED T-Cells
    • Better tolerated than muromonab-CD3
    • Allergy to mouse proteins
  18. Adalimumab
    • Immunosuppressive antibody
    • Binds to TNF-α, decreases its activity
    • Not for patients w/ chronic/recurrent infection or TB.
    • Not if patient has traveled to regions w/ endemic fungal infections.
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