1. Define Allograft
    A transplanted organ or tissue from a genetically non-identically member of the same species
  2. Define Autoimmune disease
    Immune response of the body against substances normally present in the body
  3. Briefly describe these auto immune diseases:
    • Systemic lupus erithmatosis: AB against histone complex
    • Myasthenia Gravis: AB against AchR or MuSK
    • Thyroiditis: AB against thyroid tissue
    • Graves: AB activate TSH receptor
    • Hemolytic Anemia: abnormal breakdown of RBC
    • Thrombocytopenia: low platelet count
  4. True or False: cytotoxic immunosuppressants target all dividing cell
  5. Name 6 classes of cytotoxic immunosuppressants and give one example of each
    • Alkylating agents: cyclophosphamide
    • Anti-folates: methotrexate
    • Purine analogs: azathioprine
    • Antibiotics: Doxorubicin
    • Glucocorticoids: Hydrocortisone
    • NSAIDS: Aspirin
  6. Briefly describe the actioins of Cytoxan (cyclophosphamide)
    • It is an alkylating agaent; activated in the liver; used in allografts and autoimmune disease
    • Adds an alkyl group to guanine
    • Slows cell growth
  7. Describe the mechanism of action of Methotrexate
    • Anti-folate drug; prevent DNA synthesis; preventing WBC proliferation
    • Inhibits enzyme, dihydrofolate reductase
    • This inhibits tetrahydroflorate (1-C donor)
    • Prevents purine synthesis
    • Inhibits IL-1 production
    • Inhibits LTB4 production; preventing extravasation of WBC
  8. Briefly describe the actions of immuran (Azathioprine)
    • Purine analog
    • prevents DNA synthesis
    • Inhibits WBC proliferation
  9. Briefly describe the actions of Doxorubicin
    • Antibiotic
    • Intercalates DNA (fitting between two base pairs)
    • Prevents DN replication
  10. Briefly describe the actions of Hydrocotisone
    • Glucocorticoid
    • modulates genes
  11. Describe the mechanism of action of NSAIDS
    • Inhibition of COX
    • Prevents formation of TXA2, PGE2, PGI2
  12. What is the role of PGE2
    • mediates fever
    • GI smooth muscle contraction
    • vascular and GI smooth muscle relaxation
    • Gastric mucosal protection
  13. Name two classes of immunosuppressants
    • Cytotoxic
    • Selective
  14. What the heck is Tolypocladium Inflatum
    • Fungus found in Norwegian soils
    • Produces cyclosporine
  15. Discuss the mechanism of action of Cyclosporine
    • Binds in cyclophilin
    • Cyclosporin-cyclophilin complex inhibits calcineurin
    • Calcineurin is a Ca-dependent phosphotase which activates NFATc
    • NFAT (transcription factor) enters nucleus and upregulates IL2 gene
    • IL2 stimulates proliferation and differention of T-cells
    • Therefore cyclosporine prevent IL2 production
  16. Name 2 kinds of immunophilins
    • Cyclophilin, which binds to cyclosporine
    • FKBP12 whichbinds to Tacrolimus and Sirolimus
  17. What are immunophilins?
    • Isomerases
    • Catalyze the cis-trans isomerization of peptide bonds at proline residues
    • facilitates protein folding
  18. Cyclosporin, tacrolimus, and sirolimus are metabolized in liver by BLANK A and excreted through BLANK B
    • A: Cytochrome P-450
    • B: Feces
  19. State the side effects of cyclosporin
    • Renal disfunction
    • Tremor
    • Hypertension
    • Hirsutism
  20. What in the world is Streptomyces Tsukubaensis?
    Its a fungus from which Tacrolimus was made
  21. What is the mechanism of action of Tacrolimus?
    • Binds with immunophilin: FKBP12
    • Inhibits Calcineurin
    • Calcineurin is a Ca-dependent phosphate which activates NFATc
    • NFAT (transcription factor) enters nucleus and upregulates IL2 gene
    • IL2 stimulates proliferation and differentiation of T-cells
    • There, Tacrolimus inhibits IL2 production

    *note: studies show that acute rejection incidence is lower in Tacrolimus
  22. What are the side effects of Tacrolimus?
    • Renal disfunction
    • Tremor
    • Hypertension
    • Hirsutism
  23. What in tarnation is Streptomyces Hygroscopius
    A fungus found in soil in Easter Island used to make Sirolimus
  24. Describe the mechanism of action of Sirolimus, its use, and side effects
    • Mechanism: Forms FKBP12 - Sirolimus complex, inhibits mTOR (mammalian Kinase Target of Rapamycin), blocks progression of cell cycle
    • Use: it is used as prophylaxis in organ transplants, used with Calcineurin inhibitors and glucocoticoids, used to coat stents
    • Side Effects: lymphoma, infections, impaired wound healing and thrombocytopenia

    Note: lower toxicity towards kidneys
  25. Compare and contrast the mechanism of action of Tacrolimus and Sirolimus
    • They both bind to FKBP12 receptor
    • Tacrolimus prevents production of IL2 (via calcineurin inhibition)
    • Sirolimus prevents the actions of IL2 (via inhibition of mTOR)
  26. Name 3 Sirolimus analogs
    • Zotarolimus
    • Everolimus
    • Biolimus
  27. Name two monoclonal antibodies to IL2 receptors.
    Whats their use? What's one drawback?
    • Daclizuma
    • Basiliximab
    • They decrease the chance of acute rejection in organ transplantation
    • Increase chance for oppertunistic infections
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