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Define Allograft
A transplanted organ or tissue from a genetically non-identically member of the same species
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Define Autoimmune disease
Immune response of the body against substances normally present in the body
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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
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True or False: cytotoxic immunosuppressants target all dividing cell
True
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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
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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
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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
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Briefly describe the actions of immuran (Azathioprine)
- Purine analog
- prevents DNA synthesis
- Inhibits WBC proliferation
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Briefly describe the actions of Doxorubicin
- Antibiotic
- Intercalates DNA (fitting between two base pairs)
- Prevents DN replication
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Briefly describe the actions of Hydrocotisone
- Glucocorticoid
- modulates genes
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Describe the mechanism of action of NSAIDS
- Inhibition of COX
- Prevents formation of TXA2, PGE2, PGI2
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What is the role of PGE2
- mediates fever
- GI smooth muscle contraction
- vascular and GI smooth muscle relaxation
- Gastric mucosal protection
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Name two classes of immunosuppressants
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What the heck is Tolypocladium Inflatum
- Fungus found in Norwegian soils
- Produces cyclosporine
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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
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Name 2 kinds of immunophilins
- Cyclophilin, which binds to cyclosporine
- FKBP12 whichbinds to Tacrolimus and Sirolimus
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What are immunophilins?
- Isomerases
- Catalyze the cis-trans isomerization of peptide bonds at proline residuesfacilitates protein folding
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Cyclosporin, tacrolimus, and sirolimus are metabolized in liver by BLANK A and excreted through BLANK B
- A: Cytochrome P-450
- B: Feces
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State the side effects of cyclosporin
- Renal disfunction
- Tremor
- Hypertension
- Hirsutism
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What in the world is Streptomyces Tsukubaensis?
Its a fungus from which Tacrolimus was made
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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
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What are the side effects of Tacrolimus?
- Renal disfunction
- Tremor
- Hypertension
- Hirsutism
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What in tarnation is Streptomyces Hygroscopius
A fungus found in soil in Easter Island used to make Sirolimus
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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
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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)
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Name 3 Sirolimus analogs
- Zotarolimus
- Everolimus
- Biolimus
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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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