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14 Cards in this Set
- Front
- Back
Prednisone and Prednisolone (corticosteroids) MOA?
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1. Leukocytopenia
2. Reduce size and lymphoid content of the lymph nodes and spleen 3. Interfere w/ fxn of macrophages/monocytes 4. Interfere's w/ fxn of helper T cells 5. Interferes w/ lymphokine synthesis |
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Explain the leukocytopenia.
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1. Marked reduction in circulating T and B lymphocytes
-- cells redistrib to spleen, bone marrow -- T cell content reduced more than B cell content -- CD4 cells show greater decrease than do CD8 cells -- Decreased circulating monocytes -- Decreased circulating eosinophils and basophils -- INCREASED circulating neutrophils due to release of mature cells from bone marrow and decreased movement from blood into vascular tissue |
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Explain how prednisone and prednisolone interfere w/ fxn of macrophages and monocytes?
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They block expression of the genes for IL-1 (stims TH1 cells) and IL-6 (stims TH2, B cells, plasma cells)
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Explain how prednisone and prednisolone interfere w/ fxn of helper T cells.
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1. Block expression of genes for IL-2 and IL-4
2. Blocks expression of genes for TNFb and IFNg NET EFFECTS: 1. No activation of TH1 and TH2 helper T cells 2. No activation of cytotoxic T cells 3. Prevents synthesis of TNF and IFNg by helper T cells 4. Reverses the increased expression of MHCII proteins and adhesion molecules by allograft cells |
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What are the net effects of corticosteroids (prednisone, prednisolone)?
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1. prevent activation of T cells
2. prevent proliferation of T and B cells 3. suppress the production of antibodies by B cells |
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How do prednisone and prednisolone interfere with lymphokine synthesis?
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**Block expression of the genes which code for IL-1, IL-2, IL-4, IL-6, IFNg, and TNF
NET EFFECT: 1. inhibit expression of MHCII antigens by the allograft cells 2. prevent increased expression of adhesion molec by the vascular endothel cells of the allograft 3. inhib fxn monocytes/macrophages 4. inhib activation T helpers 5. inhib clonal expansion of T cells and B cells 6. inhib activation cytotoxic T cells 7. inhib Ab production 8. generalized inhib of cellular and humoral immunity |
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Cyclosporine MOA overview?
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General:
-- blocks T cell activation -- prevents clonal expansion T cells, B cells -- prevents action cytotoxic T cells |
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Cyclosporine MOA specifics?
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1. Prevents transcription genes for IL-2, TNFb, and IFNg
2. Prevents transcription of the gene for IL-2 RECEPTORS...thus decreased expression on surface of helper T cells ***It does the above by binding to cytoplasmic protein on helper T cell (cyclophilin) which inhibits the enzymatic activity of calcineurin -- calcineurin dephosph NFATC which normally activates genes for IL-2, IL-2 receptors, TNFb, and IFNg |
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Tacrolimus MOA?
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SAME AS CYCLOSPORIN
-- bonds to the cytosolic protein FKBP of helper T cells -- tacrolimus-FKBP complex also inhibits calcineurin and thus prevents production of IL-2, IL-2 receptors, TNFb, and IFNg |
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Sirolimus (rapamycin) MOA?
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Interacts w/ intracellular immunophyllins to block T and B cell activation by cytokines caysing the cells to go into cell cycle arrest.
DOES NOT inhibit IL-2 production by activated T cells |
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Mycophenolate mofetil MOA?
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1. Potent inhibitor of inosine monophosphate dehydrogenase, an enzyme critical in the de novo synthesis of the purine guanine by T and B lymphocytes
2. Acts specifically on lymphocytes b/c these cells, unlike others derived from bone marrow, have no alternative pathway (HGPRT salvage pathway) for purine biosynthesis |
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Azathioprine MOA?
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1. Converted to 6-mercaptopurine which in turn is eventually converted to thio-GTP. This purine analog is incorporated into the DNA where it inhibs further DNA synth and prevents T-cell and B-cell expansion
2. 6-mercaptopurine is cytotoxic and kills stimulated lymphocytes 3. Inhibs prolif of promyelocytes in bone marrow and thus decreases number of circ monocytes capable of differentiation into macrophages |
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Cyclophosphamide MOA?
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1. Alkylation of the 7 nitrogen of guanine causes cross-linking of the DNA strands which inhibits DNA replication and translocation
2. Interferes w/ mitosis and division in rapidly proliferating cells, thus causing cell death |
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OKT3 (muromonab-CD3) MOA?
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Monoclonal Ab (produced by hybridomas)
1. Ab is directed against CD3 complex of T helper cells and cytotoxic T cells 2. CD3 protein lies right next to Ag-recognition cmplx of helper T cell receptor 3. Binding to the CD3 complex blocks binding of the foreign Ag presented by the APC; helper T cell cannot be activated to produce IL-2, etc. 4. Deactivation of the CD3 complex causes Tcell receptor Ag recognition site to endocytose 5. Fxn of cytotox T cells is blocked 6. T cells become inactive and are removed from circ by reticuloendothelial system |