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Search results for: AntiCyclophilin


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The effect of cyclosporine administration on the cellular distribution and content of cyclophilin.

Cyclophilin (CYP), an intracellular protein sharing amino acid sequence identity with the enzyme peptidyl-prolyl cis-trans isomerase has become the leading candidate for the receptor responsible for cyclosporine biological effects. Avid binding of CYP to cyclosporine and immunosuppressive cyclosporine metabolites has been demonstrated, while nonimmunosuppressive cyclosporine metabolites have tended not to bind to cyclophilin. A previous immunohistochemical analysis documented that CYP localized principally to the cytoplasmic cellular compartment, but nuclear staining was observed among some cells. This study was undertaken to more precisely define the ultrastructural distribution of CYP, and to determine whether CYP cellular content was affected by CsA therapy. Untreated Wistar rats or those receiving 7 days of CsA (15 mg/kg/day, i.p.) were anesthetized, perfusion-fixed in situ, and sacrificed. Analyses of lymph node, spleen, thymus, kidney, liver, heart, brain, and ileum used an affinity purified, rabbit anticyclophilin IgG. Transmission electron microscopy was performed after staining with anti-CYP using a horseradish peroxidase/biotin/avidin technique. Quantitative immunofluorescence was measured by confocal microscopy using anti-CYP, with a biotin/avidin/phycoerythrin technique. Cyclophilin localized to the cytoplasmic compartment--however, association with mitochondria endoplasmic reticulum, Golgi, and with the nuclear membrane among lymphocytes, as well as cells from kidney, liver and ileum--was documented. Cyclophilin was not identified within the nucleus proper. Tissues obtained from animals receiving CsA exhibited a generalized increase in CYP content compared with tissues from untreated controls, suggesting the possibility that CsA may exert a regulatory influence upon CYP gene activation. Collectively, the data were consistent with the hypothesis that CYP exerts a central role in cellular metabolism, and that CsA-mediated biologic effects result from the CsA/CYP interaction.
M L McDonald, T Ardito, W H Marks, M Kashgarian, M I Lorber

1881 related Products with: The effect of cyclosporine administration on the cellular distribution and content of cyclophilin.

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Cyclosporine--relationship of side effects to mode of action.

Although cyclosporine has high specificity for the immune system, immunosuppressive therapy with CsA is often complicated by nephrotoxicity. The main morphologic targets of CsA nephrotoxicity include the tubular epithelial and endothelial cells. These cells were investigated in vitro. CsA caused a dose- and time-dependent inhibition of cell growth, vacuolization and fatty change in adherent cells, detachment, and cell death. Inhibition of 3H-TdR incorporation in cells of both tubular epithelial and endothelial origin occurred between 3 microM and 10 microM. Electron microscopy studies revealed cellular swelling, dilatation of the endoplasmic reticulum, and the presence of lipid droplets and giant mitochondria. The content of the main CsA-binding protein, cyclophilin, in these cell-lines was 5-10 micrograms/mg protein and did not differ in various cell lines, including T cells. Immunohistochemistry using rabbit anticyclophilin antibody revealed diffuse distribution of cyclophilin in the cytosol, nuclear membrane, and nucleolus. Whereas lymphoid cell functions are inhibited at 10-100 nM, CsA had no effect on tubular epithelial and endothelial cells at these concentrations. At concentrations of 3-10 microM, CsA caused growth inhibition and cytotoxicity on cells of lymphoid and nonlymphoid origin. Present evidence shows little, if any, relationship of side-effects to the mode of action of CsA.
B Ryffel, B M Foxwell, A Gee, B Greiner, G Woerly, M J Mihatsch

2401 related Products with: Cyclosporine--relationship of side effects to mode of action.

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