Dual mechanisms of potentiation of murine antigen-specific IgE production by cyclosporin A in vitro.
Concomitant administration of cyclosporin A (CsA) with Ag has been shown to augment the production of Ag-specific IgE in vivo. We demonstrate that addition of CsA also markedly potentiated Ag-specific IgE in vitro. Low doses of CsA (3 and 10 ng/ml) added at the time of culture initiation selectively enhanced Ag-specific IgE but not IgA or IgG1 production, whereas higher doses (30 ng/ml) suppressed production of all the isotypes. Augmented IgE production was found to correlate with enhanced production of IL-4 and diminished production of IFN-gamma. Delayed addition (after 2 days) of low doses of CsA to Ag-stimulated cultures did not potentiate IgE production, even though CsA differentially affected levels of IL-4 and IFN-gamma. CsA enhanced Ag-mediated cognate T/B interaction was not affected by neutralizing doses of anti-IL-4, suggesting Ag-mediated lymphocytic "synapses" may be inaccessible to anti-IL-4. The effect of CsA on Ag presentation was determined by pulsing peritoneal exudate cells, spleen cells, or primed B cells with Ag and low doses of CsA before incubation with primed splenocytes. Enhanced Ag-specific IgE responses were detected with no effect on IL-4 or IFN-gamma levels. Thus, our study indicates that CsA potentiation of Ag-specific IgE response is due to cumulative action of CsA on two independent pathways: first, CsA differentially modulates IL-4 and IFN-gamma levels during the early phase of cognate Th2/B cell interaction; and second, CsA directly affects APC and IgE isotype-specific amplifying cellular components without apparently affecting the secretory levels of IL-4 and IFN-gamma. Dual mechanisms of CsA-potentiated IgE production are consistent with the hypothesis of two-tiered T cell regulation of Ag-specific IgE responses.
Chen
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SS
Department of Veterinary Science, University of Nebraska, Lincoln 68583-0905.
Li
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Pearlman
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Chen
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WH
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D007073:Immunoglobulin E / Q000096:biosynthesis*; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010529:Peritoneal Cavity / Q000166:cytology; D013154:Spleen / Q000276:immunology; D013997:Time Factors
D016207:Cytokines; D015847:Interleukin-4; D007073:Immunoglobulin E; D016572:Cyclosporine