The influence of ethanol (EtOH) on multiple dendritic cell (DC) subsets, either in steady state or following mobilization in vivo, has not been characterized. Herein, the generation of mouse bone marrow (BM)-derived DC in fms-like tyrosine kinase 3 ligand was inhibited by physiologically-relevant concentrations of EtOH, with selective suppression of plasmacytoid (p)DC. EtOH reduced surface expression of costimulatory (CD40, CD80, CD86) but not coinhibitory CD274 (B7-H1) molecules on resting or CpG-stimulated DC subsets. IL-12p70 production by activated DC was impaired. Consistent with these findings, EtOH-exposed (E)BMDC exhibited reduced capacity to induce naïve allogeneic T cell proliferation and impaired ability to prime T cells in vivo. Further, T cells from animals primed with EBMDC produced elevated levels of IL-10 following ex vivo challenge with donor alloantigen. DC subsets freshly-isolated from EtOH-fed mice were also examined. Liver DC, inherently immature and resistant to maturation, exhibited little change in low surface cosignaling molecule expression, whereas splenic DC showed reduced expression of cosignaling molecules in response to CpG stimulation. These splenic DC elicited reduced naïve allogeneic T cell proliferation in vitro, while the stimulatory capacity of resting but not CpG-activated liver DC was reduced by EtOH administration. In vivo, hepatic EDC elicited increased capacity to prime T cells compared to control hepatic DC. Conversely, splenic EDC exhibited impaired ability to prime T cells in vivo. This differential capacity of hepatic versus splenic EDC compared to control DC to prime T cells in vivo is likely due to several factors including differential phenotype and migratory capacity. In fact, liver EDC migrate in greater numbers to secondary lymphoid tissue compared to control liver DC. Thus, EtOH impairs cytokine-driven differentiation and function of mDC and pDC in vitro. Hepatic DC from chronic EtOH-fed mice are differentially affected compared to splenic DC. Splenic DC exhibit impaired functional maturation following CpG stimulation while hepatic DC exhibit altered migration to secondary lymphoid tissue. In addition to examining the effects of chronic EtOH exposure on DC, we have evaluated cell-mediated and humoral responses in EtOH-fed mice. In total, these results indicate potential mechanisms by which alcohol consumption is associated with immunosuppression.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04142006-105656 |
| Date | 26 April 2006 |
| Creators | Lau, Audrey Hui-Wen |
| Contributors | Adriana Zeevi, Nikola Vujanovic, Lou D. Falo, Jr., Paul D. Robbins, Angus W. Thomson, Robert L. Hendricks |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04142006-105656/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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