Lau, Audrey Hui-Wen
(2006)
Ethanol Exposure and Dendritic Cell Function.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
26 April 2006 |
| Date Type: |
Completion |
| Defense Date: |
11 April 2006 |
| Approval Date: |
26 April 2006 |
| Submission Date: |
14 April 2006 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Dendritic cell; ethanol; liver; migration; T cells |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-04142006-105656/, etd-04142006-105656 |
| Date Deposited: |
10 Nov 2011 19:37 |
| Last Modified: |
19 Dec 2016 14:35 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/7153 |
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