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American Liver Foundation
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Sunflowers for Holli Autoimmune Hepatitis Postdoctoral Research Fellowship
University of Pittsburgh Medical School, Pittsburgh, Pennsylvania
NOD2 signaling and regulation of liver dendritic cell tolerogenicity
The liver is remarkably tolerogenic compared to other transplanted organs. Many non–exclusive factors have been implicated, such as chronic exposure to gut-derived LPS that can induce a state of ‘endotoxin tolerance’ in antigen-presenting cells, and the high level of immunosuppresive cytokines (transforming growth factor β and interleukin-10) produced by various liver cell types. Nucleotide-binding oligomerization domain (NOD)2, that senses muramyl dipeptide (MDP), a breakdown product of bacterial peptidoglycan, has been reported to play a crucial role in regulating intestinal immunity. The liver is exposed continually to gut-derived MDP, but the influence of NOD2 ligation on hepatic dendritic cells (DC),- crucial regulators of innate and adaptive immunity, has not previously been investigated.
Dr. Castellaneta’s preliminary data show that freshly-isolated mouse liver and spleen plasmacytoid (p)DC express higher levels of NOD2 message than conventional myeloid (m)DC. Following MDP stimulation in vivo, liver pDC, but not mDC, upregulate expression of IFN regulatory factor 4 (IRF4), a negative regulator of TLR signaling, and induce less allogeneic T cell proliferation and IFNγ production. Their adoptive transfer failes to prime allogeneic T cells in vivo. Liver pDC from MDP-stimulated mice also display greater cell surface B7-H1. Absence of B7-H1 on liver pDC reversed the inhibitory effect of MDP.
Dr. Castellaneta’s findings suggest that differential effects of NOD2 ligation on liver pDC may play a role in regulating hepatic innate and adaptive immunity. Therefore, identifying further tolerogenic features of liver DC may provide insight into mechanisms important for controlling liver immune biology, including alloimmune responses in liver transplantation, liver autoimmune disease and liver viral disease.
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