Abstract

Liver ischemia reperfusion (I/R) induces an untoward hyperinflammatory response following partial hepatectomy, liver transplantation, and hypovolemic shock. Currently, there are no effective therapies. While dendritic cells (DCs) are now recognized as the principal mediators of immunity and inflammation throughout the body, our understanding of liver DCs has been rudimentary. During our first 5 years of funding, we primarily established the T cell stimulating capacity of freshly isolated mouse and human liver DCs. In this competitive renewal application for an additional 5 years of funding, we will investigate the innate role of hepatic DCs in liver inflammation. Toll-like receptors (TLRs) are evolutionarily conserved proteins present on immune cells that recognize pathogens, immunologic danger signals and endogenous nucleic acids and subsequently activate innate immunity. We have discovered that TLR9, the intracellular receptor that detects hypomethylated bacterial CpG motifs and endogenous DNA, modulates anti-inflammatory responses by conventional DCs in liver I/R. Additionally, we have discovered that plasmacytoid DCs exert protective effects in I/R. Thus, we hypothesize that endogenous ligands regulate DCs in the immunopathogenesis of liver I/R injury.
In Aim 1, we will determine the regulation of liver I/R by conventional DCs in response to endogenous ligands.
In Aim 2, we will establish the mechanism of protection by plasmacytoid DCs in liver I/R.
In Aim 3, we will establish the TLR requirements for injury in an in vitro model of human liver I/R. The proposed experiments will increase our knowledge regarding the mechanisms of hepatic inflammation. Our investigation has direct relevance to human disease and may lead to the use of TLR blockade for the treatment of hu- man I/R that involves the liver and other organs, such as the heart, kidney, lung, and brain.

Public Health Relevance

In this proposal, we will investigate the role of liver dendritic cells and danger signals released by the host during liver inflammation in mice and humans. Our investigations will be useful in identifying new therapies to treat ischemia reperfusion injury that occurs in humans.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068346-07
Application #
8101861
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
2004-09-01
Project End
2015-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
7
Fiscal Year
2011
Total Cost
$391,683
Indirect Cost

  Institution

Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Burga, Rachel A; Thorn, Mitchell; Point, Gary R et al. (2015) Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T. Cancer Immunol Immunother 64:817-29
Turcotte, Simon; Katz, Steven C; Shia, Jinru et al. (2014) Tumor MHC class I expression improves the prognostic value of T-cell density in resected colorectal liver metastases. Cancer Immunol Res 2:530-7
Katz, Steven C; Bamboat, Zubin M; Maker, Ajay V et al. (2013) Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases. Ann Surg Oncol 20:946-55
Ocuin, Lee M; Zeng, Shan; Cavnar, Michael J et al. (2012) Nilotinib protects the murine liver from ischemia/reperfusion injury. J Hepatol 57:766-73
Zeng, Shan; Zhang, Qing Yin; Huang, Jianzhong et al. (2012) Opposing roles of RAGE and Myd88 signaling in extensive liver resection. FASEB J 26:882-93
Ocuin, Lee M; Bamboat, Zubin M; Balachandran, Vinod P et al. (2011) Neutrophil IL-10 suppresses peritoneal inflammatory monocytes during polymicrobial sepsis. J Leukoc Biol 89:423-32
Katz, Steven C; Ryan, Kristin; Ahmed, Naseem et al. (2011) Obstructive jaundice expands intrahepatic regulatory T cells, which impair liver T lymphocyte function but modulate liver cholestasis and fibrosis. J Immunol 187:1150-6
Bamboat, Zubin M; Ocuin, Lee M; Balachandran, Vinod P et al. (2010) Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion. J Clin Invest 120:559-69
Bamboat, Zubin M; Balachandran, Vinod P; Ocuin, Lee M et al. (2010) Toll-like receptor 9 inhibition confers protection from liver ischemia-reperfusion injury. Hepatology 51:621-32
Burt, Bryan M; Plitas, George; Zhao, Zeguo et al. (2009) The lytic potential of human liver NK cells is restricted by their limited expression of inhibitory killer Ig-like receptors. J Immunol 183:1789-96

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