T cell responses in the liver sometimes eradicate pathogens, but frequently result in functional tolerance. This may lead to persistence of the pathogen in the case of an infection, or graft survival in an allogeneic liver transplant. The factors that determine whether a T cell response to liver antigens leads to immunity or tolerance are poorly understood. ? ? To explain how liver immunity is controlled, we propose three linked hypotheses. (1) In the liver, direct presentation of antigen by hepatocytes and/or cross-presentation by liver sinusoidal endothelial cells predominates over cross-presentation by bone marrow-derived APC, such as DC. The lack of cross presentation by DC causes suboptimal T cell activation, defects of function, and eventual T cell deletion. (2) Continuous exposure of liver APC populations to low levels of endotoxin from the intestine engages TLR4 and causes down-regulation of TLR signaling. This renders bone marrow-derived APC refractory to full maturation, and an effect of their immaturity is lack of cross-presentation. (3) Type 1 Interferon can bypass the effects of TLR4 desensitization, restore cross-presentation, and promote full T cell activation leading to anti-viral immunity. ? ? These hypotheses will be tested, using tools optimized to precisely define the cell populations in which antigen presentation occurs. An Adeno-Associated Virus-based vector will deliver ovalbumin as a surrogate viral antigen, to which TCR transgenic OT- 1 and OT-2 T cells will respond. Novel vectors will be created that co-express ovalbumin withTLR4, Interferon-alpha and other type 1 cytokines, and a """"""""death cassette"""""""" to promote hepatocyte apoptosis. These will be used in normal and gene-targeted mice, and in mice in which the capacity of different liver cells to present antigen has been controlled using bone marrow transplantation, orthotopic liver transplantation, or both. As a result of this project we will be able to develop a unified model of liver APC function, tolerance and immunity. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI063353-03
Application #
7210569
Study Section
Special Emphasis Panel (ZRG1-IMM-A (01))
Program Officer
Gondre-Lewis, Timothy A
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$369,790
Indirect Cost
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Crispe, Ian N (2014) Immune tolerance in liver disease. Hepatology 60:2109-17
Crispe, Ian Nicholas (2011) Liver antigen-presenting cells. J Hepatol 54:357-65
John, Beena; Klein, Ingo; Crispe, I Nicholas (2007) Immune role of hepatic TLR-4 revealed by orthotopic mouse liver transplantation. Hepatology 45:178-86
Klein, Ingo; Gassel, Heinz-Jochen; Thiede, Arnulf et al. (2007) A microsurgical approach to hepatic and extrahepatic antigen presentation and its effects on the migration pattern of activated CD8(+) T cells. Microsurgery 27:289-94
Klein, Ingo; Cornejo, Judith C; Polakos, Noelle K et al. (2007) Kupffer cell heterogeneity: functional properties of bone marrow derived and sessile hepatic macrophages. Blood 110:4077-85
Klein, Ingo; Crispe, Ian Nicholas (2006) Complete differentiation of CD8+ T cells activated locally within the transplanted liver. J Exp Med 203:437-47
Crispe, Ian N; Giannandrea, Matthew; Klein, Ingo et al. (2006) Cellular and molecular mechanisms of liver tolerance. Immunol Rev 213:101-18