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. ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IMM-A (01))
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Gondre-Lewis, Timothy A
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University of Rochester
Schools of Dentistry
United States
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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