Our goal is to develop a novel animal model for autoimmune hepatitis (AIH).
AIM i s a severe adverse immune reaction afflicting the liver, resulting in the progressive destruction of the parenchyma. To date no valid animal model is available that reflects the clinical and pathological features of human AIH and allows to study its etiology and immunopathology. A hallmark of AIH is the presence of liver/kidney microsomal antibodies that recognize the cytochrome P450 isoform 2D6 (CYP2D6) as a major target autoantigen. Thus, it is the objective to break tolerance to a transgenically expressed target antigen (human CYP2D6) in the target organ (liver) of CYP2D6-mice by infection of a liver-tropic virus (adenovirus), ensuring local inflammation and delivery of large quantities of the triggering antigen (human CYP2D6). From preliminary experiments we know that this approach results in persistent liver damage in CYP2D6-mice, which is characterized by lymphocyte infiltration, hepatic fibrosis, and high titer anti-CYP2D6 antibodies. In addition to its obvious benefit as a novel model to study AIH, the CYP2D6 mouse may also be used as a proof of principle for studying general mechanisms involved in fibrinogenesis and in drug-induced autoimmune diseases that are mediated by members of the cytochrome P450 family, such as Halothane hepatitis (CYP2E1) or procainamide-induced lupus (CYP2D6). ? ? Aim 1: Development and characterization of the CYP2D6-mouse model for autoimmune hepatitis Aim 2: Mechansims of autoimmune liver damage in the CYP2D-mouse model;
Aim 3 : Evaluation of possible treatments to abrogate autoimmunity in the CYP2D6-mouse model. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK071577-02
Application #
7267898
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Serrano, Jose
Project Start
2006-08-01
Project End
2008-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$77,680
Indirect Cost
Name
University of Frankfurt
Department
Type
DUNS #
320516586
City
Frankfurt
State
Country
Germany
Zip Code
60323
Christen, Urs; Holdener, Martin; Hintermann, Edith (2010) Cytochrome P450 2D6 as a model antigen. Dig Dis 28:80-5
Hintermann, Edith; Bayer, Monika; Pfeilschifter, Josef M et al. (2010) CXCL10 promotes liver fibrosis by prevention of NK cell mediated hepatic stellate cell inactivation. J Autoimmun 35:424-35
Christen, Urs; Hintermann, Edith; Holdener, Martin et al. (2010) Viral triggers for autoimmunity: is the 'glass of molecular mimicry' half full or half empty? J Autoimmun 34:38-44
Christen, Urs; Hintermann, Edith; Jaeckel, Elmar (2009) New animal models for autoimmune hepatitis. Semin Liver Dis 29:262-72
Holdener, Martin; Hintermann, Edith; Bayer, Monika et al. (2008) Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection. J Exp Med 205:1409-22
Hintermann, Edith; Christen, Urs (2007) Viral infection--a cure for type 1 diabetes? Curr Med Chem 14:2048-52