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  • In order to get as close as possible to the


    In order to get as close as possible to the autoaggressive immune response in human AIH and in addition being able to track and quantify autoantigen-specific immune cells, several AIH models use target and/or trigger autoantigens to which AMG 925 or T cells have been identified in patients with AIH. CYP2D6 is the immunodominant and possibly the best characterized autoantigen recognized by antibodies and T cells of patient with AIH-2 [25,26,45]. The CYP2D6 mouse model utilizes human CYP2D6 as a triggering antigen, which is delivered to the liver of wild type FVB or C57BL/6 mice by infection of an adenovirus encoding for human CYP2D6 (Ad-2D6) [120]. Since mice are lacking the human CYP2D6 the triggered autoreactivity targets the mouse Cyp homologues. Infection of mice with Ad-2D6 results in an acute hepatic inflammation that subsequently develops into chronic AIH-like disease characterized by an interface hepatitis with cellular infiltrates that exhibit CD4 and CD8 T cells, B cells, macrophages, dendritic cells, and neutrophils [121]. Further, the mice generate LKM-1-like autoantibodies that largely recognize similar CYP2D6 epitopes than AIH-2 patients [66]. T cell epitope mapping revealed the presence of one CD4 and three distinct CD8 T cell epitopes [122]. Expectedly, these T cell epitopes are different from those recognized by AIH-patients due to the different MHC molecules [17]. However, it is interesting that the T cell epitopes are located in regions of intermediate homology between the triggering human CYP2D6 and the target mouse Cyp homologues. This indicates that molecular mimicry rather than identity was required to break Cyp-epitope-specific tolerance [122]. This conclusion is supported with data from experiments with human CYP2D6 transgenic mice, which upon infection with Ad-2D6, develop an ameliorated form of AIH-like disease only [121]. In particular, the frequency of CYP2D6-specific T cells is massively reduced in human CYP2D6 transgenic mice [122]. These initial data from the CYP2D6 model identify the liver autoantigen-specific T cells as one of the main drivers of the AIH pathogenesis. In addition, it serves a proof of principle that an infection with a pathogen that confers molecular mimicry to a liver autoantigen is indeed able to elicit a liver-specific autoimmune disease. However, although a transfer of autoantigen-specific TcR transgenic T cells or the liver-specific overexpression of a particular pro-inflammatory cytokine was not required, an infection with a liver-tropic pathogen (i.e. the adenoviral CYP2D6 carrier) was needed to generate an inflammatory milieu for the chronic autoimmune destruction to be initiated and/or propagated. A subcutaneous injection of recombinant CYP2D6 emulsified in complete Freund's Adjuvant was not sufficient to cause AIH-like disease even though CYP2D6-specific B and T cells were generated [122]. It has been postulated that human autoimmune diseases occur in susceptible individuals after exposure to one or more environmental factors. Besides pathogen infection or neoantigen formation by drugs and xenobiotics, obesity might also contribute to an inflammatory milieu in the liver. In particular, patients with NAFLD or NASH seem to be prone to providing a fertile field for subsequent autoimmunity. Indeed, when mice with NAFLD are infected with Ad-2D6 the ensuing AIH-like disease is exacerbated and NAFLD mice exhibit enhanced cellular infiltrations, augmented hepatic fibrosis and a higher frequency of autoreactive T cells [55]. Further, the CYP2D6 model has been used to elucidate mechanisms involved in the persistent fibrosis associated with AIH. Upon Ad-2D6 infection HSC get chronically activated resulting in an increased deposition of extracellular matrix components like collagen I and III and elevated expression of ╬▒SMA predominantly in and underneath the liver capsule but also in the perivascular region [123]. Thereby, the route of Ad-2D6 injection was decisive for HSC activation and fibrosis development. Whereas an intraperitoneal administration caused pronounced subcapsular fibrosis and clustering of inflammatory monocytes, intravenous administration resulted in the recruitment of an increased number of NK cells, which prevented chronic HSC activation and fibrosis [123]. Besides CYP2D6, the target of LC-1 antibodies, FTCD, has been also used in an adenovirus infection model. Hardtke-Wolenski et al. infected different mouse strains with either Ad-2D6 or Ad-FTCD and demonstrated that after an initial transient acute hepatitis a chronic AIH-like disease was evolving [124]. However, in contrast to the CYP2D6 model, the presence of a genetic predisposition for autoimmunity was required, since the development of chronic AIH could only be observed in the immune regulation deficient NOD mouse, but not in mice with a wildtype background such as C57BL/6 or FVB [124]. Another model that is based on pathogen infection has been reported by Aparicio et al. who infected wildtype C57BL/6 mice with the mouse hepatitis virus A59 (MHV). Interestingly, MHV-infected mice generated autoantibodies to fumarylacetoacetat hydrolase (FAH), [125]. FAH is predominantly expressed in liver and kidney and MHV-infected mice indeed displayed features of AIH, including hypergammaglobulinemia, elevated serum aminotransferases, hepatic cellular infiltrations and antibodies to other liver autoantigens. An additional stimulation by the synthetic peptide adjuvant PADRE (Pan HLA-DR binding epitope) exacerbated the MHV-induced AIH-like disease [125].