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  • br Animal models As mentioned beforehand an

    2019-07-08


    Animal models As mentioned beforehand an ideal experimental model system would be as close as possible to the human disease. However, mice that are predominantly used to model human autoimmune diseases often do not share the same target autoantigens and in particular due to differences in the MHC class I and II molecules the specificity of the T cell response is different in mouse and men. Table 1 provides a summary of the most important features of human AIH and a listing of how these features have been reproduced in the collectivity of animal models generated. The individual models are described in detail in the following paragraphs and in Table 2. Naturally, none of the listed models perfectly reflects the human situation. However, as discussed below some models are better suited to investigate basic mechanisms of immune activation and/or regulation and some are more likely to help assessing novel therapies. In addition, it is important to realize whether a given model reproduces an acute or a chronic form of hepatic destruction. Naturally almost all animal models have been heavily influenced by observations made in AIH patients. Fig. 1 provided a rough summary of the most important players in the immunopathogenesis of human AIH. Since there is no firm proof for one or more environmental factors to be involved in the initiation and/or propagation of the disease, only descriptive observations at or after diagnosis of the disease are being considered. There are several important issues: First, several forms of autoantibodies against antigenic targets in the liver are generated and some of which are used as diagnostic tools. However, a direct pathogenicity of such SCH 58261 has not been demonstrated to date. Second, assessment of serum inflammatory factors has revealed that many soluble pro-inflammatory factors, such as chemokine and cytokines, as well as pro-fibrotic are elevated in AIH-patients. Third, a disturbed balance of the immune system has been detected with elevated levels of type 1 (Th1/Tc1) and type 3 (Th17/Tc17) T cell subtypes. Critical inflammatory factors may certainly constitute possible targets for immune intervention. Thus, to be able to evaluate therapies, such as a specific blockade of a critical cytokine, the corresponding inflammatory factor or cell population should also play a crucial role in the pathogenesis of AIH-like disease in the model system.
    Animal models: pre-transgenic area Systemic application of Concanavalin A (ConA) is another method for inducing liver injury in mice that is frequently used since the early 1990s and leads to antigen non-specific T cell activation and severe acute hepatitis [83]. The Jack bean lectin ConA causes a cytokine storm with high levels of IFN-γ and TNF-α that is amplified by an interaction between lymphocytes and macrophages and subsequently ensues inflammatory lesions, hepatocyte apoptosis, and fulminant hepatic failure [[84], [85], [86]]. Interestingly, the T cell mitogenic power of ConA is strong enough to effectively arm the T cell compartment to successfully oppose hepatoma in a murine model [87]. The pathogenesis of ConA hepatitis has been elucidated in great detail. For example, using CD1d-deficient mice that are lacking NKT cells, it has been demonstrated that NKT cells are essential for ConA-induced liver injury [88]. However, although the ConA-hepatitis model is a reliable model to investigate aspects of immune system-mediated liver damage, it represents more of a model for acute liver injury precipitated by a liver autoantigen-independent cytokine storm rather than a model of chronic AIH. Anyhow, it has been also used to evaluate possible therapies for human AIH. Very recently for example, Park et al. investigated the anti-inflammatory effect of the traditional Korean herbal medicine Yongdamsagan-tang (YST), which is essentially a mixture of several root extracts [89]. They found that YST reduced IL-6 production and blocked the expression of several factors important for hepatic fibrosis, such as TGF-β1, collagen I, and α-smooth muscle actin (α-SMA) and that treatment of mice with YST before administration of ConA protected from hepatic damage [89]. It has to be noted here that other herbal extracts, such as a medicinal herbs mixture containing Scutellaria baicalensis (Sb) and Bupleurum chinese (Bc) that have been sporadically reported to be associated with liver fibrosis, can induce rather than protect from AIH [90]. Repetitive intraperitoneal injection of Sb and Bc for up to 8 weeks resulted in hepatic damage, with moderately elevated serum aminotransferase levels, hypergammaglobulinemia, generation of ANA, as well as appearance of clusters of cellular infiltrates in the liver [90]. It might very well be that herbal toxins are causing moderate but continuous damage to the liver and thereby initiate an inflammatory milieu that promotes chronic AIH-like disease.