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  • In the early s Frank Chisari

    2019-07-08

    In the early 1990s, Frank Chisari's group generated transgenic mice expressing the hepatitis B virus surface antigen (HBsAg). An expression restricted to the liver was ensured by using a mouse albumin promoter. In order to break tolerance to HBsAg an adoptive transfer of activated T Thymoquinone from HBsAg-primed donor mice was required [101,102]. In this model, HBsAg-specific cytotoxic T-lymphocytes (CTL) triggered apoptosis of hepatocytes expressing HBsAg and released IFN-γ upon antigen encounter. However, the observed hepatic injury was only transient and resembled a delayed-type hypersensitivity reaction rather than human AIH [101]. These data indicated that inducing chronic autoimmunity in the liver might be more difficult than in other organs, such as the pancreas. Breakdown of tolerance to autoantigens in the β-cells of the islet of Langerhans can be easily achieved in models like the RIP-LCMV-GP mouse, which express the glycoprotein (GP) of the lymphocytic choriomeningitis virus (LCMV) in the β-cells. Upon infection with LCMV the mice develop T1D within 10–14 days [103,104]. Indeed, Ferber et al. demonstrated that a target autoantigen expressed solely on hepatocytes could lead to T cell tolerance by deletion, anergy, and receptor downregulation rather than autoimmunity [105]. They used, CRP-Kb mice that express the mouse MHC class I alloantigen H-2Kb under the inducible carbon-reactive protein (CRP) promoter and found that low levels of H-2Kb expression on hepatocytes induced tolerance to allogeneic skin grafts in CRP-Kb mice even when crossing CRP-Kb mice with mice that transgenically express H-2Kb-reactive TcRs [105]. These data are similar to the findings by Luth et al. that demonstrated that ectopic expression of MBP protects mice from MS-like disease by promoting the generation of MBP-specific regulatory T cells (see above) [74]. The model autoantigen H-2Kb has been further used to demonstrate that the tolerogenic milieu in the liver can only be broken by an additional strong cytokine burst. Limmer et al. used double transgenic TcRxAlb.Kb mice expressing H-2Kb in hepatocytes and a H-2Kb-specific TcR on T cells. Transient hepatic damage characterized by elevated serum aminotransferase levels and cellular infiltration of the liver was induced by either infecting the mice with the liver tropic pathogen L. monocytogenes, by transfer of tumor cells expressing both H-2Kb as well as IL-2 [106], or by repetitive injection of immunostimulatory CpG-rich oligodeoxynucleotides (CpG-ODN) triggering the innate immune system via TLR9 [107]. Interestingly, termination of CpG-ODN administration abrogated the disease indicating that a chronic inflammatory stimulus was required for the self-perturbation of autoimmunity [107]. A further model relying on the simultaneous expression of the target autoantigen H-2Kb in the liver and a H-2Kb-specific TcR on T cells was generated by Bertolino et al. In order to circumvent central tolerance, they used thymectomized Met-Kb mice that express H-2Kb under the metallothionein (Met) promoter. These Met-Kb mice were then engrafted with non-transgenic thymus and reconstituted with bone marrow from H-2Kb-specific TcR transgenic mice [108]. Such mice showed transient hepatitis with cellular infiltrates peaking at 3 to 5 weeks after bone marrow reconstitution. Interestingly, the number of H-2Kb-specific T cells was reduced in the periphery of Met-Kb mice compared to non-transgenic control mice indicating the presence of regulatory control mechanisms. Indeed, the authors could demonstrate that although hepatocytes expressing H-2Kb efficiently primed naïve CD8 T cells, they failed to promote survival signals, such as IL-2 and bcl-xl induced by CD28 interaction, resulting in T cell death by neglect [109]. Later, it has been found that in Met-Kb mice injected with T cells expressing H-2Kb-specific TcR structural changes occur in LSEC at the peak of the transient hepatitis, which are associated with an attenuation of the disease [110].