DNA Vaccination Breaks Tolerance for a Neo-Self Antigen in Liver: A Transgenic Murine Model of Autoimmune Hepatitis

Abstract

Understanding the pathogenesis of autoimmune hepatitis requires an animal model in which chronic progressive immune injury develops spontaneously or with minimal manipulations. The new transgenic mouse model proposed in this study is based on the hypothesis that infectious agents have the potential to initiate autoreactivity through molecular mimicry. A transgenic mouse expressing lymphocytic choriomeningitis virus nucleoprotein (NP) in a H-2b background developed liver injury when vaccinated with plasmids expressing NP as an intracellular or a secretory protein. Coinjection of plasmids coding for NP and IL-12 facilitated the induction of a Th1 phenotype as detected by a specific B lymphocyte response characterized by a predominance of IgG2 subclass anti-NP Abs. CTLs activated in peripheral lymphoid organs by DNA vaccination migrated to the periportal and lobular areas of the liver. Their presence was associated with a significant degree of cytolysis, as evidenced by elevated transaminases several weeks after immunization. As activated specific T lymphocytes proliferated in the periphery and caused cytolysis of target cells, this study suggests that autoimmune hepatitis can be triggered by molecular mimicry, and that local injury may not be essential to initiate autoreactivity in the liver.

Influence of genes, sex, age and environment on the onset of autoimmune hepatitis

“…Furthermore, work from Bowen et al [84] showed that specific T cells directed against a liver antigen are not properly activated if this antigen is uniquely expressed in the liver. A break of tolerance towards liver antigens could only be observed when the liver antigen was also expressed in the periphery [47,84,85] . In light of these results, both hepatotropic and non-hepatotropic viruses should be considered as potential triggering events leading to the development of an AIH, through release of autoantigens in a pro-inflammatory environment and/or by molecular mimicry between viruses and autoantigens.…”

“…In the TTR-nucleoprotein (NP) transgenic mouse, which expresses the lymphocytic choriomeningitis virus (LCMV) NP under the control of a liver-specific promoter, DNA vaccination with a plasmid coding for the LCMV-NP led to a liver-specific immune response and a progressive destruction of the hepatic parenchyma [85] . In this case, a molecular identity between the self-protein and the injected antigen was the triggering factor for AIH development.…”

Transient Expression of Transgenic IL-12 in Mouse Liver Triggers Unremitting Inflammation Mimicking Human Autoimmune Hepatitis

“…An extended strategy to mimic AIH in mice is based on the administration of Con A, which induces a strong and fast activation of hepatic lymphocytes (7,8). More relevant AIH animal models involve either the induction of an immune response against a specific liver Ag or the use of genetically modified animals expressing neoantigens, and in many cases also require the administration of adjuvants or the expression of immunostimulatory cytokines (9)(10)(11)(12). Alternatively, spontaneous hepatitis takes place in transgenic mice expressing IFN-g constitutively in hepatocytes, in programmed cell death 1 (Pd-1)-null animals subjected to neonatal thymectomy, in Tgf-b-deficient mice, and in mice with conditional deletion of the TNFR-associated factor 6 gene in thymic epithelial cells (13)(14)(15)(16)(17)(18)(19).…”

The CYP2D6 Animal Model: How to Induce Autoimmune Hepatitis in Mice

“…Alternatively, DNA-vaccination with plasmids encoding for target antigens, including CYP2D6 19 , is used to induce hepatitis. However, an additional vaccination with plasmids encoding for pro-inflammatory cytokines, such as IL-12, is required 20 . Unfortunately, with a few exceptions 15,20 hepatitis is only transient.…”