br Animal models transgenic models developing spontaneous AI
Animal models: transgenic models developing spontaneous AIH-like disease One of the most dramatic spontaneous AIH models is the NTxPD-1 −/− mouse. Such mice lack the programmed cell death 1 (PD-1) gene and are furthermore thymectomized (NT) . As in regular PD-1-deficient mice NTxPD-1 −/− mice lack a sufficient number of regulatory T LLY507 to maintain a normal T cell balance. The additional removal of the thymus resulted in the development of fatal AIH-like hepatitis characterized by T cell infiltrations into the liver parenchyma, a massive lobular necrosis, and the generation of ANA . Administration of dexamethasone (Dex) or splenectomy prevented the development of fatal AIH in NTxPD-1 −/− mice . However, whereas Dex did not prevent the production of aggressive T cells and Dex removal led to a relapse of AIH, splenectomy persistently reduced AIH-like disease indicating that the spleen is required for a continuous supply of aggressive T cells . The finding that blockade of CXCL9 suppressed the progression of fatal AIH in the NTxPD-1 −/− mouse by decreasing the frequency of CXCR3+ T cells in the liver , suggests that chemokines, such as CXCL9, are important in orchestrating T cell trafficking from the spleen to the liver. Another spontaneous model has been generated by using triple knock-out mice deficient in Tyro3, Axl, and Mer receptor tyrosine kinases involved in the negative regulation of TLR-mediated intracellular signaling pathways . In these mice an excessive TLR-dependent activation induces AIH-like disease characterized by persistently elevated serum aminotransferase levels, severe portal inflammation and piecemeal necrosis, and the generation of autoantibodies like ANA and SMA . This model is based on earlier findings that TLR3 activation results in the release of pro-inflammatory cytokines (IFN-α and TNF-α) that induce CXCL9 and CXCL10 expression, which are two key chemokines orchestrating T cell infiltration of the liver . A rather well-known knock-out line is the autoimmune regulator (Aire) deficient mouse. These mice have been used to identify mechanisms involved in the establishment of central tolerance in the thymus. Interestingly, Aire deficient humans and mice develop spontaneous autoimmune reactions against multiple target organs including the liver. In fact, patients with an Aire-deficiency, who suffer from autoimmune polyendocrine syndrome type 1 (APS-1), approximately 20% acquire AIH . In context with the generation of an AIH model, it is interesting that a subgroup of Aire-deficient mice displays AIH-like features including lymphoplasmatic and periportal infiltrates, elevated aminotransferases and generate autoantibodies to several liver-specific and unspecific antigens . Remarkably, the genetic background had a strong influence on the severity of AIH in Aire-deficient mice as AIH was less severe in mice with C57BL/6 background than in mice with a Balb/c background. Aire-deficiency in context with the autoimmunity-prone NOD/Ltj background was surprisingly also milder than in Aire −/− Balb/c mice . Similar to Aire-deficient mice, conditional Traf6ΔTEC mice lacking the E3 ubiquitin protein ligase TRAF6 specifically in the thymic epithelial cells (TEC) possess an impaired negative selection of T cells. In contrast to Aire-deficient mice, Traf6ΔTEC mice develop a rather narrow spectrum of autoimmune reactivity affecting predominantly the liver . They display histological and immunological features of human AIH, including interface hepatitis with cellular infiltrates of the liver parenchyma and the generation of ANA and anti-SLA antibodies [98,99]. Transfer of T cells isolated from Traf6ΔTEC mice into immunodeficient recipients also resulted in the development of AIH-like disease, indicating that without proper negative selection in the thymus aggressive T cells are released into the periphery that in the absence of additional peripheral regulatory mechanisms aggressively attack the liver .