Regulation of the activation status in T effector cells in blood and livers of patients with autoimmune hepatitis (AIH)

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Autoimmune hepatitis (AIH) is a chronic inflammatory, progressive liver disease. Fatal liver damage can only be prevented by lifelong, non-selective immunosuppression which is associated with serious side effects. The pathogenesis of AIH is unknown, however, it is assumed that liver damage is promoted by proinflammatory T effector cells. It remains contentious why and how proinflammatory T effector cells are able to defy immune regulation. Our preliminary studies have shown a significantly lower expression of the regulating E3-ligase Cbl-b in CD4 positive T cells of AIH patients compared to healthy controls. These results might explain the impaired immune homeostasis of AIH patients and provide novel selective treatment options. This study aims at analysing the regulation of the activation status in T effector cells from patients with AIH. Our hypothesis is that AIH is associated with a dysbalanced regulation of T cell activation. To test this hypothesis, we will analyse relevant E3-ligases, such as Cbl-b, as well as co-stimulatory and co-inhibitory molecules, and correlate these with the proinflammatory activity of T effector cells. Moreover, we plan to assess the influence of anti-TNFalpha treatment on the activation status of T effector cells. The obtained findings will be validated for specific T cell responses to AIH-related antigen. The results of the project should help to clarify the pathogenesis of AIH and provide novel, more specific treatment options avoiding the side-effects of the standard treatment.