Title: Assessment of Treg function, CD28 costimulation and immune dysregulation in autoimmune liver diseases.
Funder: The Academy of Medical Sciences

Abstract: The aetiopathogenesis of autoimmune liver diseases (AILDs) remains obscure and current treatments are of limited efficacy or associated with adverse events, hence understanding the underlying mechanisms of disease and identification of novel treatment targets is a priority. Genetic and functional studies have linked the CD28 T cell costimulation pathway with autoimmune disorders and specifically with this group of liver diseases. We have recently demonstrated unique differences in the roles of CD80 and CD86, which are the ligands for the CD28 pathway and were previously considered redundant. Preliminary data suggests that there is altered expression of these ligands in the liver of patients with autoimmune hepatitis, and we hypothesise that excess stimulatory CD28 activity may be associated with AILDs. Furthermore, we propose to study the functional interactions between the ligands of CD28 and inhibitory PD1 pathways (particularly CD80 and PD-L1), components of which are highly expressed in the liver. In this study, we will characterise the phenotype and function of immune cells isolated from liver tissue from patients with AILDs, in comparison with healthy liver, to assess the contribution and function of the CD28 pathway in these diseases. We will identify the physical interactions of relevant cell types using immunohistochemical approaches on archived patient liver biopsies and establish multiplex immunohistochemistry to immunophenotype cells in situ in the liver environment. There is direct translational potential from this work as CD28 pathway modulation represents a potential, as yet untried, treatment target in AILDs.

Lay abstract: Autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cholangitis are three liver diseases which can lead to death or liver transplantation. The causes of these diseases are not well understood, although the immune system, which normally fights infections, appears to cause tissue damage. We are interested in a pathway called CD28, which switches on immune cells that can cause tissue damage. Genetic studies in these liver diseases show an association with the CD28 pathway. We have data suggesting that components of the CD28 pathway are altered in the livers of patients with AIH. We propose to investigate whether excessive CD28 activity or failure of control mechanisms is involved in the above diseases. We will test if this is true by extracting immune cells from samples of liver tissue and testing the levels of each component of this pathway and the activity of the regulatory cells (which normally switch off immune responses and limit CD28). Examining samples from patients we will use microscopes to look at the total levels, physical interactions and distribution of cells important in this pathway. Lastly, we will exploit a powerful new microscopy technique to measure several components of this pathway at the same time in cells within patient’s tissues. If we demonstrate CD28 overactivity there are specific treatments that could be applied to these conditions.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM