Deciphering the self-antigen specific T cell signature of autoimmune liver diseases – DISTAL

There are three major autoimmune liver diseases (AILD): autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Around thirty thousand persons are affect by one of the three AILD in France with three thousand new cases per year. They are characterized by an immune attack of the hepatocytes, the intrahepatic bile ducts and the extrahepatic bile ducts, respectively. A strong genetic association of AILD with class II HLA genes in the Major Histocompatibility Complex (MHC) is observed, and specific and non-specific autoantibodies are present and used for diagnosis. The class II HLA gene predisposition and the presence of autoantibodies targeting specific self-antigens are consistent with the hypothesis of a central pathogenic involvement of self-antigen-specific CD4 T lymphocytes in AILD pathogenesis.

However, the specific signature and role of autoreactive CD4 T cells are poorly understood in AILD. In general, identification and characterization of autoreactive CD4 T cells remain difficult in patient’s blood. There is also an enormous need for innovative treatment and for biomarker to help clinicians in the management of these diseases. Although AIH patients have a good response to immunosuppressive (IS) treatment (corticosteroids and azathioprine), the risk of relapse upon treatment withdrawal is high (>60%). For PBC and PSC no efficient IS treatment exists and non-response to the standard treatment is linked to poor outcome. Moreover, it is difficult to predict clinical outcome at presentation, upon treatment and before complete withdrawal.

The main objective of the DISTAL project is to establish the molecular signature of autoimmune self-antigen-specific T cells in AILD, with three aims:
1- to get new insights into the mechanisms of autoimmunity in the liver,
2- to use autoreactive T cells as new targets for the development of specific therapeutic strategies, as alternative to the non-specific IS treatments,
3- to identify an immune biomarker to help clinicians in their management of patients with AILD.

To fulfill these ambitious goals, three tasks will be undertaken, based on original preliminary results.
In Task#1 we will establish the molecular atlas of autoreactive CD4 T cells from the blood of AILD patients, at the single-cell level, to characterize their transcriptional profile;
Task#2 will identify the peptide sequences of the dominant T cell epitopes from liver self-antigens, to track autoreactive T cells in patients and to develop future personalized peptide-immunotherapy;
Task#3 will identify a clinically relevant “autoimmune T cell signature” in the blood of patients to be used for diagnostic and prognostic assessment of AILD.

This original project will benefit from our access to a bio-collection (Bio-HAI, CHU-Nantes) of AILD blood and liver samples unique in France (more than 140 patients to date), the HEPATIMGO network (8 hospitals in the Western part of France: Angers, Brest, La Roche Sur Yon, Nantes, Orléans, Poitier, Rennes, Tours), the capacity to identify self-antigen specific memory CD4 T cell by the in vitro restimulation assay developed in the lab by Dr. Amédée RENAND (CRTI, Nantes) and from the recent development of a novel state-of-the-art integrative single-cell RNAseq (scRNAseq) method to analyze autoreactive CD4 T cells at the single-cell level (P. MILPIED, CIML, Marseille).
The impact of the DISTAL project is high and has the ambition to: 1)-identify immune biomarkers to facilitate patients’ stratification (risk of non-response to treatment, risk of relapse); 2)-understand the role of immune cell subsets in the pathogenesis of the disease; and 3)-characterize self-antigen specific CD4 T cells and the epitopes they recognize, to serve as a basis for the development of an innovative personalized therapy, as an alternative to non-specific immunosuppression.