Autoimmune Hepatitis: Progress from Global Immunosuppression to Personalised Regulatory T Cell Therapy

Abstract

Autoimmune hepatitis (AIH) is an immune mediated liver injury. The precise aetiology of AIH is still unknown but current evidence suggests both genetic and environmental factors are involved. Breakdown in peripheral self-tolerance, and impaired functions of FOXP3(+) regulatory T cell along with effector cell resistance to suppression at the tissue level seem to play an important role in AIH immunopathogenesis. AIH is predominantly a T lymphocytes driven disease but B lymphocytes are also involved in the immunopathology. Innate immune cells are crucial in the initial onset of disease and their response is followed by adaptive T (Th1, Th17, and cytotoxic T cells) and B cell responses evidenced by liver histology and peripheral blood serology. Standard treatment regimens involving steroid and immunosuppressive medications lead to global immune suppression requiring life-long therapy with many side effects. Biologic therapies have been attempted but duration of remission is short-lived. Future direction of diagnosis and treatment for AIH should be guided by "omics" and the immunology profile of the individual patient and clinicians should aim to deliver personalised medicine for their patients. Cell therapy such as infusion of autologous, antigen-specific, and liver-homing regulatory T cells to restore hepatic immune tolerance may soon be a potential future treatment for AIH patients.

Figure 1

Pathogenesis of autoimmune hepatitis. Both effector T cells (CD4, CD8) and regulatory T cells (Treg) are recruited to inflamed autoimmune hepatitis liver via hepatic sinusoids. T effector cells lead to apoptosis of hepatocytes via CD95 ligand (dead ligand) expressed on them, which binds to CD95 on the hepatocytes. This killing action of T effector cells is regulated by regulatory T cells, which suppress proliferation and cytokine secretion of effector T cells. Plasma cells are also involved in immune-pathogenesis and they secrete immunoglobulin. Liver infiltrated T effector cells consist of Th17, Th1, and cytotoxic T cells. Th1 cells express T bet transcription factor; Th17 cells express transcription factor RORc. Cytotoxic T cells secrete IFN, TNF, granzymes, and perforins. Regulatory T cells (Treg = CD4CD25^highCD127^low) express liver tissue homing chemokine receptor CXCR3, which binds to its ligands CXCL9-11 expressed on inflamed hepatic sinusoid, hepatocytes, and bile ducts. Treg also expresses its functional markers CTLA4 (interacting with CD80/CD86 on dendritic cells). Dendritic cells secrete chemokine CCL22, which attracting chemokine receptor CCR4 expressing regulatory T cells. CD39 on the Treg can generate immunosuppressive adenosis from ATP in the hepatic microenvironment. IL-2, which acts on its receptor CD25, is crucial for intrahepatic Treg survival and function. TCR: T cell receptor.

Figure 2

Current stepwise treatment algorithm of autoimmune hepatitis. Aza: azathioprine, 6-TGN: 6-thioguanine, MRCP: magnetic resonance cholangiopancreatography, IL: interleukin, MMF: mycophenolate mofetil, and 6-MP: 6-mercaptopurine.

Figure 3

Metabolism of azathioprine. Aza: azathioprine; 6-MP: 6-mercaptopurine; TPMT: thiopurine methyltransferase; 6-MMP: 6-methylmercaptopurine; 6-TU: thiouric acid; 6-TG: 6-thioguanine; HPRT: hypoxanthine phosphoribosyl transferase; 6-TGN: thioguanine nucleotide; GMPS: guanosine monophosphate synthetase; 6-TXMP: 6-thioxanthosine monophosphate; IMPDH: inosine-5′-monophosphate dehydrogenase; 6-MMPR: 6-methyl-mercaptopurine ribonucleotide; 6-TIMP: thioinosine monophosphate.

Figure 4

A diagram of regulatory T cell therapy in autoimmune hepatitis. Patients with autoimmune hepatitis undergo leukapheresis followed by isolation of highly pure, autologous, GMP grade, functional CD4 and CD25^highCD127^low regulatory T cells followed by expansion with clinical grade expander beads, IL-2, and rapamycin. These cells can be tested for their purity and stability with flow cytometry and TSDR analysis before infusing back to AIH patients.