Immunoregulation And Immunointervention in Transplantation and Autoimmunity
Sophie Conchon
Research Scientist

Research Associate INSERM

The liver plays a unique role in immune regulation, striking a delicate balance between tolerance and immunity. It is continually exposed to endotoxins and products of microbial degradation coming directly from the gut via the portal vein. The liver is also important in detoxification. These processes can lead to persistent inflammation, autoimmune disease and/or cancer. The liver is also regarded as a site of unique immune privilege and immune tolerance, particularly in the context of transplantation. Liver transplant patients can develop operational tolerance, defined as the maintenance of stable graft function with no harmful immune responses in the absence of immunosuppressive therapy. The projects we develop focus on the liver immune system with applications in cancer immunotherapy, autoimmunity and allogeneic tolerance induction.

Keywords: liver, hepatology, immunology, immunotherapy, gene transfer, tolerance.

Description

Projects

1. Immunotherapy for the treatment of hepatocellular carcinoma (HCC).

Immunotherapy is a promising strategy for the treatment of HCC, especially as an adjuvant treatment to reduce the recurrence risk after local treatment. We have developed murin models of HCC, which are highly relevant to the human pathology.

  • We have shown that, in chemically-induced HCC in mice, immunization with a synthetic vector encoding alpha-fetoprotein (AFP) achieved a 65% reduction of the tumour growth, demonstrating for the first time that AFP was indeed a good tumour-associated antigen (TAA) for HCC (Cany J. et al, J Hepatol 2011). We are involved in the preclinical optimisation and validation of the synthetic vector, which consists in the association of a plasmid DNA encoding the TAA with the polymer ICA614 (In Cell Art, Nantes), to hopefully bring it into the clinics in the near future.
  • We also investigate non-specific immunotherapy strategies for the treatment of HCC. We have demonstrated that the stimulation of the natural anti-tumour immune response by a monoclonal antibody targeting CD137 (4-1BB, member of the TNF receptor family) led to a significant therapeutic response (Gauttier V. et al, Int J Cancer, 2014). However we showed that in mice that did not respond to this treatment, HCC progression was accompanied by an increased infiltration by myeloid derived suppressor cells. We are now investigating strategies to control these cells, by targeting the SIRP-α pathway, in collaboration with Team #3 of the CRTI and with OSE Immunotherapeutics.

2. Autoimmune hepatitis : Identification of blood biomarkers and functional characterization of immune cells potentially involved in the pathogenesis.

Autoimmune hepatitis (AIH) is a rare disease characterized by an immune attack of the liver parenchyma, leading to high levels of aminotransferases, hypergammaglobulinemia, production of autoantibodies and interface hepatitis. Patients with AIH receive corticosteroid therapy, which is not always effective. Since 2015 we have established a biobank of blood samples and biospies from more than 150 patients with HAI followed at the Department of hepato-gastroenterology of Nantes Hospital (Dr J. Gournay), associated with a detailed clinical database. Our aim is to identify markers that could help clinicians in their management of the patients, and to identify immune cells that could be involved in the pathogenesis. We have recently shown in an extensive multiparametric flow cytometry analysis that compared to healthy controls, patients with AIH have an altered blood immune phenotype, which persist despite treatment (Renand et al, Hepatol Comm, 2018).

We have now focused our studies on a particular subset of cells which plays a key role in the pathogenesis : the self-antigen-specific CD4+ T lymphocytes. Single cell RNAseq, combined with TCR seq, functional assays and flow cytometry are on-going to decipher the signature and mechanisms of action of these cells in liver autoimmune diseases (project DISTAL, ANR2019).

3. Liver immune tolerance and allogeneic transplantation

The liver has specific immunological properties as demonstrated by the high incidence of liver transplanted patients who become tolerant to their allograft. These patients can stop their immunosuppressive treatment while maintaining a stable graft function. Tolerogenic properties of the liver involve both immune cells and hepatocytes.

Our aim is to decipher the cellular and molecular mechanisms of this tolerance and to develop tools to predict and to induce tolerance to allogeneic transplantation of organs or cells. Recently, two main projects have been undertaken:

  • Analysis of blood immunophenotype and transcritpome in patients with combined liver-kidney transplantation (Dumontet E et al, Liver Int. 2016).
  • A second project is to develop an innovative strategy of allogeneic tolerance induction by “hijacking” the tolerogenic properties of the liver. Research in the field of gene therapy has demonstrated for several years that gene transfer to the liver could induce tolerance toward the product of the transgene, be it a model or a therapeutic protein. We have recently extended this concept to the hepatic expression of an allo-antigen, in order to induce tolerance to a fully allogeneic graft. We have shown that the adeno associated virus (AAV)-mediated transduction of the liver of mice (H-2b, C57BL/6) allows the long-term expression of an allogeneic MHC class I molecule H-2Kd. More than 40% of these mice tolerated a transplantation of fully allogeneic pancreatic islets (H-2d, BALB/c). Mechanistically, we have demonstrated the expansion in the liver of a population of CD8+ regulatory T lymphocytes instrumental to the induction of tolerance (Le Guen V et al, J Hepatol, 2017). Our current work consists in the characterization of these liver CD8+ Treg cells at a transcriptomic level, and in testing the robustness of the tolerance induced.

 

Related publications

  • Cany J, Barteau B, Tran L, Gauttier V, Archambeaud I, Couty JP, Turlin B, Pitard B, Vassaux G, Ferry N & Conchon S. AFP-specific immunotherapy impairs growth of autochthonous hepatocellular carcinoma in mice. J Hepatol 2011, 54 : 115-121.
  • Gauttier V, Judor J-P, Le Guen V, Cany J, Ferry N and Conchon S. Agonistic anti-CD137 antibody treatment leads to anti-tumour response in mice with liver cancer. Int J Cancer 2014, 135: 2857–2867
  • Dumontet E, Danger R, Vagefi P, Londoño M, Pallier A, Lozano JJ, Giral M, Degauque N, Soulillou JP, Martinez-Llordella M, Latournerie M, Boudjema K, Dulong J, Tarte K, Sanchez-Fueyo A, Feng S, Brouard S*, Conchon S*. Peripheral phenotype and gene expression profiles of combined liver kidney transplant patients. Liver Int 2016, 36(3):401-409.
  • Le Guen V, Judor JP, Boeffard F, Gauttier V, Ferry N, Soulillou JP, Brouard S, Conchon S. Alloantigen gene transfer to hepatocytes promotes tolerance to pancreatic islet graft by inducing CD8+ regulatory T cells. J Hepatol, 2017, 66 : 765-777.
  • Renand A, Habes S, Mosnier J-F, Aublé H, Judor J-P, Vince N, Hulin P, Nedellec S, Métairie S, Archambeaud I, Brouard S, Gournay J, Conchon S. Immune alterations in patients with type 1 autoimmune hepatitis persist upon stansard immunosuppressive treatment. Hepatol Comm 2018, 2 : 968-981.