Autoantigen-specific regulatory T-cells: a new tool for tolerance induction in autoimmune hepatitis
Lead Research Organisation:
King's College London
Department Name: Gene and Cell Based Therapy
Abstract
CD4+CD25+ regulatory T-cells (T-regs) control immune system over-reaction. Autoimmune hepatitis (AIH) is a severe liver disorder, affecting children and adults, whose immune system attacks components of the liver having failed to recognise them as self. AIH is seen six-fold more frequently in children referred to our specialised centre than 10 years ago. Patients with AIH need life-long immunosuppression, despite which they often progress to transplant-requiring end-stage liver disease. In AIH T-regs are impaired in number and function. These cells can, however, be expanded and their function boosted in the test tube, thus providing a potential therapeutic option to halt the autoimmune attack. I plan to investigate complementary approaches to generate and expand functional T-regs from AIH patients in the laboratory to obtain them in sufficient numbers to be used as a novel and more specific mode of treatment. The safety of these cells will be tested in mice. The information obtained will be important not only for AIH, but also for other disabling autoimmune disorders, collectively representing 5% of human disease. All facilities required for the clinical application of this project are available within the KCL Division of Gene and Cell based Therapy at King‘s College Hospital.
Technical Summary
Autoimmune hepatitis (AIH) is a severe liver disorder requiring life-long immuno-suppressive treatment, which may cause serious side-effects and despite which transplant-requiring end-stage liver disease may occur. Due to its frequently acute presentation, AIH offers the unique opportunity to follow the evolution of liver damage from the very onset to cirrhosis and/or transplantation.
The involvement of autoreactive B, CD4 and CD8 T-cells in AIH is well documented with the three arms of the immune response converging on discrete antigenic regions. We have provided evidence that this multipronged immune attack is associated to a numerical and functional impairment of regulatory CD4+CD25+ T-cells (T-regs), a cell subset central to immune-tolerance. Though functionally inefficient, T-regs from patients with AIH can expand in number and augment their suppressor function when exposed to high dose interleukin-2 and anti-CD3/anti-CD28 T-cell expander. T-regs expanded for up to 4 weeks maintain phenotypic characteristics of the original T-regs, such as the forkhead-winged helix transcription factor BOX P3 (FOXP3) and suppress much more efficiently than freshly isolated T-regs. Using the same approach I also succeeded in obtaining T-regs from CD4+CD25- T-cells, a subset mainly composed of effectors, but also including a proportion of cells with regulatory potential. T-reg ability to expand and to suppress has been mainly investigated in a non-antigen-specific setting. There is evidence, and I have supporting preliminary data, that antigen-specific suppress more efficiently than non-antigen-specific T-regs. AIH provides an ideal model for the generation and potential therapeutic use of antigen-specific T-regs, as the autoantigenic targets are known. Using different approaches I propose to generate and expand antigen-specific T-regs from CD4+CD25+ and CD4+CD25- T-cells. The goal is to generate and expand cells with therapeutic potential due to their ability of delivering suppressive signals to effectors of the autoimmune attack. I will investigate whether T-regs maintain their functional commitment over time. To this end I will focus on a subset of T-regs expressing the ecto-enzyme CD39, a molecule recently proposed as marker of T-reg ‘stability‘. As a first step towards clinical application, I will test the safety of patients-derived antigen-specific T-regs following injection into NOD/SCID/gamma mice and I will evaluate their survival in vivo. If successful, this study would provide proof-of-principle for the feasibility of tolerance induction not only in AIH but also in other autoimmune disorders, collectively representing 5% of the human disease.
The involvement of autoreactive B, CD4 and CD8 T-cells in AIH is well documented with the three arms of the immune response converging on discrete antigenic regions. We have provided evidence that this multipronged immune attack is associated to a numerical and functional impairment of regulatory CD4+CD25+ T-cells (T-regs), a cell subset central to immune-tolerance. Though functionally inefficient, T-regs from patients with AIH can expand in number and augment their suppressor function when exposed to high dose interleukin-2 and anti-CD3/anti-CD28 T-cell expander. T-regs expanded for up to 4 weeks maintain phenotypic characteristics of the original T-regs, such as the forkhead-winged helix transcription factor BOX P3 (FOXP3) and suppress much more efficiently than freshly isolated T-regs. Using the same approach I also succeeded in obtaining T-regs from CD4+CD25- T-cells, a subset mainly composed of effectors, but also including a proportion of cells with regulatory potential. T-reg ability to expand and to suppress has been mainly investigated in a non-antigen-specific setting. There is evidence, and I have supporting preliminary data, that antigen-specific suppress more efficiently than non-antigen-specific T-regs. AIH provides an ideal model for the generation and potential therapeutic use of antigen-specific T-regs, as the autoantigenic targets are known. Using different approaches I propose to generate and expand antigen-specific T-regs from CD4+CD25+ and CD4+CD25- T-cells. The goal is to generate and expand cells with therapeutic potential due to their ability of delivering suppressive signals to effectors of the autoimmune attack. I will investigate whether T-regs maintain their functional commitment over time. To this end I will focus on a subset of T-regs expressing the ecto-enzyme CD39, a molecule recently proposed as marker of T-reg ‘stability‘. As a first step towards clinical application, I will test the safety of patients-derived antigen-specific T-regs following injection into NOD/SCID/gamma mice and I will evaluate their survival in vivo. If successful, this study would provide proof-of-principle for the feasibility of tolerance induction not only in AIH but also in other autoimmune disorders, collectively representing 5% of the human disease.