Framework of current positioning
A growing number of individuals are diagnosed with autoimmune diseases including type-1 diabetes, multiple sclerosis, lupus. Almost 10% of the general population is affected by an autoimmune disease or disorder, which is caused by a deregulated reaction of the immune system against self. Use of immunosuppressors to lessen the strength of the self-directed immune reactions has been a real step forward in the treatment of autoimmunity. However, immunosuppressive treatments constitute a risk factor for the development of malignancies or infections, do not cure autoimmunity and have important side effects. In this context, the development of new therapeutic strategies to fight more specifically against autoimmunity has become a priority. These strategies aim at restoring a state of tolerance of the patient’s immune system. The immunological cell population with regulatory functions (Tregs) play a key role in the control of the self-reactivity. Tregs and the other T cell populations arise from the differentiation of thymocyte precursors in the thymus. This differentiation is driven by the interactions with thymic epithelial cells (TECs). The main objective of the ThymiPS project is 1/ to differentiate human iPS into mature TECs that are able to promote a functional thymocyte differentiation, 2/ to use iPS-derived TECs to restore, as a proof of concept, a tolerant immune system in a rat-model of autoimmunity.
Proposal objectives
In this proposal, we will generate functional TECs in-vitro and evaluate their capacity to generate functional antigen-specific T cells, including Tregs, capable to restore immunodeficiency and alleviate autoimmunity.
The main objectives are to:
· differentiate human iPS cells into TECs in-vitro
· demonstrate that the generated TECs ensure a proper thymocyte differentiation and function
· show that iPS-derived rat TECs can alleviate autoimmune manifestations once grafted in Aire-KO rats.
Expected results
Completion of this project will represent a major achievement and will pave the way for use of iPS cells to regenerate and transplant functional thymocytes to restore immunity in immunodeficient patients or tolerance in patients with autoimmune disease. The main expected results are:
· Identification of a protocol to differentiate human iPS into functional TECs in vitro
· iPS-derived TECs drive the differentiation of thymocytes that are functional in vivo
· The generated TECs can alleviate autoimmune manifestations after transfer in vivo.
Methodology
The ThymiPS project uses state-of-the-art techniques and takes advantage of the complementary expertise of the main partners: immunology, stem cell research, molecular biology and animal experimentation.
· Culture and differentiation of pluripotent stem cells
· Characterization of the thymocyte differentiation inducted by the regenerated TECs
· Animal models