Generating ag-specific human regulatory T-cells by TCR gene transfer for the treatment of rheumatoid arthritis.

Riddell, Victoria

Abstract

Rheumatoid Arthritis (RA) is a systemic autoimmune disease that develops when the immune system loses tolerance to self, resulting in effector cells erroneously causing joint damage. Despite advances in biological therapy there is currently no cure for RA. Regulatory T-cells (Tregs) can regulate a broad range of immune effector cells when specific antigens (Ag) activate them through their individual T cell receptors (TCR). Using retroviral gene transfer, Tregs can be modified to express a chosen disease-related TCR, producing an Ag-specific Treg population that can target and suppress inflammatory arthritis in murine models. In this study the aim was to validate a reproducible method of generating Ag-specific Tregs from human peripheral blood. The results of this research demonstrates the successful TCR transduction into isolated human Treg cells. This was achieved by completing the outlined objectives to optimise the transduction process and the isolation of Tregs from peripheral blood. By sorting on the CD4+CD25+CD127dim cell population, Tregs were isolated and the purity of the population demonstrated by the high percentage of FoxP3 expressing cells. The results further show that FoxP3 is maintained after the transduction process. It is now necessary to demonstrate the working functional capacity of the transduced Tregs using a robust antigen-specific suppression assay. With the future goal of transitioning this approach into a human clinical setting, the method requires further validation to prove a reproducible method of generating Ag-specific Tregs from human peripheral blood taken from RA patients. This has implications for the advancement for adoptive Treg therapy to treat RA and other autoimmune diseases and will highlight the necessity of considering treatments in the context of an inflammatory environment. It will be important to understand the nature of any defects in the Treg subsets and how these might be corrected.

Citation

Riddell, V. Generating ag-specific human regulatory T-cells by TCR gene transfer for the treatment of rheumatoid arthritis. (Thesis). Edinburgh Napier University. http://researchrepository.napier.ac.uk/Output/1532334

• Thesis Type: Thesis
• Deposit Date: Jan 25, 2019
• Publicly Available Date: Jan 25, 2019
• Keywords: Autoimmune Disease, Rheumatoid Arthritis, Treg Therapy,
• Public URL: http://researchrepository.napier.ac.uk/Output/1532334
• Contract Date: Jan 25, 2019
• Award Date: Nov 1, 2018