T-cell receptor- and anti-inflammatory gene-modulated T cells as therapy for autoimmune disease

Abstract

Antigen-specific immunotherapy is a future therapy that could achieve high efficacy with limited adverse effects. Although T cells are essential components in antigen-specific immunity, we do not have a practical strategy for manipulating antigen-specific T cells. We propose here that T-cell receptor (TCR) gene transfer is an effective approach for antigen-specific immunotherapy. We have confirmed the efficacy of TCR gene therapy in animal models of systemic autoimmune disease and arthritis. In lupus-prone NZB/W F1 mice, nucleosome-specific TCR and CTLA4Ig-transduced cells suppressed autoantibody production and nephritis development. In the therapeutic experiment of collagen-induced arthritis, arthritis-related TCRs were isolated from single T cells accumulating in the arthritis site. With this TCR, we demonstrated two applications of the TCR-transduced T cells. First, this arthritis-related TCR and the TNFRIg-transduced cells suppressed arthritis as a vector for therapeutic molecule. Second, arthritis-associated TCR and Foxp3-transduced cells suppressed arthritis progression and bone destruction as antigen-specific regulatory T cells. Therefore, engineered antigen-specific cells manipulated to express appropriate functional genes could be applied to specific immunotherapy.

Keywords::

• antigen-specific T cell
• autoimmune disease
• gene transfer
• T-cell receptor

Financial & competing interests disclosure

This work was supported by grants from the Japan Society for the Promotion of Science, Ministry of Health, Labor and Welfare and the Ministry of Education, Culture, Sports, and Science and Technology of Japan. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.