T cells expressing chimeric antigen receptor promote immune tolerance

Area of Science:

• Immunology
• Transplantation immunology
• Cellular therapy

Background:

• Cellular therapies using genetically modified T cells show promise for cancer treatment.
• The potential of modifying T cell subsets, like regulatory T cells (Tregs), for allograft transplantation remains largely unexplored.

Purpose of the Study:

• To investigate the efficacy of transiently modifying Tregs with a chimeric antigen receptor (CAR) system for allograft transplantation.
• To assess the ability of these modified Tregs to target allografts and modulate immune responses in vivo.

Main Methods:

• Development of a modular CAR system (mAbCAR) enabling Treg targeting via covalently modified monoclonal antibodies (mAbs).
• Transient expression of mAbCAR in Tregs for in vivo administration.
• Evaluation of Treg targeting to MHC class I proteins on allografts.
• Assessment of allograft survival, including islet and secondary skin grafts, and graft-versus-host disease (GvHD).

Main Results:

• Transient mAbCAR expression in Tregs facilitated targeted delivery to specific tissue sites.
• mAbCAR Tregs effectively mitigated allograft responses, including GvHD.
• Targeting of mAbCAR Tregs to MHC class I proteins on allografts significantly prolonged islet allograft survival.
• Survival of secondary skin grafts matched to the original islet allograft was also extended.

Conclusions:

• Transient genetic modification of Tregs to express mAbCAR provides durable immune modulation for allograft transplantation.
• This strategy offers a novel therapeutic approach for controlling alloreactivity in organ and tissue transplantation settings.