Revolutionizing Allogeneic Graft Tolerance Through Chimeric Antigen Receptor-T Regulatory Cells

Area of Science:

• Immunology
• Transplantation Biology
• Cell Therapy

Background:

• Organ transplantation faces challenges from graft rejection and immunosuppressant side effects.
• Chimeric antigen receptor (CAR) technology is being adapted for regulatory T cells (Tregs) to improve antigen-specific immunosuppression.
• Graft-versus-host disease (GvHD) is a significant complication after allogeneic transplantation.

Purpose of the Study:

• To systematically review the preclinical development of CAR-Tregs for promoting graft tolerance.
• To evaluate the efficacy of CAR-Tregs in suppressing GvHD.
• To identify challenges and future directions for CAR-Treg therapy in transplantation.

Main Methods:

• Systematic review following PROSPERO guidelines (CRD420251073207).
• Searched PubMed, Scopus, and Web of Science (2015-2024).
• Included 17 studies on CAR-Tregs in preclinical or in vivo transplant/GvHD models.

Main Results:

• CAR-Tregs demonstrated superior graft protection compared to unmodified Tregs.
• HLA-A2-specific CAR-Tregs improved graft survival and reduced inflammation in various transplant models.
• CD28 co-stimulation enhanced Treg function, but challenges like Treg exhaustion and persistence were noted. Synergistic effects with existing immunosuppressants were observed.

Conclusions:

• CAR-Tregs represent a promising strategy for targeted immunosuppression in allogeneic transplantation.
• Preclinical data support CAR-Treg potential, but optimization of CAR design and manufacturing is crucial for clinical translation.
• Further investigation into in vivo stability and overcoming Treg exhaustion is necessary.