Abstract

Current evidence indicates that Parkinson's disease (PD) involves T cell-mediated inflammation, which plays a fundamental role in promoting neuroinflammation and neurodegeneration in patients and animal models. These T cells are specific to alpha-synuclein-derived antigens, including nitrated alpha-synuclein (NalphaSyn). Here, we sought to develop an experimental immunotherapy for PD based on the generation of regulatory T cells (Treg) specific to NalphaSyn, using the chimeric antigen receptor (CAR) technology. Accordingly, we first obtained an antibody specific to human alpha-synuclein containing three nitrated tyrosine residues (3NY-halphaSyn), which displayed specific immunoreactivity in the serum of PD patients which correlated with the clinical score. Afterward, we generated CAR-Treg specific to 3NY-halphaSyn and tested them in two PD models involving human alpha-synuclein. The CAR-Treg therapy substantially inhibited the inflammatory T cell response specific to alpha-synuclein-derived antigens, neuroinflammation, neurodegeneration, and the motor decline. This preclinical study indicates that the CAR-Treg therapy represents a promising therapeutic strategy for treating PD patients.