Alpha-synuclein peptides presented on chimeric MHC class Ib molecules prevent loss of substantia nigra neurons in an animal model for Parkinson’s disease

Abstract

Abstract Aim An accumulating body of evidence suggests the involvement of alpha-synuclein (aSyn) specific autoreactive T cells in Parkinson’s disease (PD). Here, we investigate whether novel antigen-specific tolerance-inducing biomolecules, that present peptide antigens on MHC class Ib-related molecules, can inhibit neurodegeneration and prevent PD in vivo. Methods The alpha3 domain of the human MHC class Ib molecule HLA-G inhibits T cells via the human ILT-2 or the murine PIRB receptor. We fused this HLA-G alpha3 domain to MHC class I alpha1-alpha2 antigen presenting domains, antigenic peptides and beta2-microglobulin. These single-chain AutoImmunity Modifying Biologicals (AIM Bios) induce antigen-specific tolerogenic CD8+ Treg cells in human cells in vitro and in mice in vivo. We used this platform to prevent autoimmune disease symptoms in mouse models for autoimmune diseases, including an aSynA53T-AAV driven model for PD. Results Single-chain model AIM Bios with MHC-derived antigen-presenting domains and antigenic peptides polarize cognate CD8+ T cells towards a CD8+CD122+ IL-10 secreting Treg phenotype. Such antigen-specific Treg can also be induced in mice in vivo. Disease-associated aSyn CD8+ epitopes were identified in aSynA53T-AAV PD mice. Corresponding AIM Bios prevented mobility impairments. Post mortem histopathological assessment confirmed the induction a favorable in-situ immune cell composition and the rescue of substantia nigra neurons. The translational potential of this approach deserves further exploration. Supported by grants from the IZKF Wuerzburg A421 and by Aeterna Zentaris Inc.