Expansion of regulatory T cells by CD28 superagonistic antibodies attenuates neurodegeneration in A53T-α-synuclein Parkinson's disease mice

• Published in: Journal of neuroinflammation 2022-12, Vol.19 (1), p.319-319, Article 319
• Main Authors: Badr, Mohammad, McFleder, Rhonda L, Wu, Jingjing, Knorr, Susanne, Koprich, James B, Hünig, Thomas, Brotchie, Jonathan M, Volkmann, Jens, Lutz, Manfred B, Ip, Chi Wang
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - metabolism; Animals; Antibodies - pharmacology; CD28 Antigens; CD8-Positive T-Lymphocytes - metabolism; Disease Models, Animal; Dopamine; Dopaminergic Neurons - metabolism; Humans; Mice; Mice, Inbred C57BL; Neuroinflammation; Neuroprotection; Parkinson Disease - pathology; Parkinson’s disease; Regulatory T cells; Substantia Nigra - metabolism; T cells; T-Lymphocytes, Regulatory
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-022-02685-7

Regulatory CD4 CD25 FoxP3 T cells (Treg) are a subgroup of T lymphocytes involved in maintaining immune balance. Disturbance of Treg number and impaired suppressive function of Treg correlate with Parkinson's disease severity. Superagonistic anti-CD28 monoclonal antibodies (CD28SA) activate Treg and cause their expansion to create an anti-inflammatory environment. Using the AAV1/2-A53T-α-synuclein Parkinson's disease mouse model that overexpresses the pathogenic human A53T-α-synuclein (hαSyn) variant in dopaminergic neurons of the substantia nigra, we assessed the neuroprotective and disease-modifying efficacy of a single intraperitoneal dose of CD28SA given at an early disease stage. CD28SA led to Treg expansion 3 days after delivery in hαSyn Parkinson's disease mice. At this timepoint, an early pro-inflammation was observed in vehicle-treated hαSyn Parkinson's disease mice with elevated percentages of CD8 CD69 T cells in brain and increased levels of interleukin-2 (IL-2) in the cervical lymph nodes and spleen. These immune responses were suppressed in CD28SA-treated hαSyn Parkinson's disease mice. Early treatment with CD28SA attenuated dopaminergic neurodegeneration in the SN of hαSyn Parkinson's disease mice accompanied with reduced brain numbers of activated CD4 , CD8 T cells and CD11b microglia observed at the late disease-stage 10 weeks after AAV injection. In contrast, a later treatment 4 weeks after AAV delivery failed to reduce dopaminergic neurodegeneration. Our data indicate that immune modulation by Treg expansion at a timepoint of overt inflammation is effective for treatment of hαSyn Parkinson's disease mice and suggest that the concept of early immune therapy could pose a disease-modifying option for Parkinson's disease patients.