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

Autor: Badr M; Department of Neurology, University Hospital of Würzburg, Würzburg, Germany., McFleder RL; Department of Neurology, University Hospital of Würzburg, Würzburg, Germany., Wu J; Department of Neurology, University Hospital of Würzburg, Würzburg, Germany., Knorr S; Department of Neurology, University Hospital of Würzburg, Würzburg, Germany., Koprich JB; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.; Atuka Inc, Toronto, ON, Canada., Hünig T; Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany., Brotchie JM; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.; Atuka Inc, Toronto, ON, Canada., Volkmann J; Department of Neurology, University Hospital of Würzburg, Würzburg, Germany., Lutz MB; Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany., Ip CW; Department of Neurology, University Hospital of Würzburg, Würzburg, Germany. ip_c@ukw.de.
Jazyk: angličtina
Zdroj: Journal of neuroinflammation [J Neuroinflammation] 2022 Dec 31; Vol. 19 (1), pp. 319. Date of Electronic Publication: 2022 Dec 31.
DOI: 10.1186/s12974-022-02685-7
Abstrakt: Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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