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A Pilot Study to Develop Paraneoplastic Cerebellar Degeneration Mouse Model

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Abstract

Modeling paraneoplastic neurological diseases to understand the immune mechanisms leading to neuronal death is a major challenge given the rarity and terminal access of patients’ autopsies. Here, we present a pilot study aiming at modeling paraneoplastic cerebellar degeneration with Yo autoantibodies (Yo-PCD). Female mice were implanted with an ovarian carcinoma cell line expressing CDR2 and CDR2L, the known antigens recognized by anti-Yo antibodies. To boost the immune response, we also immunized the mice by injecting antigens with diverse adjuvants and immune checkpoint inhibitors. Ataxia and gait instability were assessed in treated mice as well as autoantibody levels, Purkinje cell density, and immune infiltration in the cerebellum. We observed the production of anti-Yo antibodies in the CSF and serum of all immunized mice. Brain immunoreaction varied depending on the site of implantation of the tumor, with subcutaneous administration leading to a massive infiltration of immune cells in the meningeal spaces, choroid plexus, and cerebellar parenchyma. However, we did not observe massive Purkinje cell death nor any motor impairments in any of the experimental groups. Self-sustained neuro-inflammation might require a longer time to build up in our model. Unusual tumor antigen presentation and/or intrinsic, species-specific factors required for pro-inflammatory engagement in the brain may also constitute strong limitations to achieve massive recruitment of antigen-specific T-cells and killing of antigen-expressing neurons in this mouse model.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon request.

Abbreviations

Abs:

Antibodies

CDR:

Cerebellar degeneration-related protein

CNS:

Central nervous system

FFPE:

Formalin-fixed paraffin-embedded

IFN:

Interferon

MHC:

Major histocompatibility complex

TNF:

Tumor necrosis factor

PCD:

Paraneoplastic cerebellar degeneration

PND:

Paraneoplastic neurological disease

PNS:

Paraneoplastic neurological syndrome

CFA:

Complete Freund’s adjuvant

PTX:

Pertussis toxin

PBS:

Phosphate-buffered saline

SCID:

Severe combined immunodeficiency

TCR:

T-cell receptor

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Acknowledgements

CIQLE microscopy and histology platform at the SFR Lyon Est. ALECS Animal facility at Lyon 1 university. X-ray Irradiator facility at ENS Lyon.

Funding

This study is supported by research grants from Fondation pour la recherche médicale (reference DQ20170336751) and has been developed within the BETPSY project, which is supported by a public grant overseen by the French national research agency (Agence nationale de la recherche, ANR), as part of the second “Investissements d´Avenir” program (reference ANR-18-RHUS-0012). This work was supported by the French National Research Agency within the framework of the LABEX CORTEX ANR-11-LABX-0042.

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Authors and Affiliations

  1. Synaptopathies and Autoantibodies (SynatAc) Team, Institut NeuroMyoGène (INMG)-MeLis, INSERM U1314, CNRS UMR 5284, Université de Lyon, Université Claude Bernard Lyon 1, 69373, Lyon, France

    Fabrice Faure, Bastien Joubert, Virginie Desestret & Jérôme Honnorat

  2. Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), University of Toulouse, CNRS, INSERM, UPS, 31024, Toulouse, France

    Lidia Yshii & Roland Liblau

  3. Department of Immunology, Toulouse University Hospital, 31300, Toulouse, France

    Lidia Yshii & Roland Liblau

  4. Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000, Louvain, Belgium

    Lidia Yshii

  5. Department of Neurosciences, KU Leuven, 3000, Louvain, Belgium

    Lidia Yshii

  6. Cancer Research Centre of Lyon, Université de Lyon, INSERM 1052, CNRS 5286, 69008, Lyon, France

    Toufic Renno & Isabelle coste

  7. French Reference Centre On Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, 59 Boulevard Pinel, 69677, Bron Cedex, France

    Bastien Joubert, Virginie Desestret & Jérôme Honnorat

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  1. Fabrice Faure
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  2. Lidia Yshii
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  3. Toufic Renno
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  4. Isabelle coste
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  7. Roland Liblau
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  8. Jérôme Honnorat
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Contributions

Fabrice Faure: acquisition, analysis, and interpretation of the data and drafting the manuscript for intellectual content and figures.

All authors: critical revision of the manuscript for important intellectual content.

Pr Roland Liblau, Pr Jérôme Honnorat: study concept and design, analysis and interpretation, critical revision of the manuscript for important intellectual content, study supervision.

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Correspondence to Jérôme Honnorat.

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Faure, F., Yshii, L., Renno, T. et al. A Pilot Study to Develop Paraneoplastic Cerebellar Degeneration Mouse Model. Cerebellum 23, 181–196 (2024). https://doi.org/10.1007/s12311-023-01524-6

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