2021 Fiscal Year Research-status Report
Invesitgation of Eomes+ Th cells: a pathogenic population controlling neuroinflammation during secondary progressive multiple sclerosis
| Project/Area Number |
20K07775
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| Research Institution | National Center of Neurology and Psychiatry |
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Principal Investigator |
Raveney Benjamin 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 免疫研究部, 科研費研究員 (70795385)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | multiple sclerosis / autoimmunity |
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| Outline of Annual Research Achievements |
The autoimmune disease multiple sclerosis (MS) can transition from a relapsing-remitting form (RRMS) into a chronic progressive form (secondary progressive MS, SPMS). SPMS pathogenesis remains poorly understood with diagnosis based entirely on retrospective clinical monitoring. We have studied the role of Eomes-expressing CD4+ T cells (Eomes+ Th cells), Th cell subset previously identified as pathogenic in a mouse model of late/chronic autoimmune CNS inflammation.
As part of Objective 1, we have examined the surface and intracellular phenotype of Eomes-expressing Th cells using flow cytometry. Using a target-scanning approach to this cytometry, we have identified a number of surface molecules associated with cytotoxic function that are potentially linked to function of these cells. Moreover, these molecules have allowed flow cytometric cell sorting of different potential subsets of Eomes+ Th cells for ongoing analysis by Nanostring. Such peripheral cells, as well as those we have sorted from the CNS of SPMS autopsy samples have been characterised by TcR repertoire sequencing and indicate oligoclonal expansion.
For objective 2, we reported the association of cytotoxic Eomes+ CD4+ Th cells with active disease in SPMS (Raveney et al., 2021). As an extension to this, we have continued to follow up patients from our cohort, to monitor Eomes+ Th cells over time with disease activity. Furthermore, we have examined these cells in a new cohort of patients that are undergoing treatment from a newly approved drug for SPMS, Siponimod, that may target CNS T cells.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
We have identified one of the pathogenic factors for SMPS and that it could be a biomarker for this disease. The findings from this study mark great advances in determination of progression from RRMS to SPMS. This work was published in PNAS.
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| Strategy for Future Research Activity |
This project can continue as planned. Under Objective 1, we will further characterise the cell populations using genetic techniques based on our flow cytometry findings. These data can then be applied to pathway analysis allowing ongoing functional analysis of these cells in human PBMC and in our mouse model as part of Objective 3 to reveal mechanistic information about the pathogenicity of these cells. Repeater analysis of our MS patients cohorts will continue under Objective 2. With additional study of patients switching to new drug treatment regimens.
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| Causes of Carryover |
<Reason> Not being able to travel to attend international meetings abroad due to COVID-19 pandemic.
<Plan> I intend to use the money on consumables and antibodies to further assist my investigation.
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[Presentation] Involvement of cytotoxic Eomes-expressing CD4+ T cells in secondary progressive multiple sclerosis2021
Author(s)
Ben JE Raveney, W Sato, D Takewaki, C Zhang, T Kanazawa, Y Lin, T Okamoto, M Araki, Y Kimura, N Sato, T Sano, Y Saito, S Oki, and T Yamamura
Organizer
NCNP annual meeting
