| 研究課題/領域番号 |
20K07775
|
|---|
| 研究機関 | 国立研究開発法人国立精神・神経医療研究センター |
|---|
研究代表者 |
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)
|
|---|
| 研究期間 (年度) |
2020-04-01 – 2023-03-31
|
| キーワード | Autoimmunity / Multiple Sclerosis / T helper cells / cytotoxic Th cells / Eomes |
|---|
| 研究実績の概要 |
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.
As part of Objectives 2 and 3: we reported (Raveney et. al PNAS 2021) the crucial involvement of cytotoxic CD4+ T cells expressing Eomes (Eomes+ Th cells) in SPMS pathogenesis - a Th cell subset previously identified in a mouse model of late/chronic autoimmune CNS inflammation.
In summary: Few Eomes+ Th cells circulate in peripheral blood from RRMS patients, primary progressive MS patients, or healthy controls, but Eomes+ Th cells were significantly increased in SPMS. In particular, the Eomes+ Th cells level was increased in SPMS patients in progressive disease phases versus SPMS patients without current disability increases. Moreover, Eomes level acted as a biomarker indicating SPMS patients at risk of developing worsening disease with over 80% accuracy (ROC-AUC=0.8276). Overall, our results indicate that granzyme B-expressing Eomes+ T helper cells are involved in the pathogenesis of SPMS.
For Objective 1: Th cells co-expressing Eomes and the cytotoxic molecule granzyme B have been isolated from SPMS autopsy brain samples. Data from similar peripheral blood Eomes/Granzyme B+ Th cells from over 100 RRMS and SPMS patients has been collected for ongoing detailed machine learning-based analysis to further elucidate the nature of the pathogenic cells involved in chronic progressive CNS autoimmune disease.
|
| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
The work progresses smoothly as we have confirmed the main finding that the cells in question are linked to pathogenic process in the disease SPMS and have reported these data in the respected international journal -PNAS. Further, we have begun to investigate the processes used by these cells to generate pathogenicity.
|
| 今後の研究の推進方策 |
Due to the risk of any future limitations on access to patient samples if the COVID-19 outbreak should worsen, we have accelerated the collection of samples to allow for future analysis. The investigator can now analyze these data for phenotyping studies that will directly lead to further delineation of the mechanisms involved.
|
| 次年度使用額が生じた理由 |
Due to COVID-19 situation. Travel for conferences and meetings with collaborators have been delayed. In addition, some detailed analysis experiments have been delayed whilst the investigator has focussed on collecting data from patient samples to mitigate any potential future virus-related restrictions.
This amount will be added to next year's budget and be used for reagents and external sequencing services of these precious samples.
|
