Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis

Abstract Most multiple sclerosis (MS) patients given currently available disease-modifying drugs (DMDs) experience progressive disability. Accordingly, there is a need for new treatments that can limit the generation of new waves T cell autoreactivity that drive disease progression. Notably, immune...

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Autores principales:	Jide Tian, Min Song, Daniel L. Kaufman
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5457f0c20d684103869242c6aa9fbc87
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spelling	oai:doaj.org-article:5457f0c20d684103869242c6aa9fbc872021-12-02T15:54:10ZHomotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis10.1038/s41598-021-84751-32045-2322https://doaj.org/article/5457f0c20d684103869242c6aa9fbc872021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84751-3https://doaj.org/toc/2045-2322Abstract Most multiple sclerosis (MS) patients given currently available disease-modifying drugs (DMDs) experience progressive disability. Accordingly, there is a need for new treatments that can limit the generation of new waves T cell autoreactivity that drive disease progression. Notably, immune cells express GABAA-receptors (GABAA-Rs) whose activation has anti-inflammatory effects such that GABA administration can ameliorate disease in models of type 1 diabetes, rheumatoid arthritis, and COVID-19. Here, we show that oral GABA, which cannot cross the blood–brain barrier (BBB), does not affect the course of murine experimental autoimmune encephalomyelitis (EAE). In contrast, oral administration of the BBB-permeable GABAA-R-specific agonist homotaurine ameliorates monophasic EAE, as well as advanced-stage relapsing–remitting EAE (RR-EAE). Homotaurine treatment beginning after the first peak of paralysis reduced the spreading of Th17 and Th1 responses from the priming immunogen to a new myelin T cell epitope within the CNS. Antigen-presenting cells (APC) isolated from homotaurine-treated mice displayed an attenuated ability to promote autoantigen-specific T cell proliferation. The ability of homotaurine treatment to limit epitope spreading within the CNS, along with its safety record, makes it an excellent candidate to help treat MS and other inflammatory disorders of the CNS.Jide TianMin SongDaniel L. KaufmanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jide Tian Min Song Daniel L. Kaufman Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis
description	Abstract Most multiple sclerosis (MS) patients given currently available disease-modifying drugs (DMDs) experience progressive disability. Accordingly, there is a need for new treatments that can limit the generation of new waves T cell autoreactivity that drive disease progression. Notably, immune cells express GABAA-receptors (GABAA-Rs) whose activation has anti-inflammatory effects such that GABA administration can ameliorate disease in models of type 1 diabetes, rheumatoid arthritis, and COVID-19. Here, we show that oral GABA, which cannot cross the blood–brain barrier (BBB), does not affect the course of murine experimental autoimmune encephalomyelitis (EAE). In contrast, oral administration of the BBB-permeable GABAA-R-specific agonist homotaurine ameliorates monophasic EAE, as well as advanced-stage relapsing–remitting EAE (RR-EAE). Homotaurine treatment beginning after the first peak of paralysis reduced the spreading of Th17 and Th1 responses from the priming immunogen to a new myelin T cell epitope within the CNS. Antigen-presenting cells (APC) isolated from homotaurine-treated mice displayed an attenuated ability to promote autoantigen-specific T cell proliferation. The ability of homotaurine treatment to limit epitope spreading within the CNS, along with its safety record, makes it an excellent candidate to help treat MS and other inflammatory disorders of the CNS.
format	article
author	Jide Tian Min Song Daniel L. Kaufman
author_facet	Jide Tian Min Song Daniel L. Kaufman
author_sort	Jide Tian
title	Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis
title_short	Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis
title_full	Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis
title_fullStr	Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis
title_full_unstemmed	Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis
title_sort	homotaurine limits the spreading of t cell autoreactivity within the cns and ameliorates disease in a model of multiple sclerosis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5457f0c20d684103869242c6aa9fbc87
work_keys_str_mv	AT jidetian homotaurinelimitsthespreadingoftcellautoreactivitywithinthecnsandamelioratesdiseaseinamodelofmultiplesclerosis AT minsong homotaurinelimitsthespreadingoftcellautoreactivitywithinthecnsandamelioratesdiseaseinamodelofmultiplesclerosis AT daniellkaufman homotaurinelimitsthespreadingoftcellautoreactivitywithinthecnsandamelioratesdiseaseinamodelofmultiplesclerosis
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Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis

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