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Sökning: WFRF:(Locati Massimo) > Heath Paul R > Amyotrophic lateral...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00005544naa a2200649 4500
001oai:gup.ub.gu.se/310855
003SwePub
008240910s2021 | |||||||||||000 ||eng|
0247 a https://gup.ub.gu.se/publication/3108552 URI
0247 a https://doi.org/10.1093/braincomms/fcab1412 DOI
040 a (SwePub)gu
041 a eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Giovannelli, Ilaria4 aut
2451 0a Amyotrophic lateral sclerosis transcriptomics reveals immunological effects of low-dose interleukin-2.
264 c 2021-06-29
264 1b Oxford University Press (OUP),c 2021
520 a Amyotrophic lateral sclerosis is a fatal neurodegenerative disease causing upper and lower motor neuron loss and currently no effective disease-modifying treatment is available. A pathological feature of this disease is neuroinflammation, a mechanism which involves both CNS-resident and peripheral immune system cells. Regulatory T-cells are immune-suppressive agents known to be dramatically and progressively decreased in patients with amyotrophic lateral sclerosis. Low-dose interleukin-2 promotes regulatory T-cell expansion and was proposed as an immune-modulatory strategy for this disease. A randomized placebo-controlled pilot phase-II clinical trial called Immuno-Modulation in Amyotrophic Lateral Sclerosis was carried out to test safety and activity of low-dose interleukin-2 in 36 amyotrophic lateral sclerosis patients (NCT02059759). Participants were randomized to 1MIU, 2MIU-low-dose interleukin-2 or placebo and underwent one injection daily for 5 days every 28 days for three cycles. In this report, we describe the results of microarray gene expression profiling of trial participants' leukocyte population. We identified a dose-dependent increase in regulatory T-cell markers at the end of the treatment period. Longitudinal analysis revealed an alteration and inhibition of inflammatory pathways occurring promptly at the end of the first treatment cycle. These responses are less pronounced following the end of the third treatment cycle, although an activation of immune-regulatory pathways, involving regulatory T-cells and T helper 2 cells, was evident only after the last cycle. This indicates a cumulative effect of repeated low-dose interleukin-2 administration on regulatory T-cells. Our analysis suggested the existence of inter-individual variation amongst trial participants and we therefore classified patients into low, moderate and high-regulatory T-cell-responders. NanoString profiling revealed substantial baseline differences between participant immunological transcript expression profiles with the least responsive patients showing a more inflammatory-prone phenotype at the beginning of the trial. Finally, we identified two genes in which pre-treatment expression levels correlated with the magnitude of drug responsiveness. Therefore, we proposed a two-biomarker based regression model able to predict patient regulatory T-cell-response to low-dose interleukin-2. These findings and the application of this methodology could be particularly relevant for future precision medicine approaches to treat amyotrophic lateral sclerosis.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Neurovetenskaper0 (SwePub)301052 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Neurosciences0 (SwePub)301052 hsv//eng
653 a amyotrophic lateral sclerosis
653 a clinical trial
653 a low-dose interleukin 2
653 a regulatory T cells
653 a transcriptomics
7001 a Bayatti, Nadhim4 aut
7001 a Brown, Abigail4 aut
7001 a Wang, Dennis4 aut
7001 a Mickunas, Marius4 aut
7001 a Camu, William4 aut
7001 a Veyrune, Jean-Luc4 aut
7001 a Payan, Christine4 aut
7001 a Garlanda, Cecilia4 aut
7001 a Locati, Massimo4 aut
7001 a Juntas-Morales, Raul4 aut
7001 a Pageot, Nicolas4 aut
7001 a Malaspina, Andrea4 aut
7001 a Andreasson, Ulf,d 1968u Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry4 aut0 (Swepub:gu)xaulfz
7001 a Suehs, Carey4 aut
7001 a Saker, Safa4 aut
7001 a Masseguin, Christophe4 aut
7001 a de Vos, John4 aut
7001 a Zetterberg, Henrik,d 1973u Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry4 aut0 (Swepub:gu)xzethe
7001 a Al-Chalabi, Ammar4 aut
7001 a Leigh, P Nigel4 aut
7001 a Tree, Timothy4 aut
7001 a Bensimon, Gilbert4 aut
7001 a Heath, Paul R4 aut
7001 a Shaw, Pamela J4 aut
7001 a Kirby, Janine4 aut
7102 a Göteborgs universitetb Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi4 org
7730 t Brain communicationsd : Oxford University Press (OUP)g 3:3q 3:3x 2632-1297
8564 u https://academic.oup.com/braincomms/advance-article-pdf/doi/10.1093/braincomms/fcab141/38837979/fcab141.pdf
8564 8u https://gup.ub.gu.se/publication/310855
8564 8u https://doi.org/10.1093/braincomms/fcab141

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