Cargando…

Therapeutic Use of a Selective S1P(1) Receptor Modulator Ponesimod in Autoimmune Diabetes

In the present study, we investigated the therapeutic potential of a selective S1P(1) receptor modulator, ponesimod, to protect and reverse autoimmune diabetes in non-obese diabetic (NOD) mice. Ponesimod was administered orally to NOD mice starting at 6, 10, 13 and 16 weeks of age up to 35 weeks of...

Descripción completa

Detalles Bibliográficos
Autores principales: You, Sylvaine, Piali, Luca, Kuhn, Chantal, Steiner, Beat, Sauvaget, Virginia, Valette, Fabrice, Clozel, Martine, Bach, Jean-François, Chatenoud, Lucienne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811978/
https://www.ncbi.nlm.nih.gov/pubmed/24204793
http://dx.doi.org/10.1371/journal.pone.0077296
_version_ 1782288907959795712
author You, Sylvaine
Piali, Luca
Kuhn, Chantal
Steiner, Beat
Sauvaget, Virginia
Valette, Fabrice
Clozel, Martine
Bach, Jean-François
Chatenoud, Lucienne
author_facet You, Sylvaine
Piali, Luca
Kuhn, Chantal
Steiner, Beat
Sauvaget, Virginia
Valette, Fabrice
Clozel, Martine
Bach, Jean-François
Chatenoud, Lucienne
author_sort You, Sylvaine
collection PubMed
description In the present study, we investigated the therapeutic potential of a selective S1P(1) receptor modulator, ponesimod, to protect and reverse autoimmune diabetes in non-obese diabetic (NOD) mice. Ponesimod was administered orally to NOD mice starting at 6, 10, 13 and 16 weeks of age up to 35 weeks of age or to NOD mice showing recent onset diabetes. Peripheral blood and spleen B and T cell counts were significantly reduced after ponesimod administration. In pancreatic lymph nodes, B lymphocytes were increased and expressed a transitional 1-like phenotype. Chronic oral ponesimod treatment efficiently prevented autoimmune diabetes in 6, 10 and 16 week-old pre-diabetic NOD mice. Treatment withdrawal led to synchronized disease relapse. Ponesimod did not inhibit the differentiation of autoreactive T cells as assessed by adoptive transfer of lymphocytes from treated disease-free NOD mice. In addition, it did not affect the migration, proliferation and activation of transgenic BDC2.5 cells into the target tissue. However, ponesimod inhibited spreading of the T cell responses to islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP). Treatment of diabetic NOD mice with ponesimod induced disease remission. However, here again, upon treatment cessation, the disease rapidly recurred. This recurrence was effectively prevented by combination treatment with a CD3 antibody leading to the restoration of self-tolerance. In conclusion, treatment with a selective S1P(1) modulator in combination with CD3 antibody represents a promising therapeutic approach for the treatment of autoimmune diabetes.
format Online
Article
Text
id pubmed-3811978
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-38119782013-11-07 Therapeutic Use of a Selective S1P(1) Receptor Modulator Ponesimod in Autoimmune Diabetes You, Sylvaine Piali, Luca Kuhn, Chantal Steiner, Beat Sauvaget, Virginia Valette, Fabrice Clozel, Martine Bach, Jean-François Chatenoud, Lucienne PLoS One Research Article In the present study, we investigated the therapeutic potential of a selective S1P(1) receptor modulator, ponesimod, to protect and reverse autoimmune diabetes in non-obese diabetic (NOD) mice. Ponesimod was administered orally to NOD mice starting at 6, 10, 13 and 16 weeks of age up to 35 weeks of age or to NOD mice showing recent onset diabetes. Peripheral blood and spleen B and T cell counts were significantly reduced after ponesimod administration. In pancreatic lymph nodes, B lymphocytes were increased and expressed a transitional 1-like phenotype. Chronic oral ponesimod treatment efficiently prevented autoimmune diabetes in 6, 10 and 16 week-old pre-diabetic NOD mice. Treatment withdrawal led to synchronized disease relapse. Ponesimod did not inhibit the differentiation of autoreactive T cells as assessed by adoptive transfer of lymphocytes from treated disease-free NOD mice. In addition, it did not affect the migration, proliferation and activation of transgenic BDC2.5 cells into the target tissue. However, ponesimod inhibited spreading of the T cell responses to islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP). Treatment of diabetic NOD mice with ponesimod induced disease remission. However, here again, upon treatment cessation, the disease rapidly recurred. This recurrence was effectively prevented by combination treatment with a CD3 antibody leading to the restoration of self-tolerance. In conclusion, treatment with a selective S1P(1) modulator in combination with CD3 antibody represents a promising therapeutic approach for the treatment of autoimmune diabetes. Public Library of Science 2013-10-24 /pmc/articles/PMC3811978/ /pubmed/24204793 http://dx.doi.org/10.1371/journal.pone.0077296 Text en © 2013 You et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
You, Sylvaine
Piali, Luca
Kuhn, Chantal
Steiner, Beat
Sauvaget, Virginia
Valette, Fabrice
Clozel, Martine
Bach, Jean-François
Chatenoud, Lucienne
Therapeutic Use of a Selective S1P(1) Receptor Modulator Ponesimod in Autoimmune Diabetes
title Therapeutic Use of a Selective S1P(1) Receptor Modulator Ponesimod in Autoimmune Diabetes
title_full Therapeutic Use of a Selective S1P(1) Receptor Modulator Ponesimod in Autoimmune Diabetes
title_fullStr Therapeutic Use of a Selective S1P(1) Receptor Modulator Ponesimod in Autoimmune Diabetes
title_full_unstemmed Therapeutic Use of a Selective S1P(1) Receptor Modulator Ponesimod in Autoimmune Diabetes
title_short Therapeutic Use of a Selective S1P(1) Receptor Modulator Ponesimod in Autoimmune Diabetes
title_sort therapeutic use of a selective s1p(1) receptor modulator ponesimod in autoimmune diabetes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811978/
https://www.ncbi.nlm.nih.gov/pubmed/24204793
http://dx.doi.org/10.1371/journal.pone.0077296
work_keys_str_mv AT yousylvaine therapeuticuseofaselectives1p1receptormodulatorponesimodinautoimmunediabetes
AT pialiluca therapeuticuseofaselectives1p1receptormodulatorponesimodinautoimmunediabetes
AT kuhnchantal therapeuticuseofaselectives1p1receptormodulatorponesimodinautoimmunediabetes
AT steinerbeat therapeuticuseofaselectives1p1receptormodulatorponesimodinautoimmunediabetes
AT sauvagetvirginia therapeuticuseofaselectives1p1receptormodulatorponesimodinautoimmunediabetes
AT valettefabrice therapeuticuseofaselectives1p1receptormodulatorponesimodinautoimmunediabetes
AT clozelmartine therapeuticuseofaselectives1p1receptormodulatorponesimodinautoimmunediabetes
AT bachjeanfrancois therapeuticuseofaselectives1p1receptormodulatorponesimodinautoimmunediabetes
AT chatenoudlucienne therapeuticuseofaselectives1p1receptormodulatorponesimodinautoimmunediabetes