title: Therapeutic use of a selective S1P1 receptor modulator ponesimod in autoimmune diabetes.
abstract: In the present study, we investigated the therapeutic potential of a selective S1P1 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 S1P1 modulator in combination with CD3 antibody represents a promising therapeutic approach for the treatment of autoimmune diabetes.
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Paris, France ; Institut National de la Santé et de la Recherche Médicale, Unité 1013, Paris, France.
authors.forename: Sylvaine
authors.initials: S
authors.lastname: You
authors.forename: Luca
authors.initials: L
authors.lastname: Piali
authors.forename: Chantal
authors.initials: C
authors.lastname: Kuhn
authors.forename: Beat
authors.initials: B
authors.lastname: Steiner
authors.forename: Virginia
authors.initials: V
authors.lastname: Sauvaget
authors.forename: Fabrice
authors.initials: F
authors.lastname: Valette
authors.forename: Martine
authors.initials: M
authors.lastname: Clozel
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bach
authors.forename: Lucienne
authors.initials: L
authors.lastname: Chatenoud
mesh_terms: D000284:Administration, Oral; D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D004334:Drug Administration Schedule; D015870:Gene Expression; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D051379:Mice; D016688:Mice, Inbred NOD; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D012008:Recurrence; D017634:Self Tolerance; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000906:Antibodies; D017252:CD3 Complex; D007004:Hypoglycemic Agents; D049349:Receptors, Lysosphingolipid; D013844:Thiazoles; C550169:ponesimod; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse