title: Amelioration of collagen-induced arthritis by a novel S1P1 antagonist with immunomodulatory activities.
abstract: Sphingosine 1-phosphate (S1P) regulates lymphocyte trafficking through the type 1 sphingosine 1-phosphate receptor (S1P(1)) and participates in many pathological conditions, including autoimmune diseases. We developed a novel S1P(1)-selective antagonist, TASP0277308, which is structurally unrelated to S1P. This antagonist competitively inhibited S1P-induced cellular responses, such as chemotaxis and receptor internalization. Furthermore, differing from previously reported S1P(1) antagonists, TASP0277308 demonstrated in vivo activities to induce lymphopenia, a block in T cell egress from the thymus, displacement of marginal zone B cells, and upregulation of CD69 expression on both T and B cells, all of which recapitulate phenotypes of S1P(1)-deficient lymphocytes. In a mouse collagen-induced arthritis model, TASP0277308 significantly suppressed the development of arthritis, even after the onset of disease. These findings provide the first chemical evidence to our knowledge that S1P(1) antagonism is responsible for immunosuppression in the treatment of autoimmune diseases and also resolve the discrepancies between genetic and chemical studies on the functions of S1P(1) in lymphocytes.
authors: Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan. y.fujii@po.rd.taisho.co.jp
authors: Yasuyuki
authors: Y
authors: Fujii
authors: Takehiro
authors: T
authors: Hirayama
authors: Hidenori
authors: H
authors: Ohtake
authors: Naoya
authors: N
authors: Ono
authors: Tomoyuki
authors: T
authors: Inoue
authors: Takanobu
authors: T
authors: Sakurai
authors: Tetsuo
authors: T
authors: Takayama
authors: Kayo
authors: K
authors: Matsumoto
authors: Narutoshi
authors: N
authors: Tsukahara
authors: Shinya
authors: S
authors: Hidano
authors: Nobue
authors: N
authors: Harima
authors: Kiyoshi
authors: K
authors: Nakazawa
authors: Yasuyuki
authors: Y
authors: Igarashi
authors: Ryo
authors: R
authors: Goitsuka
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D008231:Lymphopenia / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008246:Lysophospholipids / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D013450:Sulfones / Q000494:pharmacology* / Q000633:toxicity; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology; D014230:Triazoles / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D013450:Sulfones; C569989:TASP0277308; D014230:Triazoles; C060506:sphingosine 1-phosphate; D013110:Sphingosine