Amiselimod (MT-1303), a novel sphingosine 1-phosphate receptor-1 functional antagonist, inhibits progress of chronic colitis induced by transfer of CD4+CD45RBhigh T cells
| Autor: | Hirotoshi Kataoka, Koichi Oshita, Kyoko Shimano, Sachiko Mochizuki, Kunio Sugahara, Mikako Murase, Yasuhiro Maeda, Hiroyuki Utsumi |
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| Rok vydání: | 2019 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male 0301 basic medicine Adoptive cell transfer Physiology Sphingosine-1-phosphate receptor Lymphocyte Administration Oral Mice SCID Pharmacology Immune Receptors Biochemistry Inflammatory bowel disease Propanolamines Mice White Blood Cells chemistry.chemical_compound 0302 clinical medicine Animal Cells Medicine and Health Sciences Lymphocytes Mice Inbred BALB C Immune System Proteins Multidisciplinary T Cells Chemistry Animal Models Colitis Adoptive Transfer medicine.anatomical_structure Physiological Parameters Experimental Organism Systems Medicine Female Cellular Types Anatomy Research Article Signal Transduction Colon Science Immune Cells T cell Immunology Mouse Models Gastroenterology and Hepatology Research and Analysis Methods 03 medical and health sciences Model Organisms medicine Animals T Helper Cells Sphingosine-1-Phosphate Receptors Blood Cells Sphingosine Inflammatory Bowel Disease Body Weight Antagonist Biology and Life Sciences Proteins Cell Biology medicine.disease Gastrointestinal Tract T Cell Receptors Disease Models Animal 030104 developmental biology Animal Studies Leukocyte Common Antigens Digestive System 030217 neurology & neurosurgery |
| Zdroj: | PLoS ONE PLoS ONE, Vol 14, Iss 12, p e0226154 (2019) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0226154 |
| Popis: | Amiselimod (MT-1303) is a novel sphingosine 1-phosphate receptor-1 (S1P1 receptor) modulator with a more favorable cardiac safety profile than other S1P1 receptor modulators. MT-1303 phosphate (MT-1303-P), an active metabolite of MT-1303, exhibits S1P1 receptor agonism at a lower EC50 value than other S1P1 receptor modulators currently being developed. We aimed to evaluate the efficacy of MT-1303 and its mode of action in chronic colitis using an inflammatory bowel disease (IBD) model. Oral administration of MT-1303 (0.3 mg/kg) once daily for 3 days to mice almost completely abolished S1P1 receptor expression on CD4+ T cells from mesenteric lymph nodes, which corresponded to a marked decrease in CD4+ T cell count in peripheral blood, indicating that MT-1303-P acts as a functional antagonist of the S1P1 receptor. The potential benefit of MT-1303 for IBD was assessed using immunodeficient SCID mice with chronic colitis induced by adoptive transfer of CD4+CD45RBhigh T cells from BALB/c mice. An oral dose of 0.1 and 0.3 mg/kg MT-1303 administered daily one week after the cell transfer inhibited the development of chronic colitis with an efficacy comparable to that of an anti-mTNF-α mAb (250 μg/mouse). In addition, MT-1303 administration significantly reduced the number of infiltrating Th1 and Th17 cells into the lamina propria of the colon in colitis mice. Our results suggest that MT-1303 acts as a functional antagonist of the S1P1 receptor on lymphocytes, regulates lymphocyte trafficking, and inhibits infiltration of colitogenic Th1 and Th17 cells into the colon to inhibit the development of chronic colitis. |
| Databáze: | OpenAIRE |
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