Abstract FTY720, a novel immunosuppressant, prolonged the survival of WKAH skin allografts transplanted into MHC-incompatible F344 rats. In this allograft model, median time control group was 7 days, whereas those groups given FTY720 orally at 0.1 mg/kg and cyclosporin A (CsA) 10 were 10.5 11 respectively. contrast, (0.1 mg/kg) combined with CsA (10 synergistically exceeding 70 days. To elucidate mechanisms remarkable synergistic effect, mRNA expressions IL-2 IFN-γ that CD3 (δ-chain), which...

Dendritic cells (DCs) and lymphocytes are known to show a migratory response the phospholipid mediator, sphingosine 1-phosphate (S1P). However, it is unclear whether same S1P receptor subtype mediates migration of DCs toward S1P. In this study, we investigated involvement subtypes in S1P-induced CD4 T bone marrow-derived mice. A potent agonist, (S)-enantiomer FTY720-phosphate [(S)-FTY720-P], at 0.1 nM or higher selective type 1 (S1P(1)) SEW2871, muM induced dose-dependent down-regulation...

Background and Purpose We conducted preclinical clinical studies to examine the pharmacological, particularly cardiac, effects of amiselimod (MT‐1303), a second‐generation sphingosine 1‐phosphate (S1P) receptor modulator, designed reduce bradycardia associated with fingolimod other S1P modulators. Experimental Approach The selectivity active metabolite phosphate (amiselimod‐P) for human receptors activation G‐protein‐coupled inwardly rectifying K + (GIRK) channels in atrial myocytes were...

Tumor-derived adhesion factor (TAF) was previously identified as a cell molecule secreted by human bladder carcinoma line EJ-1. To elucidate the physiological function of TAF, we examined its distribution in normal and tumor tissues. Immunochemical staining with an anti-TAF monoclonal antibody showed that TAF specifically accumulated small blood vessels capillaries within adjacent to nests, but not those Tumor vessel-specific observed various cancers, such esophagus, brain, lung, stomach...

Amiselimod (MT-1303) is a novel sphingosine 1-phosphate receptor-1 (S1P1 receptor) modulator with more favorable cardiac safety profile than other S1P1 receptor modulators. MT-1303 phosphate (MT-1303-P), an active metabolite of MT-1303, exhibits agonism at lower EC50 value modulators currently being developed. We aimed to evaluate the efficacy and its mode action in chronic colitis using inflammatory bowel disease (IBD) model. Oral administration (0.3 mg/kg) once daily for 3 days mice almost...

Abstract Interleukin (IL)-21-producing T peripheral helper (Tph) cells are thought to contribute extra-follicular B cell activation and play a pathogenic role in autoimmune diseases. In this study, we investigated the relationship between Tph interferons (IFNs) several diseases because our previous study demonstrated that type I IFNs promote differentiation of IL-21-producing Tph-like cells. The frequency blood as well serum IFN-α2a IFN-λ1 were markedly elevated patients with active systemic...

It is thought that systemic sclerosis (SSc) might be a T helper 17 (Th17) cell-driven autoimmune disease. Noticeably, pulmonary arterial hypertension (PAH) leading cause of death in patients with SSc. Here, we investigated the association between serum Th17-related cytokines and prevalence PAH SSc patients. This study included 72 51 healthy controls (HC). We determined clinical manifestations, immunophenotypes including Th subsets peripheral blood lymphocytes, levels interleukin (IL)-17A,...

Abstract T peripheral helper (Tph) cells are thought to contribute extra-follicular B cell activation and play a pathogenic role in autoimmune diseases. However, the of Tph subsets is not fully elucidated. Here, we investigate immunological functions their involvement systemic lupus erythematosus (SLE). We have defined four (Tph1: CXCR3 + CCR6 − , Tph2: Tph17: Tph1-17: ) performed RNA sequencing after sorting. Tph1 Tph17 express substantial levels IL21 indicating functions. Tph2 Tph1-17 low...

Sphingosine 1-phosphate (S1P) and its receptor, S1P receptor type 1 (S1P1), are essential for lymphocyte egress from secondary lymphoid organs (SLO). Fingolimod (FTY720), the modulator, inhibits SLO decreases circulating lymphocytes; however, it also induces a significant decrease in number of peripheral blood lymphocytes alymphoplasia (aly/aly) mice lacking SLO. In this study, we demonstrated that administration FTY720 induced sequestration mature lymphocytes, particularly T cells, into...

Conventional αβ T cells require sphingosine 1-phosphate (S1P) receptor 1 (S1P1) for circulation through the lymph nodes (LN); however, it is unclear whether γδ use similar mechanisms. In this study, we found that treatment with fingolimod (FTY720, mg/kg, orally) markedly reduced not only conventional CD4 but also circulating (Vγ4(+) and Vγ4(-) subsets) in blood of mice. contrast, IL-17(+)Vγ4(+), IL-17(+)Vγ4(-), IL-17(-)Vγ4(-) subsets were significantly accumulated LN after 6 h FTY720...

We developed a real-time (RT) PCR quantitative assay to measure the level of integrated viral genome HTLV-1 in host peripheral blood-mononuclear cells (PB-MNC) from healthy carriers and patients with adult T-cell leukemia (ATL). All clinical specimens were serologically molecularly characterized by enzyme-linked immunosorbent (ELISA) Southern blot hybridization (SBH) analyses. The system for quantifying proviral copy was sensitive, accurate, reproducible over wide range density 100 0.1%...

A series of 2-substituted 2-aminopropane-1,3-diols having a biphenyl moiety and their phosphate esters were synthesized to obtain sphingosine 1-phosphate receptor-1 (S1P(1)) receptor agonists with potent immunomodulatory activity accompanied by little or no effect on heart rate. Many the compounds sufficiently decreased number peripheral blood lymphocytes. Some phosphates had agonism at S1P(1) but S1P(3), which been reported be responsible for rate reduction. Although high S1P(1)/S1P(3)...

Abstract Sphingosine 1-phosphate (S1P) and S1P receptor 1 (S1P1) play an important role in the egress of mature CD4 or CD8 single-positive (SP) thymocytes from thymus. Fingolimod hydrochloride (FTY720), S1P1 functional antagonist, induced significant accumulation CD62LhighCD69low SP thymic medulla. Immunohistochemical staining using anti-S1P1 antibody revealed that is predominantly expressed on medulla strongly down-regulated even at 3h after FTY720 administration....

Summary Tumour necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) induces apoptosis in many transformed cells, but not normal and hence TRAIL has recently emerged as a novel anti‐cancer agent. Adult T‐cell leukaemia lymphoma (ATLL) is neoplasm of T‐lymphocyte origin aetiologically associated with human T‐lymphotropic virus type 1 (HTLV‐I), resistant to standard therapy. We thus characterized the sensitivity ATLL cells this study. Although most primary cell lines expressed death...

Amiselimod (MT-1303) is a novel and selective sphingosine 1-phosphate receptor-1 (S1P 1 ) modulator with more favorable cardiac safety profile than other S1P receptor modulators. In this study, we evaluated the effects of MT-1303 on progression lupus nephritis in two well-known murine systemic erythematosus (SLE) models, MRL/ lpr NZBWF1 mice, compared those FK506. Daily oral doses 0.1 0.3 mg/kg not only inhibited development when administered before onset mice but also improved symptoms...

Abstract T follicular helper (Tfh) cells and peripheral (Tph) produce interleukin (IL)-21 are thought to contribute extra-follicular B-cell activation, respectively, in autoimmune diseases. It is known that programmed cell death-1 (PD-1)-positive CXCR5+ Tfh-like differentiated from human naive CD4+ by IL-12 plus transforming growth factor (TGF)-β. However, it remains unclear what cytokines required for Tph differentiation. In this study, we found interferon (IFN)-α IFN-β reduce the frequency...