Kenji Chiba

• PhD
• Fellow at Mitsubishi Tanabe Pharma Corporation

We explored effective therapeutic targets for systemic sclerosis (SSc) patients with high risk for pulmonary arterial hypertension (PAH) by plasma proteomics analysis. A total of fifty-seven patients with SSc were enrolled in the study and the prevalence of PAH was 19.3%. On the other hand, 75.4% of SSc patients showed the ratio of forced vital cap...

Background Incidence of late-onset rheumatoid arthritis (LORA) has been increasing recently. Patients with LORA have unique clinical characteristics compared to those with young-onset RA (YORA), but the underlying immunological condition is not understood. It is essential to elucidate the pathogenesis to develop an optimal treatment strategy for LO...

T peripheral helper (Tph) cells are thought to contribute to extra-follicular B cell activation and play a pathogenic role in autoimmune diseases. However, the role of Tph subsets is not fully elucidated. Here, we investigate the immunological functions of Tph subsets and their involvement in systemic lupus erythematosus (SLE). We have defined four...

Objectives: To clarify the clinical and immunological characteristics of IgG4-RD based on the underlying diseases. Methods: Consecutive patients with IgG4-RD treated at Keio University Hospital between 2010 and 2021 were divided according to the presence of malignancy or allergy into three groups. The clinical characteristics and 56 immune cell...

Interleukin (IL)-21-producing T peripheral helper (Tph) cells are thought to contribute to extra-follicular B cell activation and play a pathogenic role in autoimmune diseases. In this study, we investigated relationship between Tph cells and interferons (IFNs) in several autoimmune diseases because our previous study demonstrated that type I IFNs...

T follicular helper (Tfh) cells and T peripheral helper (Tph) cells produce interleukin (IL)-21 and are thought to contribute to follicular and extra-follicular B cell activation, respectively, in autoimmune diseases. It is known that programmed cell death-1 (PD-1)-positive CXCR5 + Tfh-like cells are differentiated from human naïve CD4 + T cells by...

Background: Low levels of serum magnesium perturb renal tubular cell function and lymphocytes, resulting in renal deterioration and an imbalance in mononuclear cells. This study investigated the mechanism and influence of hypomagnesemia in patients with connective tissue disease. Methods: We retrospectively evaluated patients with connective tissue...

Objective To clarify relevant proteins and clinical characteristics of a phenotype of IgG4-related disease (IgG4-RD) with lymphadenopathy. Methods We enrolled patients newly diagnosed with IgG4-RD in our department between January 2000 and June 2018 and performed proteomic analysis to measure serum concentrations of 1305 proteins. We extracted pro...

Background: Low levels of serum magnesium (Mg) perturb renal tubular cell function and, lymphocyte resulting in renal deterioration and an imbalance in mononuclear cells. Here, we investigated the influence of hypomagnesaemia in patients with connective tissue disease (CTD). Methods: We retrospectively evaluated CTD patients who visited our hospita...

Fingolimod is a first-in-class of sphingosine-1-phosphate (S1P) receptor modulator and is widely used a therapeutic drug for multiple sclerosis (MS), autoimmune disease in the central nervous system. About 25 year ago, a natural product, myriocin was isolated from culture broths of the fungus Isaria sinclairii. Myriocin, a rather complex amino acid...

Background: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease that affects small- to medium-sized blood vessels. Despite treatments having been improved, patients often experience disease relapses. It remains unclear how the immune cells involve in the development of vasculitis and how they fluctuate...

Background: Large vessel vasculitis (LVV) is a type of vasculitis characterized by granulomatous inflammation of medium- and large-sized arteries. Clinical assessment of acute phase reactants has been conventionally used to diagnose and monitor diseases; however, accurate assessment of vascular disease activity status can be difficult. In this stu...

Objectives: To elucidate the association between clinical characteristics and immuno-phenotypes in patients with ANCA-associated vasculitis (AAV). Methods: Peripheral blood from 36 patients with active AAV and 18 healthy controls was examined for numbers of circulating T cells, B cells, NK cells, dendritic cells, monocytes and granulocytes using...

Background and Purpose It is well known that BAFF (B cell activating factor) signaling is involved in the pathogenesis of autoimmune diseases. To search for specific inhibitors against BAFF signaling, we have established our original high throughput screening system and discovered a pyrroloprymidine derivative, BIK-13, which inhibits BAFF binding t...

Background We reported that BAFF robustly increases IL-6 production by peripheral monocytes of patients with primary Sjögren’s syndrome (pSS) and that the BAFF-induced IL-6 production and serum IgG levels of the patients were positively correlated with the expression level of a BAFF receptor (BR3) in pSS monocytes. Moreover, we found that IgG produ...

Background Although the mainstream of pathogenesis of systemic lupus erythematosus (SLE) is thought to be interactions between antigen-presenting cells like dendritic cells, helper T cells, B cells and cytokines, previous reports suggested CD8 T cells also involve in the pathogenesis of SLE1,2. However the associations between subsets of CD8 T cell...

Development of social cognition, a unique and high-order function, depends on brain maturation from childhood to adulthood in humans. Autism spectrum disorder (ASD) and schizophrenia have similar social cognitive deficits while age of onset in each disorder is different. Pathogenesis of these disorders is complex and contains several features inclu...

A phenotypic screening of thienodiazepines derived from a hit compound found through a binding assay targeting co-stimulatory molecules on T cells and antigen presenting cells successfully led to the discovery of a thienotriazolodiazepine compound (7f) possessing potent immunosuppessive activity. A chemical biology approach has succeeded in reveali...

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 T cells use similar mechanisms. In this study, we found that treatment with fingolimod (FTY720, 1 mg/kg, orally) markedly reduced not only conventional CD4 T cells but also circulating γδ T...

Recent advanced immunological analyses have revealed that the diversity and plasticity of macrophages lead to the identification of functional polarization states (classically activated M1 type and alternatively activated M2 type) which are dependent on the extracellular environment. M1 and M2 polarization states of macrophages play an important ro...

Psychiatric disorders such as schizophrenia and major depressive disorder were thought to be caused by neurotransmitter abnormalities. Patients with these disorders often experience relapse and remission; however the underlying molecular mechanisms of relapse and remission still remain unclear. Recent advanced immunological analyses have revealed t...

Sphingosine 1-phosphate (S1P), a multi-functional phospholipid mediator, is generated from sphingosine by sphingosine kinases and binds to five known G protein-coupled S1P receptors (S1P1, S1P2, S1P3, S1P4, and S1P5). It is widely accepted that S1P receptor 1 (S1P1) plays an essential role in lymphocyte egress from the secondary lymphoid organs (SL...

Fingolimod hydrochloride (FTY720) is the first-in-class immune modulator known as sphingosine 1-phosphate (S1P) receptor agonists. FTY720 has also been reported to exert a variety of physiological functions such as antitumor effect, angiogenesis inhibition, and Ca(2+) mobilization. Here, we show that FTY720 treatment induced reactive oxygen species...

Interleukin (IL)-15 and IL-17 are thought to play an important role in the pathogenesis of rheumatoid arthritis (RA) because both pro-inflammatory cytokines are found in synovial fluid of RA patients. In this study, we examined the pharmacological profiles of Y-320, a new phenylpyrazoleanilide immunomodulator. Y-320 inhibited IL-17 production by CD...

Sphingosine 1-phosphate (S1P) and S1P receptor 1 (S1P1) play an important role in egress of mature CD4 or CD8 single-positive (SP) thymocytes from the thymus. Fingolimod hydrochloride (FTY720), an S1P1 functional antagonist, induced significant accumulation of CD62L(high)CD69(low) mature SP thymocytes in the thymic medulla. Immunohistochemical stai...

Fingolimod hydrochloride (FTY720) is the first in class of sphingosine 1-phosphate (S1P) receptor modulator approved to treat multiple sclerosis via down-regulation of G protein-coupled S1P receptor 1 by its phosphorylated form (FTY720-P). Many studies have revealed that FTY720 exerts various biological effects, including antitumor activities, angi...

Sphingosine 1-phosphate (S1P), a lysophospholipid mediator, is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors. S1P receptor 1 (S1P1) plays an essential role in lymphocyte egress from secondary lymphoid organs (SLO), as evinced by the inability of lymphocytes to exit from the SLO in mice lacking lymphoc...

抄録 フィンゴリモド塩酸塩（イムセラ®／ジレニア®）は，世界初のスフィンゴシン1-リン酸（S1P）受容体1型（S1P1受容体）の機能的アンタゴニストであり，経口投与が可能な新規の多発性硬化症治療薬である．免疫系で中心的な役割を担うリンパ球は，リンパ節などの二次リンパ組織，リンパ液および血液中を循環し，抗原と出会った際に免疫応答を引き起こす．リンパ球循環の過程で，リン脂質メディエーターであるS1Pと，その受容体の1サブタイプでリンパ球上に存在するS1P1受容体は，二次リンパ組織からリンパ液中へのリンパ球の移出に必須の役割を果している．フィンゴリモドは冬虫夏草の一種Isaria sinclairii 菌由来の天然物マイリオシンの構造変換によって見出された新規化合物であり，スフィンゴシンと類似構造...

Fingolimod (FTY720) is a first-in-class, orally active, sphingosine 1-phosphate (S1P)-receptor modulator with a structure closely related to sphingosine. The compound was discovered by chemical modification of a natural product, myriocin. Phosphorylated form of FTY720 acts as a functional antagonist at S1P receptor type 1 (S1P(1)), inhibits lymphoc...

Mesenchymal stem cells (MSCs) have been proposed to be a useful tool for treatment of rheumatoid arthritis (RA), not only because of their multipotency but also because of their immunosuppressive effect on lymphocytes, dendritic cells, and other proinflammatory cells. Since bone destruction caused by activated osteoclasts occurs in RA, we undertook...

FTY720 (Fingolimod) is a first-in-class sphingosine 1-phosphate (S1P) receptor modulator that inhibits S1P-dependent lymphocyte egress from secondary lymphoid organs. Oral administration of FTY720 shows a superior efficacy compared to interferon (IFN)-β in relapsing remitting multiple sclerosis (MS), the most common inflammatory disorder of the cen...

Fingolimod (FTY720), a sphingosine 1-phosphate (S1P) receptor modulator, is highly effective in experimental autoimmune encephalomyelitis (EAE) and decreases circulating mature lymphocytes by inhibiting S1P-dependent lymphocyte egress from secondary lymphoid organs. Infiltration of encephalitogenic CD4 T cells plays a critical role in the developme...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Fingolimod (FTY720), a sphingosine 1-phosphate (S1P) receptor modulator, inhibits S1P-dependent lymphocyte egress from secondary lymphoid organs and is highly effective in experimental autoimmune encephalomyelitis (EAE) in mice. In this study, we directly compared the therapeutic effects of FTY720 and recombinant mouse interferon (rm-IFN)-β on rela...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Fingolimod (FTY720), a sphingosine 1-phosphate (S1P) receptor modulator, is highly effective in various autoimmune disease models and decreases circulating mature lymphocytes by inhibiting S1P-dependent lymphocyte egress from secondary lymphoid organs (SLO). On the contrary, FTY720 at an oral dose of 1 mg/kg also induces a significant decrease in t...

Sphingosine 1-phosphate (S1P) and its receptor, S1P receptor type 1 (S1P(1)), are essential for lymphocyte egress from secondary lymphoid organs (SLO). Fingolimod (FTY720), the S1P receptor modulator, inhibits lymphocyte egress from SLO and decreases circulating lymphocytes; however, it also induces a significant decrease in the number of periphera...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The goal of this paper is to investigate the effects of activated complement C5a on vascular endothelium during vessel formation. A human microvascular endothelial cell line (HMEC-1) derived from post-capillary venules in skin was used to measure DNA synthesis, proliferation and cell-cycle progression. In vitro ring-shaped formation by the cells wa...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Fingolimod (FTY720) is the first substance in the new immunomodulator class called sphingosine 1-phosphate (S1P) receptor modulators. We isolated an immunosuppressive natural product, myrocin, from the culture broth of Isaria sinclairii, a kind of vegetative wasp. The chemical modification of myriocin yielded a new compound, FTY720, which has more...

Through the optimization of the active metabolite 2 of the piperidine derivative 1, we discovered a potent new drug candidate for the treatment of RA, Y-320 that inhibits T cell activation induced by IL-15 and shows a therapeutic effect on collagen-induced arthritis in DBA/1J mice. Design and structure-activity relationships are described.

In research for a new immunomodulator, we discoverd a novel hydroxypiperidine derivative 9h which was a potent inhibitor of IL-15induced T cell activation. Further modification of 9h gave a potent and orally active agent 10 which was effective in a mouse CIA model.

Ursodeoxycholic acid (UDCA) is widely used for the therapy of liver dysfunction. In this study, we investigated the protective effect of UDCA in concanavalin A-induced mouse liver injury. The treatment with UDCA at oral doses of 50 and 150 mg/kg at 2 h before concanavalin A injection significantly reduced the elevated plasma levels of aminotransfer...

Fingolimod (FTY720) is the first of a novel class: sphingosine 1-phosphate (S1P) receptor modulator and is currently in phase 3 clinical trials for multiple sclerosis (MS). FTY720 was first synthesized in 1992 by chemical modification of an immunosuppressive natural product, ISP-I (myriocin). ISP-I was isolated from the culture broth of Isaria sinc...

Over production of interleukin (IL)-15 and IL-17 was observed in synovial fluids of rheumatoid arthritis (RA) patients. IL-15 activates T cells and induces IL-17 production whereas IL-17 stimulates synoviocytes to release several mediators of inflammation including IL-6, TNF-alpha, IL-8, and CCL2. Thus, it is presumed that IL-15 and IL-17 play impo...

Dendritic cells (DCs) and lymphocytes are known to show a migratory response to the phospholipid mediator, sphingosine 1-phosphate (S1P). However, it is unclear whether the same S1P receptor subtype mediates the migration of lymphocytes and DCs toward S1P. In this study, we investigated the involvement of S1P receptor subtypes in S1P-induced migrat...

Sphingosine 1-phosphate (S1P), a pleiotropic lysophospholipid, regulates signal transduction pathway via G-protein-coupled receptors termed S1P1-5 in several types of the cells including lymphocytes. Higher levels of S1P4 mRNA as well as S1P1 mRNA are expressed in lymphoid tissues such as the spleen, thymus, lymph nodes, and Payer's patches. In con...

Circulation of mature lymphocytes between blood and secondary lymphoid tissues plays a central role in the immune system. Homing of lymphocytes from blood into secondary lymphoid tissues beyond high endothelial venules is highly dependent on the interaction between the chemokines CCL19, CCL21, CXCL12, and CXCL13, and their receptors CCR7, CXCR4 and...

FTY720, a sphingosine 1-phosphate receptor modulator, induces a marked decrease in the number of peripheral blood lymphocytes and exerts immunomodulating activity in various experimental allograft and autoimmune disease models. In this study, we evaluated the effect of FTY720 and its active metabolite, (S)-enantiomer of FTY720-phosphate [(S)-FTY720...

FTY720 is the first of a new immunomodulator class: sphingosine 1-phosphate (S1P) receptor agonist. In 1994, an immunosuppressive natural product, ISP-I (myriocin), was isolated from the culture broth of Isaria sinclairii, a type of vegetative wasp. The chemical modification of ISP-I yielded a new compound, FTY720, which has more potent immunosuppr...

FTY720, a new class of immunomodulator, induces lymphopenia by sequestration of circulating lymphocytes into secondary lymphoid tissues. FTY720 at 0.1 to 1 mg/kg significantly prolonged the allograft survival in a dose-dependent manner and showed a marked synergistic effect in combination with cyclosporine (CsA) in rat skin and cardiac allograft mo...

A practical asymmetric synthesis of both enantiomers of the immunosuppressive FTY720-phosphate (2) was accomplished, and the enantiomers were pharmacologically evaluated. Several lipases showed considerable activity and enantioselectivity for O-acylation of N-acetyl FTY720 (3) or N-benzyloxycarbonyl FTY720 (7) in combination with vinyl acetate or b...

Rho-associated coiled-coil-forming protein kinase (ROCK) is pivotally involved in invasion by tumor cells and their evolution to metastasis. We have developed a novel inhibitor of ROCK, Wf-536 [(+)-(R)-4-(1-aminoethyl)-N-(4-pyridyl) benzamide monohydrochloride]. In the present study, we investigated its effect on in vitro invasion and in vivo pulmo...

The pharmacokinetics and cell trafficking dynamics of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (FTY720), a novel immunosuppressive agent, were examined in cynomolgus monkeys (three males and three females). After single doses of 0.1 mg/kg p.o. or i.v. bolus and 1 mg/kg p.o. were administered to the animals, the concentration...

Anti-arthritic effect of FTY720, a novel immunosuppressant, was compared with those of immunosuppressants cyclosporin A and tacrolimus in adjuvant-induced arthritis in rats. Male LEW rats. FTY720 (0.03-0.3 mg/kg), cyclosporin A (1-10 mg/kg) or tacrolimus (0.3-3 mg/kg) were orally administered to rats for 21 days beginning on the day (day 0) of adju...

FTY720, a potent immunosuppressant, dramatically decreases the number of peripheral blood lymphocytes within a few hours after administration. The current study assessed the significance of timing of FTY720 administration on the immunosuppressive effect to prolong rat skin allograft survival (WKAH donor to F344 recipient). The median survival time...

A series of 2-substituted 2-aminopropane-1,3-diols was synthesized and evaluated for their lymphocyte-decreasing effect and immunosuppressive effect on rat skin allograft. A phenyl ring was introduced into the alkyl chain of the lead compound 3, which is an immunosuppressive agent structurally simplified from myriocin (1, ISP-I) via compound 2. The...

One major role of the thymus is to provide the peripheral immune system with mature T cells, but the mechanisms involving the cellular export are not fully understood. In this study, we examined the ability of a novel immunosuppressive reagent, FTY720, to inhibit T cell export from the thymus. Daily administration of FTY720 at a dose of 1 mg / kg r...

We thank Dr R. Zinkernagel, Institute for Experimental Immunology, University of Zuerich, Switzerland, for supporting the viral studies, Dr U. Steinhoff, Max-Planck-Institute for Infectious Diseases, Berlin, Germany, for the bacterial studies, Drs R. Schmouder, T. Sablinski and P. Heining, Novartis, for the update on the clinical trials and preclin...

FTY720, a novel immunosuppressant, sequesters circulating mature lymphocytes, especially T cells, within lymph nodes and Peyer's patches by accelerating lymphocyte homing, and thereby causes lymphocyte depletion in the blood. The FTY720-induced acceleration of lymphocyte homing appears to be mediated by lymphocyte homing receptors including CD62L,...

FTY720, a novel immunosuppressant, prolonged the survival of WKAH skin allografts transplanted into MHC-incompatible F344 rats. In this allograft model, the median survival time of the control group was 7 days, whereas those of the groups given FTY720 orally at 0.1 mg/kg and cyclosporin A (CsA) at 10 mg/kg were 10.5 and 11 days, respectively. In co...

FTY720, given i.v. or orally at 0.03 mg/kg or more, significantly prolonged skin allograft survival in a dose-dependent manner and showed more potent immunosuppressive activity than cyclosporin A (CsA) or tacrolimus (FK506) in MHC-incompatible rat strains of WKAH donors and F344 recipients. However, unlike CsA or FK506, FTY720 up to 1000 nM did not...

FTY720 induces apoptosis, specifically in lymphocytes, and prolongs allograft survival in rats and dogs. The purpose of this study was to define an effective range of FTY720 doses that could be combined with a suboptimal dose (10 mg/kg) of cyclosporin for canine kidney allograft recipients. The combination significantly prolonged allograft survival...

Several immunosuppressants, ISP-I [(2S,3R,4R)-(E)-2-amino-3,4-dihydroxy-2-(hydroxymethyl)-14-oxoeicos++ +-6-enoic acid, myriocin = thermozymocidin] and mycestericins A-G, were isolated from culture broths of Isaria sinclairii and Mycelia sterilia, respectively. In order to investigate structure-activity relationships, extensive modifications of ISP...

The 2-aminoalcohol series of immunosuppressants showed a bell-shaped relationship between the activity and the carbon number. The (R)-isomers were more potent than the (S)-isomers, and (R)-2-aminohexadecanol displayed comparably activity to a potent immunosuppressant, FTY720.

Mycestericins D, E, F and G were isolated from the culture broth of Mycelia sterilia ATCC 20349 as potent immunosuppressants. Mycestericins F and G were identical with dihydromycestericins D and E, respectively. Their absolute configurations were determined by use of the modified MOSHER'S method and by comparison of the CD spectra of their benzoate...