Human and mouse NK cells use different families of receptors to recognize MHC class I (MHC I) on ... more Human and mouse NK cells use different families of receptors to recognize MHC class I (MHC I) on target cells. Although human NK cells express both Ig-like receptors and lectin-like receptors specific for MHC I, all the MHC I-specific receptors identified on mouse NK cells to date are lectin-like receptors, and no Ig-like receptors recognizing MHC I have been identified on mouse NK cells. In this study we report the first MHC I-specific Ig-like receptor on mouse NK cells, namely, murine CD160 (mCD160). The expression of mCD160 is restricted to a subset of NK cells, NK1.1+ T cells, and activated CD8+ T cells. The mCD160-Ig fusion protein binds to rat cell lines transfected with classical and nonclassical mouse MHC I, including CD1d. Furthermore, the level of mCD160 on NK1.1+ T cells is modulated by MHC I of the host. Overexpression of mCD160 in the mouse NK cell line KY-2 inhibits IFN-γ production induced by phorbol ester plus ionomycin, whereas it enhances IFN-γ production induced b...
TCRαβ+NK1.1+ (NKT) cells are known to express various NK cell-associated molecules including the ... more TCRαβ+NK1.1+ (NKT) cells are known to express various NK cell-associated molecules including the Ly49 family of receptors for MHC class I, but its functional significance has been unclear. Here, we examined the expression of Ly49A, C/I and G2 on various NKT cell populations from normal and MHC class I-deficient C57BL/6 mice as well as their responsiveness to α-galactosylceramide (α-GalCer), a potent stimulator of CD1d-restricted NKT cells. The frequency and the level of Ly49 expression varied among NKT cells from different tissues, and were regulated by the expression of MHC class I and CD1d in the host. Stimulation of various NKT cells with α-GalCer suggested that Ly49 expression inversely correlates with the responsiveness of NKT cells to α-GalCer. Moreover, α-GalCer presented by normal dendritic cells stimulated purified Ly49−, but not Ly49+, splenic NKT cells, whereas MHC class I-deficient dendritic cells presented α-GalCer to both Ly49+ and Ly49− NKT cells equally well. Therefo...
The efficacy of natalizumab was evaluated in Japanese patients with relapsing-remitting multiple ... more The efficacy of natalizumab was evaluated in Japanese patients with relapsing-remitting multiple sclerosis (RRMS) in a 24-week, phase 2 bridging study. An open-label, 2-year extension study from this trial was conducted to assess the safety and efficacy of natalizumab treatment in Japanese patients. A total of 97 patients (43 previously on placebo; 54 previously on natalizumab) who had completed the bridging study were treated with 300 mg natalizumab every 4 weeks. Multiple sclerosis relapses, changes in Expanded Disability Status Scale (EDSS) scores, and adverse events were assessed at regular intervals. Anti-natalizumab and anti-JC virus (JCV) antibodies were measured. After 2 years of natalizumab treatment, the mean adjusted annualized relapse rate was 0.30 (95% confidence interval [CI]: 0.18-0.52) among previously-on-placebo patients and 0.13 (95% CI: 0.05-0.29) among previously-on-natalizumab patients. The mean change in EDSS score from baseline to week 120 was -0.03 among prev...
Although T cells were previously believed to recognize only peptide antigen associated with the m... more Although T cells were previously believed to recognize only peptide antigen associated with the major histocompatibility complex (MHC), recent studies have shown that there are unique T cells specialized for recognition of lipid or glycolipid antigens bound to the MHC class I-like CD1 molecules (CD1a, b, c or d). Among these lipid-specific T cells, CD1d-restricted T cells, also referred to as natural killer (NK) T cells, are of special interest as a target of drug development, since their role in immunoregulation has been indicated in various physiological or disease conditions including autoimmunity. They are unique in their homogeneous ligand specificity for alpha-glycosylated sphingolipid and secrete large amounts of regulatory cytokines shortly after T cell receptor (TCR) engagement. The first glycolipid identified as an NKT cell ligand was alpha-galactosylceramide (alpha-GalCer) derived from marine sponges. alpha-GalCer exhibits significant immunomodulatory effects by stimulating NKT cells. However, we found that an altered analogue of alpha-GalCer with a shorter sphingosine chain (OCH), is more useful than alpha-GalCer for treatment of autoimmune disease models, because of its ability to selectively induce IL-4, a key cytokine for control of autoimmunity. As such, altered glycolipid ligands (AGL) of alpha-GalCer appear to be promising reagents for treatment of human autoimmune diseases.
Experimental autoimmune encephalomyelitis (EAE) is a prototype autoimmune disease mediated by typ... more Experimental autoimmune encephalomyelitis (EAE) is a prototype autoimmune disease mediated by type 1 helper T (TH1) cells and under the control of regulatory cells. Here we report that a synthetic glycolipid ligand for CD1d-restricted natural killer T (NKT) cells expressing the semi-invariant T-cell receptor (Valpha14+) is preventive against EAE. The ligand is an analogue of alpha-galactosylceramide (alpha-GC), a prototype NKT
CD1d-restricted natural killer (NK)T cells are known to potently secrete T helper (Th)1 and Th2 c... more CD1d-restricted natural killer (NK)T cells are known to potently secrete T helper (Th)1 and Th2 cytokines and to mediate cytolysis, but it is unclear how these contrasting functional activ- ities are regulated. Using lipid antigen-loaded CD1d tetramers, we have distinguished two sub- sets of CD1d-restricted T cells in fresh peripheral blood that differ in cytokine production and cytotoxic activation. One
To clarify the molecular background underlying the heterogeneity of multiple sclerosis (MS), we c... more To clarify the molecular background underlying the heterogeneity of multiple sclerosis (MS), we characterized the gene expression profile of peripheral blood CD3+ T cells isolated from MS and healthy control (CN) subjects by using a cDNA microarray. Among 1258 cDNAs on the array, 286 genes were expressed differentially between 72 untreated Japanese MS patients and 22 age- and sex-matched CN
Proceedings of The National Academy of Sciences, 2005
A form of -galactosylceramide, KRN7000, activates CD1d-restricted V14-invariant (V14i) natural ki... more A form of -galactosylceramide, KRN7000, activates CD1d-restricted V14-invariant (V14i) natural killer (NK) T cells and initiates multiple downstream immune reactions. We report that substituting the C26:0 N-acyl chain of KRN7000 with shorter, unsaturated fatty acids modifies the outcome of V14i NKT cell activation. One analogue containing a diunsaturated C20 fatty acid (C20:2) potently induced a T helper type 2-biased cytokine
Proteolipid protein (PLP) is the major protein of central nervous system (CNS) myelin. SJL(H-2<... more Proteolipid protein (PLP) is the major protein of central nervous system (CNS) myelin. SJL(H-2<sup>S</sup>) mice immunized with a synthetic peptide corresponding to PLP residues 139–151 (HSLGKWLGHPDKF) develop acute experimental allergic encephalomyelitis (EAE). ...
Human and mouse NK cells use different families of receptors to recognize MHC class I (MHC I) on ... more Human and mouse NK cells use different families of receptors to recognize MHC class I (MHC I) on target cells. Although human NK cells express both Ig-like receptors and lectin-like receptors specific for MHC I, all the MHC I-specific receptors identified on mouse NK cells to date are lectin-like receptors, and no Ig-like receptors recognizing MHC I have been identified on mouse NK cells. In this study we report the first MHC I-specific Ig-like receptor on mouse NK cells, namely, murine CD160 (mCD160). The expression of mCD160 is restricted to a subset of NK cells, NK1.1+ T cells, and activated CD8+ T cells. The mCD160-Ig fusion protein binds to rat cell lines transfected with classical and nonclassical mouse MHC I, including CD1d. Furthermore, the level of mCD160 on NK1.1+ T cells is modulated by MHC I of the host. Overexpression of mCD160 in the mouse NK cell line KY-2 inhibits IFN-γ production induced by phorbol ester plus ionomycin, whereas it enhances IFN-γ production induced b...
TCRαβ+NK1.1+ (NKT) cells are known to express various NK cell-associated molecules including the ... more TCRαβ+NK1.1+ (NKT) cells are known to express various NK cell-associated molecules including the Ly49 family of receptors for MHC class I, but its functional significance has been unclear. Here, we examined the expression of Ly49A, C/I and G2 on various NKT cell populations from normal and MHC class I-deficient C57BL/6 mice as well as their responsiveness to α-galactosylceramide (α-GalCer), a potent stimulator of CD1d-restricted NKT cells. The frequency and the level of Ly49 expression varied among NKT cells from different tissues, and were regulated by the expression of MHC class I and CD1d in the host. Stimulation of various NKT cells with α-GalCer suggested that Ly49 expression inversely correlates with the responsiveness of NKT cells to α-GalCer. Moreover, α-GalCer presented by normal dendritic cells stimulated purified Ly49−, but not Ly49+, splenic NKT cells, whereas MHC class I-deficient dendritic cells presented α-GalCer to both Ly49+ and Ly49− NKT cells equally well. Therefo...
The efficacy of natalizumab was evaluated in Japanese patients with relapsing-remitting multiple ... more The efficacy of natalizumab was evaluated in Japanese patients with relapsing-remitting multiple sclerosis (RRMS) in a 24-week, phase 2 bridging study. An open-label, 2-year extension study from this trial was conducted to assess the safety and efficacy of natalizumab treatment in Japanese patients. A total of 97 patients (43 previously on placebo; 54 previously on natalizumab) who had completed the bridging study were treated with 300 mg natalizumab every 4 weeks. Multiple sclerosis relapses, changes in Expanded Disability Status Scale (EDSS) scores, and adverse events were assessed at regular intervals. Anti-natalizumab and anti-JC virus (JCV) antibodies were measured. After 2 years of natalizumab treatment, the mean adjusted annualized relapse rate was 0.30 (95% confidence interval [CI]: 0.18-0.52) among previously-on-placebo patients and 0.13 (95% CI: 0.05-0.29) among previously-on-natalizumab patients. The mean change in EDSS score from baseline to week 120 was -0.03 among prev...
Although T cells were previously believed to recognize only peptide antigen associated with the m... more Although T cells were previously believed to recognize only peptide antigen associated with the major histocompatibility complex (MHC), recent studies have shown that there are unique T cells specialized for recognition of lipid or glycolipid antigens bound to the MHC class I-like CD1 molecules (CD1a, b, c or d). Among these lipid-specific T cells, CD1d-restricted T cells, also referred to as natural killer (NK) T cells, are of special interest as a target of drug development, since their role in immunoregulation has been indicated in various physiological or disease conditions including autoimmunity. They are unique in their homogeneous ligand specificity for alpha-glycosylated sphingolipid and secrete large amounts of regulatory cytokines shortly after T cell receptor (TCR) engagement. The first glycolipid identified as an NKT cell ligand was alpha-galactosylceramide (alpha-GalCer) derived from marine sponges. alpha-GalCer exhibits significant immunomodulatory effects by stimulating NKT cells. However, we found that an altered analogue of alpha-GalCer with a shorter sphingosine chain (OCH), is more useful than alpha-GalCer for treatment of autoimmune disease models, because of its ability to selectively induce IL-4, a key cytokine for control of autoimmunity. As such, altered glycolipid ligands (AGL) of alpha-GalCer appear to be promising reagents for treatment of human autoimmune diseases.
Experimental autoimmune encephalomyelitis (EAE) is a prototype autoimmune disease mediated by typ... more Experimental autoimmune encephalomyelitis (EAE) is a prototype autoimmune disease mediated by type 1 helper T (TH1) cells and under the control of regulatory cells. Here we report that a synthetic glycolipid ligand for CD1d-restricted natural killer T (NKT) cells expressing the semi-invariant T-cell receptor (Valpha14+) is preventive against EAE. The ligand is an analogue of alpha-galactosylceramide (alpha-GC), a prototype NKT
CD1d-restricted natural killer (NK)T cells are known to potently secrete T helper (Th)1 and Th2 c... more CD1d-restricted natural killer (NK)T cells are known to potently secrete T helper (Th)1 and Th2 cytokines and to mediate cytolysis, but it is unclear how these contrasting functional activ- ities are regulated. Using lipid antigen-loaded CD1d tetramers, we have distinguished two sub- sets of CD1d-restricted T cells in fresh peripheral blood that differ in cytokine production and cytotoxic activation. One
To clarify the molecular background underlying the heterogeneity of multiple sclerosis (MS), we c... more To clarify the molecular background underlying the heterogeneity of multiple sclerosis (MS), we characterized the gene expression profile of peripheral blood CD3+ T cells isolated from MS and healthy control (CN) subjects by using a cDNA microarray. Among 1258 cDNAs on the array, 286 genes were expressed differentially between 72 untreated Japanese MS patients and 22 age- and sex-matched CN
Proceedings of The National Academy of Sciences, 2005
A form of -galactosylceramide, KRN7000, activates CD1d-restricted V14-invariant (V14i) natural ki... more A form of -galactosylceramide, KRN7000, activates CD1d-restricted V14-invariant (V14i) natural killer (NK) T cells and initiates multiple downstream immune reactions. We report that substituting the C26:0 N-acyl chain of KRN7000 with shorter, unsaturated fatty acids modifies the outcome of V14i NKT cell activation. One analogue containing a diunsaturated C20 fatty acid (C20:2) potently induced a T helper type 2-biased cytokine
Proteolipid protein (PLP) is the major protein of central nervous system (CNS) myelin. SJL(H-2<... more Proteolipid protein (PLP) is the major protein of central nervous system (CNS) myelin. SJL(H-2<sup>S</sup>) mice immunized with a synthetic peptide corresponding to PLP residues 139–151 (HSLGKWLGHPDKF) develop acute experimental allergic encephalomyelitis (EAE). ...
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Papers by Takashi Yamamura