2003 Fiscal Year Final Research Report Summary
Therapeutic potential of gylcolipid ligands for natural killer (NK) T cells in the suppression of autoimmune diseases
| Project/Area Number |
14370169
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
内科学一般
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| Research Institution | National Center of Neurology and Psychiatry |
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Principal Investigator |
MIYAKE Sachiko National Center of Neurology and Psychiatry (NCNP), National Institute of Neuroscience, Dept. of Immunology, Section Chief, 神経研究所・免疫研究部, 室長 (50266045)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMURA Takashi National Center of Neurology and Psychiatry (NCNP), National Institute of Neuroscience, Dept. of Immunology, Director, 神経研究所・疾病研究第六部, 部長 (90231670)
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| Project Period (FY) |
2002 – 2003
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| Keywords | NKT cells / Glycolipid / Autoimmune disease / Th2 cytokine / Collagen-induced arthritis / Type I diabetes / Experimental autoimmune encepahlomyelitis / Lupus model |
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| Research Abstract |
NKT cells emerge as important regulatory cells in autoimmune responses. Abnormalities in the numbers and functions of NKT cells have been observed in patients with autoimmune diseases as well as in a variety of mouse strains that are genetically predisposed for development of autoimmune diseases. We recently developed a synthetic glycolipid ligand OCH for NKT cells, an analogue of α-galactosylceramide (α-GC) with a truncated sphingosine chain. OCH induces a selective production of Th2 cytokines such as IL-4 and IL-10,whereas α-GC stimulates NKT cells to produce both IFN-γ and IL-4. We also demonstrated that administration of OCH inhibited experimental autoimmune encephalomyelitis (EAE). Here we show that administration of OCH, but not α-GC inhibits different Th1-mediated autoimmune disease models, collagen induced arthritis (CIA) and type I diabetes in NOD mouse by inducing Th2 bias of autoimmune T cells. Injection of OCH significantly suppressed EAE, CIA and diabetes clinically and histologically. The suppressive effect of OCH was not seen on EAE and CIA induced in CD1 knockout mouse, indicating OCH-mediated inhibition is dependent on NKT cells. Administration of anti-IL-4 or anti-IL-10 mAb abolished the inhibitory effect of OCH for CIA, suggesting Th2 cytokines secreted from NKT cells are critical for the suppression of CIA by OCH. Administration of OCH effectively inhibited CIA induced SJL mouse and diabetes in NOD mouse. SJL and NOD mice have been reported to be reduced in frequency and to have a defect in cytokine secretion from NKT cells upon activation as seen in the patients with autoimmune diseases, suggesting OCH is effective in these atuoimmune-prone mice. The lack of polymorphism of CD1d and cross-reactive response of mouse and human NKT cells to the same ligand indicates that targeting NKT cells with this ligand may be an attractive means for intervening in human autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
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[Publications] Koike F, Satoh J-i, Miyake S, Yamamoto T, Kawai M, Kikuchi S, Nomura K, Yokoyama K, Ota K, Kanda T, Fukazawa T, Yamamura T.: "Microarray analysis identifies interferon β-regulated genes in multiple sclerosis."J.Neuroimmunol.. 139(1-2). 109-118 (2003)
Description
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[Publications] Stanic AK, Shashidharamurthy R, Bezbradica JS, Matsuki N, Yoshimura Y, Miyake S, Choi EY, Schell TD, Van Kaer L, Tevethia SS, Roopenian DC, Yamamura T, Joyce S.: "Another view of T cell antigen recognition : cooperative engagement of glycolipid antigens by Vα14Jα18 natural TCR."J.Immunol.. 171(9). 4539-4551 (2003)
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[Publications] Nakai Y, Iwabuchi K, Fujii S, Ishimori N, Dashtsoodol N, Watano K, Mishima T, Iwabuchi C, Kato K, Tanaka S, Bezbradica JS, Nakayama T, Tanigchi M, Miyake S, Yamamura T, Kitabatake A, Joyce S, Van Kaer L, Onoe K.: "Natural killer T cells accelerate atherogenesis in mice."Blood. (In press).
Description
「研究成果報告書概要(欧文)」より
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[Publications] Satoh J-i, Nakanishi M, Koike F, Miyake S, Yamamuto T, Kawai M, Kikuchi S, Nomura K, Yokoyama K, Ota K, Kanda T, Fukazawa T, Yamamura T.: "Microarray analysis identifies an aberrant expression of apoptosis and DNA damage-regulatory genes in multiple sclerosis."Neurobiol.Dis.. (In press).
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