2007 Fiscal Year Final Research Report Summary
Therapeutic potential of glicolipid for iNKT cells for autoimmunes and allergic diseases
| Project/Area Number |
18390295
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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 |
膠原病・アレルギー・感染症内科学
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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, National Institute of Neurosciense, NCNP Dept. of Immunol, Section Chief (50266045)
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| Project Period (FY) |
2006 – 2007
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| Keywords | iNKT celld(2) / CD1 / Glycolipid ligand / arthrits / Cytokine |
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| Research Abstract |
CD1d-restricted invariant natural killer T (iNKT) cells are a unique subset of T cells that express an invariant TCRα chain and recognize glycolipid antigens in the context of CD1d iNKT cells are an attractive target for the development of immunotherapies not only because they contribute to various kinds of immunoregulation but also because several synthetic glycolipid ligands exert specific activation of iNKT cells. α-galactosylceramide (α-GalCer) is a synthetic glycolipid originally isolated from marine sponges Agelas mauritanius, and later, a synthetic analogue of this compound has been used in experimental studies and several cancer clinical trials to date. These findings led us to screen a panel of analogues of α-GalCer to suppress antibody-mediated arthritis and found an analogue with an elongation of shpingoshine chain (SGL-S23).
SGL-S23 strongly suppressed K/BxN serum transfer arthritis by inhibiting inflammatory cellular infiltration and subsequent destruction of cartilage and bone. The inhibitory effect mediated by SGL-S23 was abolished by neutralization of IFN-γ. Systemic administration of IFN-γ prevented the development of the inflammatory arthritis. Histamine release was suppressed by administration of SGL-S23 or IFN-γ. Degranulated mast cells in the synovium was significantly reduced in SGL-S23-treated mice, suggesting the suppression of mast cell activation contributes to the inhibition of arthritis.
This study suggests that activation of iNKT cells with glycolipid ligands holds therapeutic possibilities for autoimmune disease such as rheumatoid arthritis. SGL-S23 has clinical benefit over α-galactosylceramide as it induces a weaker cytokine production response in iNKT cells therefore reducing potential side-effect due to excessive cytokine release.
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