2001 Fiscal Year Final Research Report Summary
Development of disease-specific diagnosis and immunotherapy for Sjogren's syndrome
| Project/Area Number |
12557022
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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 | 展開研究 |
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| Research Field |
Experimental pathology
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| Research Institution | The University of Tokushima |
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Principal Investigator |
HAYASHI Yoshio The University of Tokushima School of Dentistry, Department of Pathology, Professor, 歯学部, 教授 (00127854)
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| Project Period (FY) |
2000 – 2001
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| Keywords | autoimmune disease / Sjogren's syndrome / autoantigen / specific diagnostic system / ELISA assay / α-fodrin cDNA / fusion protein / peptide-based immunotherapy |
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| Research Abstract |
Previously we have identified a 120 kD α-fodrin as a common autoantigen in the pathogenesis of primary Sjogren's syndrome (SS) in humans, but the mechanisms underlying the immunodominant epitope recognition remain unclear. SS in human is a T cell-mediated autoimmune disease in the salivary and lacrimal glands, leading to clinical symptoms of dryness of the mouth and eyes (sicca syndrome). Recombinant α-fodrin protein, the cDNA encoding human α-fodrin (JS-1) was constructed by inserting cDNA into EcoR1 site of pGEX-2T, To establish disease-specific diagnostic system, approximately 200 sera from patients with SS were tested with ELISA assay using JS-1 recombinant protein. Autoreactive T cell clones that recognize synthetic N-terminal portion of α-fodrin autopeptide were established, which produced Th1 cytokines, and showed cytotoxic activities. Alanine scanning mutagenesis of the epitope peptide indicate that the two amino acid substitutions of MHC contact points within epitope are sufficient to alter peptide binding and MHC restriction. Moreover, it is evident that only two TCR contact points are essential for initiation of antigen-specific T cell response. An analogue peptide-based vaccination prevented the disease through downregulation of Th1 responses and autoantibody production. Blockade of pathogenic T cell activity through an analogue peptide-based immunotherapy is highly effective for T cell-mediated autoimmune disease such as human SS.
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