| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1997: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
The class II HLA molecule (HLA-DR, -DQ or -DP) is expressed on various antigen presenting cells (APC), B cells and activated T cells in humans. Proteolytic fragments of peptides processed by APC that match thc physicochemical character of the peptide-binding grooves formed by alpha and beta chains of class II HLA molecules are expressed on the surface of APC to be recognized by T cells. The highly polymorphic amino acid residues of the class II HLA molecules reside within the grooves, indicating that genetic polymorphism accounts for the wide spectrum of peptides capable of binding. Side chains of an HLA-DR1-binding peptide project from the peptide backbone approximately every 130ﾟC within the groove. Many DR-binding peptide motifs reported to date follow the 9-mer peptide pattern AxxBxCDxE, with A, B, C, D, and E residues functioning for binding to HLA, thereby designated as "anchors". On the contrary, the x residues are recognized by T cells through T-cell receptor (TCR). Analogue peptides with single residue substitutions at x residues changed signals in T cells, leading to quantitative (TCR antagonism, etc.) and qualitative (anergy/survival, etc.) changes in human T-cell clonal responses. Certain analogues changed signals in monocytes, leading to the up-regulation of IL-12. Furthermore, cross-linking of class II HLA molecules on monocytes using mAbs lead to up-regulation of monokines, in which HLA-DR, -DQ, and -DP play differential roles. Thus, HLA molecules when recognized by TCR, not only present peptide antigens to T cells but also transmit signals to APC, where the polymorphism and heterogeneity of HLA molecules play important roles.
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