臺灣博碩士論文加值系統

骨頭保護素 (OPG) 為腫瘤壞死因子受體 (TNFR) 家族中的一員，它是 TRANCE 和 TRAIL 的可溶性受體。目前為大家所熟知骨頭保護素可藉由阻斷 TRANCE 的作用來抑制蝕骨細胞 (osteoclast) 的分化及活化。此外，由骨頭保護素的基因剔除小鼠 (OPG-/-) 所得到的骨髓源性樹狀細胞 (bone marrow-derived dendritic cell) 具有較強的能力來刺激異體 T 細胞的增生，且會分泌較多的發炎性細胞激素，由此顯示骨頭保護素在免疫反應中對於調控樹狀細胞的功能扮演著一個重要的角色。為了了解骨頭保護素是否可藉由調控樹狀細胞的分化來調空其功能，我們生產了重組的骨頭保護素來研究其在人類 CD14+ 單核細胞分化成樹狀細胞的過程中所扮演的角色。我們的研究結果顯示重組骨頭保護素與人類 IgG1 Fc 融合蛋白 (OPG.Fc)、交聯之重組骨頭保護素與 FLAG 融合蛋白 (cross-linked OPG.FLAG) 及重組骨頭保護素與突變的人類 IgG1 Fc 融合蛋白 (OPG.Fcmut) 皆具顯著的能力來調節由單核細胞分化而來之樹狀細胞的形態，其中包括表面抗原 CD1a、CD80/B7.1及 DC-SIGN 表現量的下降，而表面抗原 CD86/B7.2 的表現量則上升。此外， 重組骨頭保護素與人類 IgG1 Fc 融合蛋白處理過之樹狀細胞刺激 CD4+ T 細胞增生的能力明顯地減弱，且顯著地激活了 CD4+ T 細胞產生較高量的 IFN-γ 及 IL-4。有趣的是，骨頭保護素所引起的調節作用並非藉由與其已知的配體，TRANCE 及 TRAIL ，之結合。骨頭保護素所引起的調節作用乃藉由骨頭保護素 C 端會和肝磷脂 (heparin) 結合的區域和單核細胞表面的硫酸肝素蛋白多糖 (HSPG) 之間的交互作用所造成。這些結果顯示骨頭保護素可藉由交聯單核細胞表面之硫酸肝素蛋白多糖來調節免疫反應，同時也為未來提供了一個新穎的療法即利用交聯細胞表面之硫酸肝素蛋白多糖來調節宿主之免疫反應。

Osteoprotegerin (OPG), a member of tumor necrosis factor receptor superfamily, is a soluble receptor for both TRANCE and TRAIL. It is well known that OPG regulates bone metabolism by blocking the effects of TRANCE to inhibit osteoclast differentiation and activation. Moreover, the bone marrow-derived dendritic cells (DCs) from OPG-/- mice are more efficiently in stimulating allogeneic T cells and secrete elevated amounts of inflammatory cytokines, suggesting OPG plays an important role in the immune response regulating the function of DCs. To understand whether OPG affects the functions of DCs through modulating DC differentiation, we generate recombinant OPG proteins to investigate its role in the differentiation of human CD14+ monocytes to DCs. We find that OPG.Fc, cross-linked OPG.FLAG, and OPG.Fcmut all have profound effects to modulate the phenotype of CD14+ monocytes-derived immature DCs, including the down-regulation of CD1a, CD80, and DC-SIGN, as well as the up-regulation of CD86. Moreover, OPG.Fc-primed immature DCs suppress CD4+ T cell proliferation, and up-regulate IFN-γ and IL-4 secretion of CD4+ T cells in allogeneic mixed lymphocyte reaction (MLR). Interestingly, the modulatory effects exerted by OPG are not through binding to its natural ligands, TRANCE and TRAIL. Instead, OPG-mediated modulation is via the interactions of the heparin-binding <a href="http://www.ntsearch.com/search.php?q=domain&v=56">domain</a> located at the C-terminus of OPG to heparan sulfate proteoglycans (HSPGs) expressed on the surface of CD14+ monocytes. These results reveal that cross-linking of HSPG on CD14+ monocytes by OPG can modulate immune responses, and suggest a novel therapeutic utility by cross-linking HSPG to modulate <a href="http://www.ntsearch.com/search.php?q=host&v=56">host</a> immunity in the future.

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