Low-dose peptide tolerance therapy of lupus generates plasmacytoid dendritic cells that cause expansion of autoantigen-specific regulatory T cells and contraction of inflammatory Th17 cells
Low-dose peptide tolerance therapy of lupus generates plasmacytoid dendritic cells that cause expansion of autoantigen-specific regulatory T cells and contraction of inflammatory Th17 cells
复制标题
DOI：
10.4049/jimmunol.178.12.7849
复制
发表时间：
2007-06-15
影响因子：
4.4
通讯作者：
Datta, Syamal K.
中科院分区：
文献类型：
--
作者：
Kang, Hee-Kap;Liu, Michael;Datta, Syamal K.
当将亚纳摩尔剂量的一种未改变的、天然存在的核小体组蛋白肽表位H4(71 - 94)皮下注射到易患狼疮的小鼠体内时，通过产生分泌转化生长因子 - β（TGF - β）的CD4(+)25(+)和CD8(+)调节性T细胞（Treg），显著延长了寿命。诱导产生的Treg细胞抑制核自身抗原特异性的辅助性T细胞（Th）和B细胞，并阻断肾脏炎症。脾脏树突状细胞（DC）迅速摄取皮下注射的H4(71 - 94)肽，并表现出耐受表型。耐受动物的树突状细胞，尤其是浆细胞样树突状细胞，在通过核小体自身抗原和其他配体经Toll样受体 - 9（TLR - 9）通路刺激时，产生更多的转化生长因子 - β，但白细胞介素 - 6（IL - 6）减少；并且这些浆细胞样树突状细胞通过同时诱导自身抗原特异性Treg细胞和抑制浸润未治疗狼疮小鼠肾脏的炎性Th17细胞，阻断了狼疮自身免疫疾病。尽管狼疮免疫系统自发地预先对自身表位有反应倾向，但H4(71 - 94)的低剂量耐受仍然有效。因此，优先针对致病性自身免疫细胞的H4(71 - 94)肽耐受疗法可以使狼疮患者避免长期接受有毒药物或全身性免疫抑制剂，并通过恢复自身抗原特异性Treg细胞来维持缓解。
Subnanomolar doses of an unaltered, naturally occurring nucleosomal histone peptide epitope, H4(71-94), when injected s.c. into lupus-prone mice, markedly prolong lifespan by generating CD4(+)25(+) and CD8(+) regulatory T cells (Treg) producing TGF-P. The induced Treg cells suppress nuclear autoantigen-specific Th and B cells and block renal inflammation. Splenic dendritic cells (DC) captured the s.c.-injected H4(71-94) peptide rapidly and expressed a tolerogenic phenotype. The DC of the tolerized animal, especially plasmacytoid DC, produced increased amounts of TGF-beta, but diminished IL-6 on stimulation via the TLR-9 pathway by nucleosome autoantigen and other ligands; and those plasmacytoid DC blocked lupus autoinumme disease by simultaneously inducing autoantigen-specific Treg and suppressing inflammatory Th17 cells that infiltrated the kidneys of untreated lupus mice. Low-dose tolerance with H4(71-94) was effective even though the lupus immune system is spontaneously preprimed to react to the autoepitope. Thus, H4(71-94) peptide tolerance therapy that preferentially targets pathogenic autoimmune cells could spare lupus patients from chronically receiving toxic agents or global immunosuppressants and maintain remission by restoring autoantigen-specific Treg cells.