Presentation of a major histocompatibility complex class 1-binding peptide by monocyte-derived dendritic cells incorporating hydrophobized polysaccharide-truncated HER2 protein complex: implications for a polyvalent immuno-cell therapy
Presentation of a major histocompatibility complex class 1-binding peptide by monocyte-derived dendritic cells incorporating hydrophobized polysaccharide-truncated HER2 protein complex: implications for a polyvalent immuno-cell therapy
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DOI：
10.1182/blood.v99.10.3717
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发表时间：
2002-05-15
期刊：
影响因子：
20.3
通讯作者：
Shiku, H
中科院分区：
文献类型：
--
作者：
Ikuta, Y;Katayama, N;Shiku, H
对树突状细胞(DC)作为专业抗原提呈细胞的重要作用的认识促使研究人员寻找将DC用作免疫治疗的天然佐剂的方法。针对癌细胞的CD8(+)细胞毒性T淋巴细胞(CTL)识别的一系列抗原寡肽已经应用于DC的临床试验。这种针对特定类型的HLA1分子具有单一表位的单价疫苗是有效的。然而，多价疫苗可能更有效。我们设计了一种新型的蛋白质递送系统，该系统由疏水多糖与靶蛋白络合而成。制备了含有147个N端氨基酸的截短的HER2蛋白，包括9聚体HER2p63-71肽(HER2p63)，TYLPTNASL，这是一种抗原性小鼠肿瘤排斥反应多肽的人类同源物。我们在此报道，人类白细胞抗原-A2402(+)树突状细胞可以结合疏水多糖截短的HER2蛋白复合体，并将其加工成主要组织相容性复合体1类结合HER2p63的多肽。这些复合体通过吞噬进入树突状细胞，然后截短的蛋白质通过类似于内源性蛋白质的途径进行加工。由这些复合体致敏的DC在HLA-A2402的背景下启动和增强HER2p63特异性CD8+T细胞。在表达HER2的小鼠肿瘤模型中，接种含有这些复合体的DC可完全抑制肺转移。我们还从CHP/HER2-147处理的小鼠的淋巴细胞中产生了3个与不同的HER2衍生的25聚肽反应的CD4(+)克隆。因此，疏水多糖-蛋白质复合体是构建多价疫苗的有前途的候选者。(C)2002年，由美国血液病学会公布。
Recognition of the essential role of dendritic cells (DCs) as professional antigen-presenting cells has prompted investigators to search for methods to use DCs as natural adjuvants in Immunotherapy. A number of antigenic oligopeptides, recognized by CD8(+) cytotoxic T lymphocytes (CTLs) specific for cancer cells, have been applied in clinical trials using DCs. Such a monovalent vaccine with a single epitope for a particular type of HLA class 1 molecule would be effective. However, a polyvalent vaccine might be more potent. We designed a novel protein delivery system consisting of hydrophobized polysaccharides complexed with target proteins. The truncated HER2 protein encompassing 147 N-terminal amino acids, including the 9-mer HER2p63-71 peptide (HER2p63), TYLPTNASL, the human homologue of an antigenic murine tumor rejection peptide, was prepared. We report here that HLA-A2402(+) DCs could incorporate hydrophobized polysaccharide-truncated HER2 protein complexes and process the protein to present major histocompatibility complex class 1-binding HER2p63 peptide. The complexes enter DCs by phagocytosis, and then the truncated protein is processed through a pathway similar to that for endogenous proteins. DCs sensitized by these complexes primed and boosted HER2p63-specific CD8+ T cells in the context of HLA-A2402. Vaccination with DCs incorporating these complexes completely suppressed lung metastases in a HER2-expressing murine tumor model. We also generated 3 CD4(+) clones reactive with different HER2-derived 25-mer peptides from lymph node cells in mice treated with CHP/HER2-147. Thus, hydrophobized polysaccharide-protein complexes are promising candidates for the construction of polyvalent vaccines. (C) 2002 by The American Society of Hematology.