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Immunotherapy for childhood leukemia and solid tumors using dendritic cells

使用树突状细胞治疗儿童白血病和实体瘤的免疫疗法

基本信息

批准号：
18591191
负责人：
MATSUZAKI Akinobu
金额：
$ 2.49万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591191/
关键词：
dendritic cell tumor antigen child immunotherapy leukemia

项目摘要

(1)Generation of leukemia cell-derived dendritic cells (DCs): In order to establish the effective immunotherapy using DCs, DCs were generated directly from leukemia cells. When primary leukemia blasts were cultured in the presence of GM-CSF, TNF- a , Flt-3 ligand, and IL-4, the blasts from the patients with AML M4 and M5a expressed CD 11c, CD80, CD83, CD86. These findings suggested that the leukemia cells of some AML subtypes can differentiate into DCs and might present leukemia-specific antigens directly to T lymphocytes.(2) Expression of cytokine-associated genes in DCs: The expression of cytokine-associated genes in DCs derived from umbilical cord blood (UCB) and adult peripheral blood (APB) was compared. The expression of the Th1 response-related genes and chemokine genes was significantly lower in UCB-DCs than in APB-DC in both maturation states. Calgranulins A and B, which are speculated to induce immune tolerance, showed higher expression in UCB-DCs. The expression of particular genes related to immune responses was significantly different between UCB-and APB-DCs, which may cause functional difference in DC-mediated immunity between newborns and adults.(3)The utility of recombinant Sendai virus(rSeV) for effective DC-mediated immunotherapy against childhood cancer; The ex vivo infection of immature DCs with rSeV induces their spontaneous maturation and activation. We tried to apply this result to the treatment for patients with childhood cancer to setablish a new powerful DC-mediated immunotherapy. Peripheral blood mononuclear cells were isolated from the children with cancer and were cultured in the presence 10% autologous serum, GM-CSF, IL-4 and TNF-α to generate DCs. When the generated DCs were infected with rSeV, the expression of CD80, CD83 and CD86 was markedly enhanced. These findings suggested that rSeV could be a powerful booster for DC-mediated cancer immunotherapy, which might improve the prognosis of children with cancer.

（1）白血病细胞衍生的树突状细胞（DC）的产生：为了建立使用DC的有效免疫疗法，直接从白血病细胞产生DC。当原代白血病原始细胞在GM-CSF、TNF-α、Flt-3配体和IL-4存在下培养时，来自AML M4和M5 a患者的原始细胞表达CD 11 c、CD 80、CD 83、CD 86。提示某些AML亚型的白血病细胞可分化为DC，并可直接向T淋巴细胞提呈白血病特异性抗原。(2)树突状细胞中精氨酸相关基因的表达：比较脐带血（UCB）和成人外周血（APB）来源的树突状细胞中精氨酸相关基因的表达。在两种成熟状态下，UCB-DC中Th 1应答相关基因和趋化因子基因的表达均显著低于APB-DC。推测可诱导免疫耐受的钙颗粒蛋白A和B在UCB-DCs中表现出较高的表达。UCB-和APB-DCs免疫应答相关基因的表达存在明显差异，这可能是新生儿和成人DCs免疫功能差异的原因之一。（3）重组仙台病毒（rSeV）在DC介导的有效免疫治疗中的应用：rSeV体外感染未成熟DC诱导其自发成熟和活化。我们尝试将这一结果应用于儿童癌症患者的治疗，以建立一种新的强大的DC介导的免疫治疗。分离肿瘤患儿外周血单个核细胞，在10%自体血清、GM-CSF、IL-4和TNF-α的共同作用下诱导分化为DC。rSeV感染DC后，DC表面CD 80、CD 83和CD 86的表达明显增强。这些发现表明，rSeV可能是DC介导的癌症免疫治疗的有力助推器，这可能会改善癌症儿童的预后。