Overcome to avoidance from the anti-leukemia immunity by using combination therapy with HSP and dendritic cells targeted to both tumor and tumor angiogenesis

通过使用针对肿瘤和肿瘤血管生成的 HSP 和树突状细胞联合疗法，克服抗白血病免疫的回避

• 批准号: 20591143
• 负责人: SATO Kazuya
• 金额: $ 2.91万
• 依托单位: Asahikawa Medical College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20591143/
• 关键词: 腫瘍血管内皮; 熱ショック蛋白(HSP); VEGF; 白血病特異免疫; 腫瘍血管新生; 細胞不死化; IGF; hTERT; 白血病; VEGFR1; 不死化; 熱ショックタンパク(HSP)

In this study, we tried induction of the anti-leukemia immunity by using heat shock protein (HSP) targeted to both tumor and tumor angiogenesis. We demonstrated the presence of tumor angiogenesis in the A20-bearing mouse by endothelium cell (EC)-marker CD31 immunostaining. It was difficult to obtain the enough amount of EC by MACS with anti-CD31 antibody (Ab). We therefore originated GFP transduced A20-cells, and then GFP-negative fraction was sorted from A20-tumor tissue. Now we tried to separate the A20-tumor-associated EC (A20-EC) by using sorted GFP-negative fraction. To increase the number of EC, a vector containing immortalizing gene teromerase reverse transcriptase (TERT) was constructed. After successful A20-EC separation, transduction of TERT gene to A20-ESs and expansion of them will be performed, and then purification of A20-EC-derived HSP will be planed. To obtain the useful information of tumor endotherial antigen in the B-cell neoplasms, the specimen of solitary plasmacytoma in POEMS syndrome, which is known as one of the angiogenic B-cell neoplasms, was immunostained with angiogenic factors, and we demonstrated that the expression levels of VEGF and IGF were very high in the tumor. In addition, we showed the possibility that anti-idiotype Ab of mouse B-cell neoplasm may inhibit the angiogenesis in the microenvironment of the B-cell tumor through humoral immunity by the CDC. These findings enable the approach by novel immunotherapy against tumor ECs with unique motifs, such as HSPs derived from B-cell neoplasm associated ECs or anti-idiotype Ab.

在这项研究中，我们通过使用针对肿瘤和肿瘤血管生成的热休克蛋白（HSP）尝试诱导抗白血病免疫。我们证明了通过内皮细胞（EC）标记CD31免疫染色在A20耐A2的小鼠中存在肿瘤血管生成。具有抗CD31抗体（AB）的MAC很难获得足够量的EC。因此，我们起源于GFP转导A20细胞，然后从A20肿瘤组织中对GFP阴性分数进行分类。现在，我们尝试通过使用分类的GFP阴性分数分离与A20肿瘤相关的EC（A20-EC）。为了增加EC的数量，构建了含有永生基因结构酶逆转录酶（TERT）的载体。成功的A20-EC分离后，将执行TERT基因向A20-ESS的转导，然后计划纯化A20-EC衍生的HSP。为了获得B-Cell肿瘤中肿瘤吸收性抗原的有用信息，诗歌综合征中单生的浆细胞瘤标本（称为血管生成B细胞肿瘤之一）是用血管生成因子免疫染色的，我们证明了VEGFF和IGF的表达水平很高。此外，我们还表明了小鼠B细胞肿瘤的抗二动型AB可能会通过CDC通过体液上的体液免疫来抑制B细胞肿瘤微环境中的血管生成。这些发现可以通过针对具有独特基序的肿瘤EC的新型免疫疗法，例如源自B细胞肿瘤相关的EC或抗IDiotype AB的HSP。

项目成果

A Crucial Cytotoxic Role of Anti-Idiotypic Antibody in Immunotherapy for B-Cell Neoplasms with Tumor Cell-Derived Heat Shock Protein 70

抗独特型抗体在使用肿瘤细胞衍生的热休克蛋白 70 进行 B 细胞肿瘤免疫治疗中的重要细胞毒性作用

• 发表时间: 2009
• 作者: Kazuya Sato;Junko Jimbo;Naoka Okamura;Takaaki Hosoki;Motohiro Shindo;Katsuya Ikuta;Yusuke Mizukami;Yoshihiro Torimoto;Yutaka Kohgo
• 通讯作者: Yutaka Kohgo

Development of POEMS Syndrome after an Initial Manifestation of Solitary Plas macytoma

孤立性浆细胞瘤初始表现后 POEMS 综合征的发展

• 发表时间: 2011
• 期刊: International Journal of Hematology
• 影响因子: 2.1
• 作者: Motohiro Shindo;Kazuya Sato;Masayo Yamamoto;Yasumichi Toki;Mayumi Hatayama;Satoshi Ito;Kazuhiko Ichiki;Naoka Okamura;Takaaki Hosoki;Katsuya Ikuta;Junki Inamura;Shinji Watanabe;Yoshihiro Torimoto;Yutaka Kohgo
• 通讯作者: Yutaka Kohgo

Development of POEMS syndrome after an initial manifestation of solitary plasmacytoma

孤立性浆细胞瘤初始表现后出现 POEMS 综合征

• 发表时间: 2011
• 期刊: Int J Hematol. (Epub ahead of print)
• 作者: Shindo M;Sato K;Yamamoto M;Toki Y;Hatayama M;Ito S;Ichiki K;Okamura N;Hosoki T;Ikuta K.Inamura J;Watanabe S;Torimoto Y;Kohgo Y
• 通讯作者: Kohgo Y

マウス白血病細胞に対する熱ショック蛋白70を用いた免疫療法における液性免疫応答の誘導Humoral immune responses in immunotherapy with HSP70 against leukemia in mice

HSP70 在小鼠白血病免疫治疗中诱导体液免疫反应

• 作者: 神保絢子;佐藤一也;細木卓明;進藤基博;生田克哉;鳥本悦宏;高後裕
• 通讯作者: 高後裕

Transplanting normal vascular proangiogenic cells to tumor-bearing mice triggers vascular remodeling and reduces hypoxia in tumors.

• DOI: 10.1158/0008-5472.can-10-0412
• 发表时间: 2010-08-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Sasajima J;Mizukami Y;Sugiyama Y;Nakamura K;Kawamoto T;Koizumi K;Fujii R;Motomura W;Sato K;Suzuki Y;Tanno S;Fujiya M;Sasaki K;Shimizu N;Karasaki H;Kono T;Kawabe J;Ii M;Yoshiara H;Kamiyama N;Ashida T;Bardeesy N;Chung DC;Kohgo Y
• 通讯作者: Kohgo Y