A higher immune system model by combination of several types of artificial tissues (connective tissue, carcinoma tissue, and lymphoid tissue)

多种人工组织（结缔组织、癌组织、淋巴组织）组合而成的高级免疫系统模型

• 批准号: 13470240
• 负责人: KATANO Mitsuo
• 金额: $ 10.3万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470240/
• 关键词: artificial connective tissue; artificial carcinoma tissue; artificial lymphoid tissue; higher immune system; immunotherapy; tumor immunity; 人工結合織; 人工血管; 人工リンパ節; 高次免疫組織

This study was focused on the construction of "a higher in vitro immune system model" by combining several types of artificial tissues, including connective tissues, carcinoma tissues, lymphoid tissues, and blood vessel. To perform the research plan, a new research area "tumor technology" was organized by collaboration of "Division of tumor immunology" and "Division of medical technology".Data obtained for duration of this study are as follows:(1) Development of artificial connective tissue: we reconstituted an in vitro connective tissue model which is made up of human fifroblasts and human umbrical vein-derived endothelial cells (HUVEC) in a type-I collagen gel. In this model, HUVEC migrate and form nets of fine blood vessels without addition of any special growth factors.(2) Development of artificial carcinoma tissue: we reconstituted two types of artificial carcinoma tissue. One is a soft tissue type in which we are able to observe microscopically the growth of the two cell types (c … More arcinoma cells and fibroblasts) in real time for more than 30 days. Another is a hard tissue type which is prepared for immunohistochemical analysis. In this model, we can control the growth pattern of carcinoma cells, i.e., expansive or invasive growth, by combination of cytokines used.(3) Development of artificial lymphoid tissue: artificial lymphoid tissue is organized in a type I collagen net supplemented with OKT-3 and fibrinogen, human fibroblasts, lymphocytes, and IL-2. In this model, lymphocytes well proliferate and secrete several types of cytokines such as IFN-g for more than 10 days.(4) Development of preliminary immune system model: we reconstituted a preliminary higher immune system model which is organized in three layers, i.e., dendritic cell layer (lower), carcinoma tissue layer (middle), and lymphoid tissue layer (upper). In this model, we are able to observe microscopically migration of dendritic cells into carcinoma tissue and capture of necrotic carcinoma cells by migrating dendritic cells in real time. We also estimate simply and quickly immunological quality of dendritic cells by measuring IL-12 concentration secreted by dendritic cells.We succeed in developing several types of artificial tissues using various types of cells obtained from surgically resected specimens. However, we did not succeed in connecting these artificial tissues with artificial blood vessel within this research period. Less

这项研究的重点是通过结合多种类型的人工组织，包括结缔组织、癌组织、淋巴组织和血管，构建“更高的体外免疫系统模型”。为了执行该研究计划，“肿瘤免疫学部”和“医学技术部”合作组建了新的研究领域“肿瘤技术”。本研究期间获得的数据如下：（1）人工结缔组织的开发：我们在I型细胞中重建了由人成纤维细胞和人脐静脉源性内皮细胞（HUVEC）组成的体外结缔组织模型。 胶原蛋白凝胶。在该模型中，HUVEC在不添加任何特殊生长因子的情况下迁移并形成细血管网。(2)人工癌组织的发育：我们重建了两种类型的人工癌组织。一种是软组织类型，我们能够在 30 多天内实时显微镜观察两种细胞类型（例如癌瘤细胞和成纤维细胞）的生长。另一种是为免疫组织化学分析而准备的硬组织类型。在该模型中，我们可以通过组合使用的细胞因子来控制癌细胞的生长模式，即扩张或侵袭性生长。（3）人工淋巴组织的发育：人工淋巴组织组织在I型胶原网中，辅以OKT-3和纤维蛋白原、人成纤维细胞、淋巴细胞和IL-2。在该模型中，淋巴细胞良好增殖并分泌IFN-g等多种细胞因子，持续时间超过10天。（4）初步免疫系统模型的建立：我们重建了初步的高级免疫系统模型，该模型分为三层，即树突状细胞层（下）、癌组织层（中）和淋巴组织层（上）。在该模型中，我们能够在显微镜下观察树突状细胞迁移到癌组织中，并通过迁移树突状细胞实时捕获坏死的癌细胞。我们还通过测量树突状细胞分泌的IL-12浓度来简单快速地评估树突状细胞的免疫学质量。我们使用从手术切除的标本中获得的各种类型的细胞成功地开发了几种类型的人工组织。然而，在本研究期间，我们并没有成功将这些人造组织与人造血管连接起来。较少的

项目成果

片野光男: "免疫学を基盤とした重症感染症制御"日本臨床麻酔学会雑誌. 22. 115-123 (2002)

Mitsuo Katano：“基于免疫学的严重传染病控制”日本临床麻醉学会杂志 22. 115-123 (2002)。

Hashizume K: "Candidate host marker for peritoneal dissemination"Anticancer Research. (in press).

Hashizume K：“腹膜传播的候选宿主标记”抗癌研究。

Kojima M: "Association of enhanced cyclooxygenase-2 expression with possible local immunosuppression in human colorectal carcinomas"Annals of Surgical Oncology. 8. 458-465 (2001)

Kojima M：“人类结直肠癌中环氧合酶 2 表达增强与可能的局部免疫抑制的关联”《肿瘤外科年鉴》。

Onishi H: "Dysfunctional and short-lived subsets in monocyte-derived dendritic cells from patients with advanced cancer"Clinical Immunology. 105. 286-295 (2002)

Onishi H：“来自晚期癌症患者的单核细胞衍生的树突状细胞的功能障碍和短命亚群”临床免疫学。

Hashizume K.: "Candidate host marker for peritoneal dissemination"Anticancer Research. 22. 1781-1786 (2002)

Hashizume K.：“腹膜传播的候选宿主标记”抗癌研究。