Basic Research for The Immuno-genetherapy of Brain Tumors

脑肿瘤免疫基因治疗的基础研究

• 批准号: 09671409
• 负责人: IWADATE Yasuo
• 金额: $ 1.79万
• 依托单位: CHIBA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671409/
• 关键词: gene therapy; brain tumor; interleukin-2; immunity; Brain Neoplasm; Gene Thetapy; Antitumor Immumty; Major Histocoispastibility Complex; Herpes Sumpley Virus-Thymidine Kinase; IL-2; IL-12

Enhancement of host antitumor response using cytokine-producing tumor cells has been investigated in various types of cancers. The central nervous system, however, shows tolerance for activated immune reactions, and this relative unresponsiveness may lessen the efficacy of immunotherapy for brain tumors. Using interleukin-2 (IL-2)-producing 9L rat gliosarcoma cells (9L/IL-2), we examined whether secretion of IL-2 from subcutaneous (s.c.) and/or intracranial (i.c.) tumors can elicit augmented immunological response to brain tumors. Syngeneic rats could reject 9L/IL-2 cells inoculated s.c., but developed i.c. 9L/IL-2 tumors. The growth of i.c. 9L/IL-2 tumors was, however, significantly retarded compared with that of wild-type tumors. The growth of i.c. wild-type tumors was also suppressed, when the rats concurrently received 9L/IL-2 cells s.c.. Moreover, most of the rats which inoculated i.c. with 9L/IL-2 cells did not developed brain tumors, when concurrently injected s.c. with 9L/IL-2 cells. Immunohistochemical analysis revealed that migration of CD4- positive T cells, CD8-positive T cells, monocytes/ microglias and macrophages in i.c. 9L/IL-2 tumors was less notable than that in s.c. 9L/IL-2 tumors, but was more significant than that in i.c. wild-type tumors. When the rats were inoculated s.c. with 9L/IL-2 cells, the cellular infiltration into intracranial 9L/IL-2 tumors was markedly augmented to a similar level as found in s.c. 9L/IL-2 tumors. The present study may raise a possibility of a therapeutic strategy for brain tumors by the combinatory expression of IL-2 gene using s.c. immunization followed by the direct gene transfer into brain tumors.

已经在各种类型的癌症中研究了使用产生细胞因子的肿瘤细胞增强宿主抗肿瘤反应。然而，中枢神经系统对激活的免疫反应表现出耐受性，这种相对无反应可能会降低脑肿瘤免疫治疗的疗效。使用产生白介素 2 (IL-2) 的 9L 大鼠神经胶质肉瘤细胞 (9L/IL-2)，我们检查了皮下 (s.c.) 和/或颅内 (i.c.) 肿瘤分泌的 IL-2 是否可以引发对脑肿瘤的增强免疫反应。同系大鼠可以排斥皮下接种的 9L/IL-2 细胞，但皮下接种时会产生排斥反应。 9L/IL-2 肿瘤。 IC 的成长然而，与野生型肿瘤相比，9L/IL-2 肿瘤的生长明显迟缓。 IC 的成长当大鼠皮下同时接受9L/IL-2细胞时，野生型肿瘤也受到抑制。此外，大多数皮下接种的大鼠也受到抑制。当同时皮下注射 9L/IL-2 细胞时，未形成脑肿瘤。与 9L/IL-2 细胞。免疫组织化学分析显示，i.c. 中 CD4 阳性 T 细胞、CD8 阳性 T 细胞、单核细胞/小胶质细胞和巨噬细胞的迁移。 9L/IL-2 肿瘤不如皮下肿瘤明显。 9L/IL-2 肿瘤，但比 i.c. 中的肿瘤更显着。野生型肿瘤。当大鼠皮下接种时使用 9L/IL-2 细胞，颅内 9L/IL-2 肿瘤的细胞浸润显着增强至与皮下发现的相似水平。 9L/IL-2 肿瘤。本研究可能提出通过皮下联合表达 IL-2 基因来治疗脑肿瘤的可能性。免疫后将基因直接转移到脑肿瘤中。

项目成果

Y.Iwadate,et al.: "In vivo bystander effect in the intracranial model with rat glioma cells reflects the clonal difference of HSV-TK positive cells" Internatinal Journal of Oncology. 9. 521-525 (1996)

Y.Iwadate等人：“大鼠神经胶质瘤细胞颅内模型中的体内旁观者效应反映了HSV-TK阳性细胞的克隆差异”国际肿瘤学杂志。

岩立康男、他: "サイトカイン遺伝子導入による脳腫瘍の獲得免疫誘導能" 神経免疫研究. 10. 65-70 (1997)

Yasuo Iwadate 等：“通过细胞因子基因转移诱导脑肿瘤获得性免疫”《神经免疫学研究》10. 65-70 (1997)。

Yasuo Iwadate, et al.: "In vivo bystander effect in the intracranial model with rat glioma cells reflects the clonal defference of HSV:TK positive cells" International Journal of Oncology. 9. 521-525 (1996)

Yasuo Iwadate 等人：“大鼠神经胶质瘤细胞颅内模型中的体内旁观者效应反映了 HSV:TK 阳性细胞的克隆差异”国际肿瘤学杂志。

Yasuo Iwadate, et al: "Induction of Acquired Immunity in Rats that Have Eliminated Intractiial Galiosarema Cells by the Expression of HSV-TK Gene and GCV Administration" Oncology. 54. 329-334 (1997)

Yasuo Iwadate 等人：“通过 HSV-TK 基因的表达和 GCV 给药来消除体内 Galiosarema 细胞的大鼠获得性免疫的诱导”肿瘤学。

岩立康男、他: "サイトカイン遺伝子導入による脳腫瘍の獲得免疫誘導能" 神経免疫研究. 10. 177-181 (1997)

Yasuo Iwadate 等：“通过细胞因子基因转移诱导脑肿瘤获得性免疫”《神经免疫学研究》10. 177-181 (1997)。