Th2-like response and anti-tumor effect of anti-lL-4 mAb in mice bearling renal cell carclinoma

抗IL-4 mAb对肾细胞癌小鼠的Th2样反应和抗肿瘤作用

• 批准号: 05807144
• 负责人: TAKEUCHI Takumi
• 金额: $ 1.15万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05807144/
• 关键词: Th1; Th2; cytokine; anti-IL-4-mAb; renca; 腎腫瘍; T細胞; サイトカイン; IC-4; 腎癌

Tumor regr ession in experimental systems has been linked to the activities of Th1 cells. It is therefore conceivable that Th2 cells interrupt the expression of tumor immunity since IL-4 & IL-10 inhibit the generation of Th1 from precursors and modulate the competence of antigen-presenting cells to activate this lymphocyte subpopulation. Naive murine renal cell carcinoma (renca) cells (1*10^5) were implanted into the subcapsule of the left kidney of Balb/c and Balb/c nude mice at 6-8 weeks of age. Fourteen days later, Th2 cytokine (IL-4 and IL-10) mRNAs as well as TGF-b1 mRNA assesed by RT-PCR were up-regulated in the spleen of hosts upon naive renca tumor acceptance, while Th1 cytokine (IL-2 and IFN-g) mRNAs were almost undetectable. in the renca tumor, IL-10 mRNA was detected but IL-2, IFN-g, and IL-4 mRNA were not. Intraperitoneal administration of anti-mouse IL-4 mAb (11B11) reduced the renca tumor size (p=0.018) and prolonged host survival (p=0.03), but did not reduce the acceptan … More ce rate of the tumor (p=0.18). However, prior depletion of CD4+ or CD8+ cells with monoclonal antibodies abrogated the anti-tumor effects of anti-IL-4 mAb. Additionally, the significant anti-tumor effect of anti-IL-4 mAb was not observed in Balb/c nude hosts. Renca cells were transfected with the mammalian expression vector pCAGGS containing murine IL-4, cDNA or vector alone, then stable IL-4 transfectants (RencaL,RencaH : low or high lL-4 producing, respectively) and control renca cells (RencaC) were obtained, RencaL cells, RencaH cells, or RencaC cells (1*10^5 each) were implanted into the subcapsule of the left kidney of Balb/c, Balb/c nude, and allogenic C3H/HeJ mice, then tumor formation was evaluated 14 days later. When RencaH cells were inoculated into syngeneic Balb/c hosts, tumor volume was marginally suppressed (p=0.03) and tumors tended to be rejected (p=0.06) were observed compared with RencaC cells. However, those effects were not observed in Balb/c nude mice. RencaC,RencaL,and RencaH cells were not accepted by allogeneic C3H mice with or without FK506 administration or donor specific transfusion. The administration of anti-mouse lL-4 mAb to Balb/c mice significantly suppressed renca tumor growth by a CD4+ and CD8+ T cell dependent mechanism. On the contrary, relatively high-levels of IL-4 production by renca cells and T cells seemed to be required to induce the rejection and growth suppression of IL-4 producing renca cells in syngeneic hosts. Less

实验系统中的肿瘤消退与Th 1细胞的活性有关。因此，可以想象，Th 2细胞中断肿瘤免疫的表达，因为IL-4和IL-10抑制从前体产生Th 1并调节抗原呈递细胞的能力以激活该淋巴细胞亚群。将未处理的鼠肾细胞癌（renca）细胞（1*10^5）植入6-8周龄的Balb/c和Balb/c裸鼠的左肾的包膜下。14 d后，经RT-PCR检测，脾脏中Th 2细胞因子（IL-4和IL-10）mRNA和TGF-β 1 mRNA表达上调，而Th 1细胞因子（IL-2和IFN-γ）mRNA几乎检测不到。肾癌组织中IL-10 mRNA表达阳性，而IL-2、IFN-γ、IL-4 mRNA表达阴性。腹腔注射抗小鼠IL-4单抗（11B 11）可缩小肾肿瘤的大小（p=0.018），延长宿主的存活时间（p=0.03），但不能减少受体的数量（p= 0.001）。 ...更多信息 肿瘤的发生率（p=0.18）。然而，用单克隆抗体预先耗尽CD 4+或CD 8+细胞消除了抗IL-4 mAb的抗肿瘤作用。此外，在Balb/c裸宿主中未观察到抗IL-4 mAb的显著抗肿瘤作用。用含有鼠IL-4的哺乳动物表达载体pCAGGS、cDNA或单独的载体转染Renca细胞，然后用稳定的IL-4转染细胞，（RencaL，RencaH：分别为低或高IL-4产生）和对照renca细胞（RencaC），RencaL细胞、RencaH细胞或RencaC细胞（各1*10^5）植入Balb/c、Balb/c裸小鼠和同种异体C3 H/HeJ小鼠的左肾的包膜下，然后在14天后评价肿瘤形成。当将RencaH细胞接种到同基因Balb/c宿主中时，与RencaC细胞相比，观察到肿瘤体积轻微抑制（p=0.03）并且肿瘤倾向于被排斥（p=0.06）。然而，在Balb/c裸鼠中未观察到这些作用。无论是否给予FK 506或供体特异性输血，同种异基因C3 H小鼠均不接受RencaC、RencaL和RencaH细胞。向Balb/c小鼠施用抗小鼠IL-4 mAb通过CD 4+和CD 8 + T细胞依赖性机制显著抑制肾癌肿瘤生长。相反，由renca细胞和T细胞产生的相对高水平的IL-4似乎是诱导排斥反应和生长抑制产生IL-4的renca细胞在同基因宿主中所必需的。少