Takeuchi T, Ueki T, Sasaki Y, Kajiwara T, Li B, Moriyama N, Kawabe K
Department of Urology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Japan.
Cancer Immunol Immunother. 1997 Jan;43(6):375-81. doi: 10.1007/s002620050347.
Tumor regression 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 interleukin-4 (IL-4) and 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 x 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. After 14 days, Th2 cytokine (IL-4 and IL-10) mRNAs as well as transforming growth factor beta1 mRNA, assessed by reverse transcriptase/polymerase chain reaction were upregulated in the spleen of hosts upon naive renca tumor acceptance, while Th1 cytokine (IL-2 and interferon gamma) mRNAs were almost undetectable. In the renca tumor, IL-10 mRNA was detected but IL-2, interferon gamma, and IL-4 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 acceptance rate of the tumor (P = 0.18). However, prior depletion of CD4+ or CD8+ cells with monoclonal antibodies abrogated the antitumor effects of anti-IL-4 mAb. In addition, the significant antitumor 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 or RencaH, low- or high-IL-4-producing respectively) and control renca cells (RencaC) were obtained. RencaL cells, RencaH cells, or RencaC cells (1 x 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 innoculated into syngeneic Balb/c hosts, tumor volume was marginally suppressed (P = 0.03) and tumors tended to be rejected (P = 0.06) 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 IL-4) mAb to Balb/c mice significantly suppressed renca tumor growth by a CD4+ and CD8+ T-cell-dependent mechanism. By contrast, 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.
实验系统中的肿瘤消退与Th1细胞的活性有关。因此，可以想象Th2细胞会干扰肿瘤免疫的表达，因为白细胞介素-4（IL-4）和IL-10会抑制Th1从前体细胞的生成，并调节抗原呈递细胞激活该淋巴细胞亚群的能力。将1×10⁵个未经处理的小鼠肾细胞癌（renca）细胞植入6至8周龄的Balb/c和Balb/c裸鼠左肾的被膜下。14天后，通过逆转录酶/聚合酶链反应评估，在宿主接受未经处理的renca肿瘤后，其脾脏中Th2细胞因子（IL-4和IL-10）的mRNA以及转化生长因子β1的mRNA上调，而Th1细胞因子（IL-2和干扰素γ）的mRNA几乎检测不到。在renca肿瘤中，检测到了IL-10的mRNA，但未检测到IL-2、干扰素γ和IL-4。腹腔注射抗（小鼠IL-4）单克隆抗体（11B11）可减小renca肿瘤的大小（P = 0.018）并延长宿主存活时间（P = 0.03），但并未降低肿瘤的接受率（P = 0.18）。然而，事先用单克隆抗体清除CD4⁺或CD8⁺细胞会消除抗IL-4单克隆抗体的抗肿瘤作用。此外，在Balb/c裸鼠宿主中未观察到抗IL-4单克隆抗体的显著抗肿瘤作用。用含有小鼠IL-4 cDNA的哺乳动物表达载体pCAGGS或单独的载体转染renca细胞，然后获得稳定的IL-4转染细胞（分别为低IL-4产生的RencaL或高IL-4产生的RencaH）和对照renca细胞（RencaC）。将RencaL细胞、RencaH细胞或RencaC细胞（各1×10⁵个）植入Balb/c、Balb/c裸鼠和同种异体C3H/HeJ小鼠的左肾被膜下，然后在14天后评估肿瘤形成情况。当将RencaH细胞接种到同基因的Balb/c宿主中时，与RencaC细胞相比，肿瘤体积略有抑制（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效果。无论是否给予FK506或进行供体特异性输血，同种异体C3H小鼠均不接受RencaC、RencaL和RencaH细胞。给Balb/c小鼠注射抗（小鼠IL-4）单克隆抗体可通过CD4⁺和CD8⁺ T细胞依赖性机制显著抑制renca肿瘤生长。相比之下，renca细胞和T细胞产生相对高水平的IL-4似乎是诱导同基因宿主中产生IL-4的renca细胞被排斥和生长受抑制所必需的。
