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

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，由于IL-4和IL-10抑制来自前体的Th1的产生并调节抗原呈递细胞激活该淋巴细胞亚群的能力，Th2细胞中断肿瘤免疫的表达。6-8周龄Balb/c和Balb/c裸鼠左肾亚囊内植入1*10^5的幼年小鼠肾细胞癌（renca）细胞。14天后，经RT-PCR检测，原发性肝癌接受后，宿主脾脏中Th2细胞因子（IL-4、IL-10） mRNA和TGF-b1 mRNA表达上调，而Th1细胞因子（IL-2、IFN-g） mRNA几乎检测不到。renca肿瘤中检测到IL-10 mRNA，但未检测到IL-2、IFN-g和IL-4 mRNA。腹腔注射抗小鼠IL-4 mAb （11B11）可减小肿瘤大小（p=0.018），延长宿主生存时间（p=0.03），但未降低肿瘤的接受率（p=0.18）。然而，先前用单克隆抗体消耗CD4+或CD8+细胞会取消抗il -4单抗的抗肿瘤作用。此外，抗il -4单抗在Balb/c裸宿主中未观察到明显的抗肿瘤作用。将含有小鼠IL-4、cDNA或单独载体的动物表达载体pCAGGS转染Renca细胞，获得稳定的IL-4转染物（RencaL、RencaH：分别低或高分泌IL-4）和对照Renca细胞（RencaC），分别将RencaL细胞、RencaH细胞和RencaC细胞（各1*10^5）植入Balb/c、Balb/c裸体和同种异体C3H/HeJ小鼠左肾亚囊，14天后观察肿瘤形成情况。将RencaH细胞接种到同基因Balb/c宿主中，与RencaC细胞相比，肿瘤体积受到轻微抑制（p=0.03），肿瘤倾向于排斥（p=0.06）。然而，在Balb/c裸鼠中没有观察到这些影响。RencaC、RencaL和RencaH细胞不被同种异体C3H小鼠接受，无论是否给予FK506或供者特异性输血。给Balb/c小鼠注射抗小鼠lL-4单抗，通过CD4+和CD8+ T细胞依赖机制显著抑制renca肿瘤的生长。相反，似乎需要renca细胞和T细胞产生相对高水平的IL-4才能诱导同源宿主中产生IL-4的renca细胞的排斥和生长抑制。少

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