Regulation Of Immune Responses In Humans and in Experimental Animals

几种实验性肿瘤启动了一种反免疫监视机制，破坏了免疫系统控制肿瘤生长的能力。这种反免疫监视是由肿瘤激活的NKT细胞启动的，NKT细胞产生IL-13，从而向Gr-1+细胞(单核细胞或中性粒细胞)发出信号，产生转化生长因子-1，一种细胞因子，然后抑制溶细胞CD8+T细胞的活性，否则将抑制肿瘤生长。在目前的研究中，我们表明在两个肿瘤模型(CT-26转移性结肠癌和15-12RM纤维肉瘤退化子模型)中，这种反监视机制需要在CD11bHighGr-1中间细胞上表达第二个IL-13受体，IL-13R；2：通过体内注射特定的siRNA或诱骗寡核苷酸，下调IL-13R；2受体的表达或由该受体产生的AP-1信号，导致失去转化生长因子-1的产生。此外，根据我们先前的研究表明，IL-13R；2的表达(部分)是由肿瘤坏死因子诱导的，我们证明，给予肿瘤坏死因子中和剂，R-FC(依那西普)，可以抑制IL-13R；2受体的表达和转化生长因子-1的产生。利用后一个事实，我们随后在CT-26模型中证明，给予肿瘤坏死因子-R-Fc可以抑制抗CT-26特异性CD8+细胞杀伤活性，并极大地减少CT-26转移瘤结节。使用15-12RM纤维肉瘤模型获得确证数据。这些研究指出，用一种毒性最小的可用药物来预防转移性癌症。

Several experimental tumors initiate a counter-immunosurveillance mechanism that undermines the ability of the immune system to control tumor growth. Such counter-immunosurveillance is initiated by tumor-activated NKT cells that produce IL-13 and therefore signal Gr-1+ cells (monocytic or neutrophilic cell) to produce TGF-β1, a cytokine that then suppresses the activity of cytolytic CD8+ T cells that would otherwise inhibit tumor growth. In the present studies we showed that in two tumor models (the CT-26 metastatic colon cancer and the 15-12RM fibrosarcoma regressor models) this counter-surveillance mechanism requires the expression of a second IL-13 receptor, IL-13Rα2, on CD11bhighGr-1intermediate cells: down-regulation of IL-13Rα2 receptor expression or the AP-1 signal generated by the receptor via in vivo administration of specific siRNA or decoy oligonucleotides leads to loss of TGF-β1 production. Furthermore, from our prior studies showing that IL-13Rα2 expression was induced (in part) by TNF-α, we demonstrated that IL-13Rα2 receptor expression and TGF- β1 production is inhibited by administration of a TNF-α neutralizing agent, TNF-αR-Fc (etanercept). Taking advantage of this latter fact, we then demonstrated in the CT-26 model that counter-immunosurveillance could be inhibited, anti-CT-26-specific CD8+ cytolytic activity restored, and CT-26 metastatic tumor nodules greatly decreased by administration of TNF-αR-Fc. Corroborative data was obtained using the 15-12RM fibrosarcoma model. These studies point to the prevention of metastatic cancer with an available agent having minimal toxicity.