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。 这种反免疫监视由肿瘤活化的NKT细胞启动，所述NKT细胞产生IL-13并因此向Gr-1+细胞（单核细胞或嗜中性细胞）发出信号以产生TGF- 1，TGF-1是一种细胞因子，然后抑制细胞溶解性CD 8 + T细胞的活性，否则所述细胞溶解性CD 8 + T细胞将抑制肿瘤生长。在目前的研究中，我们发现在两种肿瘤模型（CT-26转移性结肠癌和15- 12 RM纤维肉瘤消退模型）中，这种反监督机制需要在CD 11bhighGr-1中间细胞上表达第二种IL-13受体IL-13 R 2：通过体内给予特异性siRNA或诱饵寡核苷酸下调IL-13 R 2受体表达或受体产生的AP-1信号，导致TGF-1产生的损失。此外，从我们先前的研究表明IL-13 R2表达（部分）由TNF-α诱导，我们证明IL-13 R2受体表达和TGF-1产生被TNF-α中和剂TNF-R-Fc（依那西普）抑制。利用后一事实，我们随后在CT-26模型中证明，通过施用TNF-R-Fc，可以抑制反免疫监视，恢复抗CT-26特异性CD 8+细胞溶解活性，并且CT-26转移性肿瘤结节大大减少。使用15- 12 RM纤维肉瘤模型获得了确证性数据。这些研究指出了用具有最小毒性的可用药剂预防转移性癌症。

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.