Regulation Of Immune Responses In Humans and in Experimental Animals

一些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。这种抗免疫监视是由肿瘤激活的NKT细胞启动的，它产生IL-13，从而信号Gr-1+细胞（单核细胞或中性细胞）产生TGF- 1， TGF- 1是一种细胞因子，然后抑制细胞溶解性CD8+ T细胞的活性，否则会抑制肿瘤生长。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15-12RM纤维肉瘤回归因子模型）中，这种反监视机制需要在cd11bhighgr -1中间细胞上表达第二种IL-13受体IL-13R&#945；2：下调IL-13R&#945；2受体表达或通过体内给药特异性siRNA或诱引寡核苷酸下调该受体产生的AP-1信号导致TGF-&#946；1产生的损失。此外，我们之前的研究表明，IL-13R&#945；2的表达（部分）是由TNF-&#945；诱导的，我们证明IL-13R&#945；2受体的表达和TGF- &#946；1的产生可以通过给予TNF-&#945；中和剂TNF-&#945；R-Fc（依那西普）来抑制。利用后一事实，我们随后在CT-26模型中证明，通过给药TNF-&#945；R-Fc，可以抑制抗免疫监视，恢复抗CT-26特异性CD8+细胞溶解活性，并大大减少CT-26转移性肿瘤结节。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.