Erdman Susan E, Rao Varada P, Poutahidis Theofilos, Ihrig Melanie M, Ge Zhongming, Feng Yan, Tomczak Michal, Rogers Arlin B, Horwitz Bruce H, Fox James G
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Cancer Res. 2003 Sep 15;63(18):6042-50.
Roles for host immune response in carcinogenesis are not well defined. Recent studies have shown that microbially driven inflammation can lead to colon cancer and that prior transfer of regulatory lymphocytes expressing CD4 and CD25 prevents the innate inflammatory events that lead to colon cancer in mice. To further examine the ability of regulatory lymphocytes to inhibit carcinogenesis, 129/SvEv Rag-2-deficient mice were inoculated by gastric gavage with Helicobacter hepaticus, an enteric bacterial pathogen of mice. Mice were then treated at 1, 3, or 12 months after infection with adoptive transfer of CD4(+)CD45RB(lo)CD25(+)-regulatory cells. Mice dosed with regulatory cells at 4 or 12 weeks after H. hepaticus infection had reduced severity of inflammatory bowel disease and significantly lower risk of colon cancer during the 8 month observation period, compared with infected mice that had not received cells. This suggested that regulatory cells were able to interrupt the ongoing innate immune events in the stepwise progression to cancer. Transfer of regulatory cells into chronically infected mice with established cancer reduced severity of colitis, epithelial dysplasia, and cancer, but did not eliminate all tumors. Regulatory cells lacking anti-inflammatory cytokine interleukin (IL)-10 were unable to inhibit inflammatory bowel disease, dysplasia, or cancer, showing that IL-10 was required for the protective effects of lymphocytes in this setting. Taken together, the data suggest that IL-10-mediated suppression of host innate inflammatory response was pivotal in interrupting carcinogenesis. Regulatory lymphocytes and cytokines may have implications for novel therapies for colon cancer in humans.
宿主免疫反应在致癌过程中的作用尚未明确界定。最近的研究表明，微生物驱动的炎症可导致结肠癌，并且先前转移表达CD4和CD25的调节性淋巴细胞可预防导致小鼠患结肠癌的先天性炎症事件。为了进一步研究调节性淋巴细胞抑制致癌作用的能力，通过胃内灌胃给129/SvEv Rag-2缺陷小鼠接种肝螺杆菌，这是一种小鼠肠道细菌病原体。然后在感染后的1、3或12个月，用CD4(+)CD45RB(lo)CD25(+)调节性细胞进行过继转移治疗小鼠。与未接受细胞的感染小鼠相比，在肝螺杆菌感染后4或12周给予调节性细胞的小鼠，在8个月的观察期内炎症性肠病的严重程度降低，患结肠癌的风险显著降低。这表明调节性细胞能够在癌症逐步发展过程中中断正在进行的先天性免疫事件。将调节性细胞转移到已患癌症的慢性感染小鼠中，可降低结肠炎、上皮发育异常和癌症的严重程度，但并未消除所有肿瘤。缺乏抗炎细胞因子白细胞介素（IL）-10的调节性细胞无法抑制炎症性肠病、发育异常或癌症，表明在这种情况下，IL-10是淋巴细胞发挥保护作用所必需的。综上所述，数据表明IL-10介导的宿主先天性炎症反应抑制在中断致癌过程中起关键作用。调节性淋巴细胞和细胞因子可能对人类结肠癌的新疗法具有重要意义。
