Shen Xiao Z, Li Ping, Weiss Daiana, Fuchs Sebastien, Xiao Hong D, Adams Jon A, Williams Ifor R, Capecchi Mario R, Taylor W Robert, Bernstein Kenneth E
Department of Pathology and Laboratory Medicine, Emory University, 101 Woodruff Circle, Atlanta, GA 30322, USA.
Am J Pathol. 2007 Jun;170(6):2122-34. doi: 10.2353/ajpath.2007.061205.
Angiotensin-converting enzyme (ACE) is a peptidase responsible for the cleavage of angiotensin I and several other peptides. Here, gene targeting was used to switch control of the ACE locus from the endogenous promoter to the macrophage-specific c-fms promoter. Challenge of these mice, called ACE 10/10, with the aggressive mouse melanoma cell line B16 showed that they are remarkably resistant to tumor growth. Tumor resistance was seen after challenge with different melanoma cell lines and in mice with different genetic backgrounds. Histological study of the tumors that did grow in ACE 10/10 mice showed an enhanced inflammatory response. ACE 10/10 mice had increased numbers of tumor epitope-specific CD8(+) T cells after challenge with melanoma or lymphoma. ACE 10/10 macrophages showed increased production of interleukin-12 and nitric oxide but reduced interleukin-10. Engraftment of wild-type mice with ACE 10/10 bone marrow transferred B16 tumor resistance. Injection of B16 tumors with ACE 10/10 macrophages also reduced tumor growth. ACE 10/10 mice may define a new means of enhancing the immune response, which may be potentially useful in several human clinical situations.
血管紧张素转换酶（ACE）是一种肽酶，负责切割血管紧张素I和其他几种肽。在此，采用基因靶向技术将ACE基因座的控制从内源性启动子转换为巨噬细胞特异性c-fms启动子。用侵袭性小鼠黑色素瘤细胞系B16攻击这些称为ACE 10/10的小鼠，结果显示它们对肿瘤生长具有显著抗性。在用不同的黑色素瘤细胞系攻击后以及在具有不同遗传背景的小鼠中均观察到肿瘤抗性。对在ACE 10/10小鼠中生长的肿瘤进行组织学研究，结果显示炎症反应增强。在用黑色素瘤或淋巴瘤攻击后，ACE 10/10小鼠中肿瘤表位特异性CD8(+) T细胞数量增加。ACE 10/10巨噬细胞显示白细胞介素-12和一氧化氮的产生增加，但白细胞介素-10减少。用ACE 10/10骨髓移植野生型小鼠可传递B16肿瘤抗性。向B16肿瘤注射ACE 10/10巨噬细胞也可减少肿瘤生长。ACE 10/10小鼠可能定义了一种增强免疫反应的新方法，这在几种人类临床情况下可能具有潜在用途。
