Taverne J, Sheikh N, de Souza J B, Playfair J H, Probert L, Kollias G
Department of Immunology, University College London Medical School, U.K.
Immunology. 1994 Jul;82(3):397-403.
Transgenic mice carrying a modified human tumour necrosis factor (huTNF)/beta-globin gene construct linked to the T-cell-specific locus control region of the human CD2 gene express huTNF in their T cells which is released into the circulation and causes the development of a wasting syndrome. We now report that the mice develop anaemia, probably through enhanced erythrophagocytosis rather than inhibition of reticulocyte production. Thus autologous erythrocytes, as well as sheep erythrocytes, were cleared more rapidly from the circulation of transgenic mice than from littermate controls. By contrast, peritoneal macrophages from transgenic mice were less phagocytic in vitro than cells from controls. They also secreted less murine (mu)TNF when stimulated by either bacterial lipopolysaccharide or toxic malarial antigens. The yields of muTNF approached normal levels, however, when these refractory cells from the transgenic mice were stimulated in the presence of a high concentration of indomethacin, suggesting that the production of muTNF was inhibited by enhanced synthesis of prostaglandins. The parasitaemia of transgenic mice infected with Plasmodium yoelii was about 10-fold less at its peak than in controls, although it followed the same time-course, and the multiplication of P. chabaudi was inhibited to an even greater degree. This control of parasitaemia may also be explained by enhancement of macrophage activity, mediated by huTNF acting on the murine p55 receptor, presumably by increasing the removal of parasites by phagocytosis or their killing by toxic products released by the activated macrophages. These observations suggest that a factor in the anaemia of human malaria may be macrophage activation caused by the secretion of TNF that occurs in this disease.
携带与人类CD2基因的T细胞特异性基因座控制区相连的修饰人类肿瘤坏死因子（huTNF）/β-珠蛋白基因构建体的转基因小鼠，其T细胞中表达huTNF，该因子释放到循环系统中并导致消瘦综合征的发展。我们现在报告，这些小鼠出现贫血，可能是通过增强红细胞吞噬作用而非抑制网织红细胞生成。因此，与同窝对照相比，转基因小鼠循环系统中的自体红细胞以及绵羊红细胞被清除得更快。相比之下，转基因小鼠的腹腔巨噬细胞在体外的吞噬作用比对照细胞弱。当受到细菌脂多糖或有毒疟原虫抗原刺激时，它们分泌的小鼠（mu）TNF也较少。然而，当在高浓度消炎痛存在的情况下刺激转基因小鼠的这些难治性细胞时，muTNF的产量接近正常水平，这表明muTNF的产生受到前列腺素合成增强的抑制。感染约氏疟原虫的转基因小鼠的虫血症峰值比对照小鼠低约10倍，尽管其病程相同，而且查巴迪疟原虫的增殖受到的抑制程度更大。这种对虫血症的控制也可能是由于huTNF作用于小鼠p55受体介导的巨噬细胞活性增强，推测是通过增加吞噬作用清除寄生虫或激活的巨噬细胞释放的有毒产物杀死寄生虫。这些观察结果表明，人类疟疾贫血中的一个因素可能是该疾病中发生的TNF分泌引起的巨噬细胞激活。
