Red blood cell-substituted NOD-scid mouse model for erythroparasitic protozoan infections.

我们之前已经开发了C.B-17 scid小鼠，其循环红细胞（RBC）已被其他动物物种的RBC取代。这种创新的动物模型系统极大地促进了对自然界中不感染小鼠的红寄生原生动物的体内研究。然而，用某些动物物种如人和马的RBC替代C.B-17 scid小鼠被证明是非常困难的，因为在C.B-17 scid小鼠中输注的RBC被快速清除。近年来，通过将C.B-17的遗传背景改变为其它小鼠品系，已经尝试开发更好的SCID小鼠，并且据报道NOD-scid小鼠（具有scid突变的非肥胖糖尿病小鼠）具有显著改善的造血异种移植可接受性。因此，在本研究中，我们研究了NOD/shi-scid与C.B-17 scid相比异种RBC的可接受性。用荧光标记的人、狗、马和牛的红细胞清除试验表明，NOD-scid小鼠的红细胞寿命明显长于C.B-17 scid小鼠。另外，慢性感染、巨噬细胞激活刺激和衰老等因素可显著增强C.B-17 scid小鼠对异种红细胞的清除能力，而NOD-scid小鼠对异种红细胞的清除能力则不明显。这些证据共同表明，NOD-scid小鼠比C.B-17 scid小鼠更适合作为制备RBC替代模型的SCID小鼠。然而，NOD-scid小鼠在施用抗小鼠RBC抗体后消除小鼠RBC的能力较低，抗小鼠RBC抗体在C.B-17 scid小鼠中有效地用于辅助快速RBC置换。我们能够证明NOD-scid小鼠可以很容易地被人RBC取代，并且人RBC取代的SCID小鼠作为从日本首次发现的人类巴贝虫病病例中分离寄生虫的极好工具。

We have previously developed C.B-17 scid mice whose circulating red blood cells (RBCs) had been substituted with RBCs of other animal species. This innovative animal model system greatly facilitated in vivo research for erythroparasitic protozoa that are in nature not infectious to mice. However, the substitution of C.B-17 scid mice with RBCs of some animal species, such as humans and horses, is proved to be very difficult, because of rapid clearance of RBCs transfused in C.B-17 scid mice. In recent years, attempts have been made to develop better SCID mice by changing the genetic background from C.B-17 into the other mice strains, and the NOD-scid mice (the non-obese diabetic mice having the scid mutation) were reported to have significantly improved hematopoietic xeno-transplant acceptability. In the present study, therefore, we examined acceptability of xenogeneic RBCs in NOD/shi-scid in comparison to C.B-17 scid. Clearance tests with fluorescent labeled RBCs of human, dog, horse and cattle showed that life spans of all these RBCs were significantly longer in NOD-scid than in C.B-17 scid mice. In addition, the ability of xeno-RBCs clearance in C.B-17 scid mice was greatly enhanced by some factors, such as optimistic infections, macrophage activating stimuli and aging, whereas such enhancement was poorly observed in NOD-scid mice. These lines of evidence collectively suggest that NOD-scid mice serve as more suitable SCID mice for preparation of the RBC-substitution model than C.B-17 scid. However, NOD-scid mice were less capable of eliminating mouse RBCs upon administration of anti-mouse RBC antibodies, which was effectively used in C.B-17 scid mice to assist rapid RBC-substitution. We were able to demonstrated that NOD-scid mice can easily substituted with human RBCs, and that the human RBC-substituted SCID mice served as an exellent tool for isolation of parasites from a human babesiosis case, which was found for the first time in Japan.