Reconstitution of human lymphoid tissue in mouse and its application

我们之前报道了具有缺陷的T和B细胞以及与NK、巨噬细胞和补体相关的先天免疫功能的新小鼠株的建立，并表明所有突变小鼠株都有效地接受了人外周血白细胞（PBL）移植（hu-PBL-scid-mouse） （J.病毒学报，71:2417-2424,1997）。在这些嵌合小鼠，hu-PBL-NOD-scid小鼠中，腹腔注射后观察到有效的HIV-1感染。感染嗜巨噬细胞的HIV-1毒株JR-FL可导致高水平的病毒血症（gag p24高于1 ~ 100 ng/ml）。病毒血症在感染后2周达到高峰，抗原血症在感染后4周消失。在这些HIV-1感染的小鼠中，人类CD3+/CD4+和CD3+/CD8+ T细胞在感染后2周内增殖。特别是在小鼠脾脏中，重建了白色浆体，在细胞凋亡的区域内聚集了hiv <gag> p24+细胞。除人T细胞外，还在小鼠脾脏中重建了人CD68+巨噬细胞。这些结果表明，hu-PBL-NOD-scid小鼠将有助于研究人类T细胞和巨噬细胞共存的组织中HIV-1的发病机制。因此，我们开始研究通过FasL、TNF或/和TRAIL等分子传递的特定信号是否参与了发病机制。TUNEL和抗fasl、抗tnf、抗TRAIL双染色显示，凋亡细胞多与TRAIL+细胞结合。另一方面，FasL+细胞或TNF+细胞与凋亡细胞无相关性。进一步分析证实，凋亡细胞和相邻的TRAIL+细胞均为CD4+人细胞。这些结果表明，在缺乏特异性免疫的情况下，许多HIV-1未感染的CD4+ T细胞在原发性病毒血症期间通过TRAIL信号在HIV-1感染的淋巴器官中发生凋亡。

We previously reported the establishment of novel mouse strains with defective T and B cells as well as innate immunological functions associated with NK, macrophage, and complement and showed that all mutant mouse strains efficiently received human PBL (peripheral blood leukocyte) engraftment (hu-PBL-scid-mouse) (J. Virol. 71 : 2417-2424, 1997). Of these chimeric mice, hu-PBL-NOD-scid mice, efficient HIV-1 infection was observed after intraperitoneal injection. High levels of viremia (more than 1〜100 ng/ml of gag p24) were obtained by infection with a macrophage-tropic HIV-1 strain, JR-FL. Peak levels of the viremia were observed at 2 weeks post infection and the antigenemia disappeared 4 weeks after infection. In these HIV-1 infected mice, human CD3+/CD4+ and CD3+/CD8+ T cells proliferated up to 2 weeks after infection. In mouse spleen especially, white pulps were reconstructed and HIV_<gag> p24+ cells accumulated in the region where apoptotic cells were also observed. In addition to human T cells, human CD68+ macrophages were also reconstituted in the mouse spleen. These results suggested that the hu-PBL-NOD-scid mouse would be useful to investigate HIV-1 pathogenesis in tissues where human T cells and macrophages coexist. Thus, we started to examine whether the specific signals through molecules such as FasL, TNF, or/and TRAIL are involved in the pathogenesis. Double staining with TUNEL and anti-FasL, anti-TNF, or anti-TRAIL, respectively, revealed that the apoptotic cells were frequently found in conjugation with TRAIL+ cells. On the other hand, FasL+ cells or TNF+ cells were not associated with the apoptotic cells. Further analysis confirmed that the apoptotic and the adjacent TRAIL+ cells were both CD4+ human cells. These results suggest that, in the absence of specific immunity, many of the HIV-1 uninfected CD4+ T cells undergo apoptosis through the TRAIL signal in HIV-1 infected lymphoid organ during primary viremia.