Abstract
In order to establish an appropriate recipient model for xenotransplantation, many efforts have been made to develop various strains of immunodeficient mice for a long period. Recently we have successfully generated a novel immunodeficient strain, NOD/Shi-scid, γcunull (NOG) mice in which truncation mutant IL-2Rγ gene lacking the cytoplasmic region was introduced to NOD/Shi-scid mice by 8 times-backcross-mating. When compared with conventional immunodeficient mice including NOD/Shi-scid mice, the NOG mice allowed the higher rate of xenotransplantation of human cells. In particular, human CD4+ T and CD8+ T cells could be easily generated after inoculation of CD34+ hematopoietic stem cells isolated from human umbilical cord blood cells and human antibodies specific against immunized antigens could also become detectable in the sera of CD34+ cell-inoculated NOG mice. Although the reason why the extremely high xenotransplantation of human cells are observed in NOG mice remains still obscure, functional deficiency of other cell lineage cells except for T, B and NK cells might be responsible.
The characteristic of NOG mice with high capacity of human cell transplantation could allow us to develop more appropriate mouse models for HIV-1, HTLV-1 infection.
NOG mice intraperitoneally inoculated with 1×107 of human peripheral blood mononuclear cells could have constantly maintained high levels of human T cells in the peritoneal fluid, while human cells could not always grow in all of NOD/Shi-scid inoculated. About 2 weeks after peritoneal inoculation of HIV-1 to PBL-NOG-hu mice, the significantly high level of HIV-1 p24 gag as well as HIV-1 RNA in plasma and cell-associated HIV-1 DNA were detected, respectively. Simultaneously, the remarkable level of human CD4+ cell depletion was observed. The administration of an anti HIV-1 agent, Zidovudine (AZT) to the HIV-1 infected mice gave a drastic recover of CD4/CD8 T cell ratio to normal level and remarkable reduction of HIV-1 p24 gag, DNA and RNA level. This HIV-1/NOG-PBL-hu system enables us to provide with faster and reliable results for evaluation of anti-HIV-1 agents, and to examine the precise pathomechanisms of HIV-1 infection.
In HTLV-1 infection NOG model, two to 3 weeks after subcutaneous inoculation of HTLV-1 infected cell lines in the post-auricular region of NOG mice, a visible tumor developed in the site. Almost all cell lines formed a progressively growing large tumor mass with leukemic infiltration of cells in various organs. This in vivo model of ATL could provide a novel system for use in clarifying the mechanisms of the growth of HTLV-1 infected cells as well as for the development of new drugs against ATL. In fact, we recently found a compound to inhibit HTLV tumorgenesis using this model.
