![]() However, in NOD/LtSz- scid and NOD/Shi- scid mice, the injection of anti-NK cell antibody before transplantation ameliorates engraftment efficiency for transplanted human cells, thus indicating that residual NK cell activity might interfere with engraftment efficiency. 13, 14 At present, the NOD/SCID mice have been considered an appropriate model for analysis of human stem cell development and function. 12 We also developed NOD/Shi- scid mice independently from NOD/LtSz- scid mice and described the high engraftment rate of human hematopoietic cells in them. The high engraftment rates of human cells in NOD/LtSz- scid mice have been attributed to immunological multidysfunction, including reductions in macrophage function, complement-dependent hemolytic activity, and NK cell activity. 7-10 As a result, NOD/LtSz- scid mice established by Grenier et al 11 were found to be superior recipients for human cells. 2 After the successful engraftment of human peripheral hematopoietic cells, especially lymphoid cells, 3, 4 and the establishment of HIV-1 infection to T cells developed in these strains, 5, 6 many attempts have been made to develop modified severe combined immunodeficiency (SCID) mice by genetic crossings with inbred or other mutant strains of mice to obtain a more efficient model. ![]() Consequently, C.B-17-Prkdc scid ( scid) mice, which are defective in rearrangements of T-cell receptor (TCR) and B-cell receptor (BCR) resulting in defects of functional T and B cells, were discovered in 1983. The epoch-making discovery of nude mice by Isaason and Cattanach in 1962 1-mice defective in the thymus with T-cell deficiency-has contributed to progress in this research. It is suggested that multiple immunological dysfunctions, including cytokine production capability, in addition to functional incompetence of T, B, and NK cells, may lead to the high engraftment levels of xenograft in NOD/SCID/γ c null mice.Įfforts to develop animal recipients for xenotransplantation, especially human cells, to establish an animal model for human diseases or to investigate mechanisms during the growth and differentiation of human stem cells have long been pursued. The interferon-γ production from dendritic cells from the NOD/SCID/γ c null mouse spleen was significantly suppressed in comparison with findings in 2 other strains of mice. To elucidate the mechanisms involved in the superior engraftment rate in NOD/SCID/γ c null mice, cytokine production of spleen cells stimulated with Listeria monocytogenesantigens was compared among these 3 strains of mice. These results suggest that NOD/SCID/γ c null mice were superior animal recipients for xenotransplantation and were especially valuable for human stem cell assay. Further, even 1 × 10 2 CD34 + cells could grow and differentiate in this strain. In addition to the high engraftment rate, multilineage cell differentiation was also observed. The same high engraftment rate of human mature cells was observed in ascites when peripheral blood mononuclear cells were intraperitoneally transferred. When human CD34 + cells from umbilical cord blood were transplanted into this strain, the engraftment rate in the peripheral circulation, spleen, and bone marrow were significantly higher than that in NOD/Shi- scid mice treated with anti-asialo GM1 antibody or in the β2-microglobulin–deficient NOD/LtSz- scid (NOD/SCID/β2m null) mice, which were as completely defective in NK cell activity as NOD/SCID/γ c null mice. To establish a more appropriate animal recipient for xenotransplantation, NOD/SCID/γ c null mice double homozygous for the severe combined immunodeficiency (SCID) mutation and interleukin-2Rγ (IL-2Rγ) allelic mutation (γ c null) were generated by 8 backcross matings of C57BL/6J-γ c null mice and NOD/Shi- scidmice.
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