B6.129S4- IL2rg tmWjl/ J mice (abbreviated as B6- IL2Rγ null) were obtained from the Animal Resources colony at The Jackson Laboratory. NOD/LtJ (abbreviated as NOD), C57BL/6J, NOD.CB17- Prkdc scid (abbreviated as NOD- scid), and B6.129S7- Rag1 tm1Mom/J (abbreviated as B6- Rag1 null) mice were raised in our research colony at The Jackson Laboratory under specific pathogen-free conditions as previously described ( 10, 18). Although improved human HSC engraftment was observed in each of these newer immunodeficient NOD models, human HSC failed to differentiate into mature human lymphoid and myeloid cells. NOD- Rag1 null Prf1 null mice have an increased life span as compared with NOD- scid mice, and they support relatively high levels of human hematolymphoid engraftment ( 19). Alternative immunodeficient NOD mouse models that have been developed include NOD mice bearing a targeted mutation at the recombination activation gene 1 (NOD- Rag1 null) ( 18) and NOD- Rag1 null mice bearing a targeted mutation at the perforin ( Prf1) locus (NOD- Rag1 null Prf1 null) ( 19). However, long term studies in NOD- scid B2m null mice have been constrained by a markedly shortened life span due to accelerated thymic lymphomagenesis ( 15). These mice are severely deficient in NK cell activity and support higher levels of human HSC engraftment than do NOD- scid mice ( 15, 16, 17). To begin to address these limitations, we developed NOD- scid mice homozygous for a targeted mutation in the β 2-microglobulin structural gene (NOD- scid B2m null mice). However, HSC function in NOD- scid mice is limited by remaining NK cell activity and a relatively short life span due to the early occurrence of thymic lymphomas. Thus, NOD- scid IL2Rγ null mice engrafted with human mobilized blood stem cells provide a new in vivo long-lived model of robust multilineage human HSC engraftment. De novo human T cell development in NOD- scid IL2Rγ null mice was validated by 1) high levels of TCR excision circles, 2) complex TCRβ repertoire diversity, and 3) proliferative responses to PHA and streptococcal superantigen, streptococcal pyrogenic exotoxin. ![]() Coadministration of human Fc-IL7 fusion protein results in high percentages of human CD4 +CD8 + thymocytes as well human CD4 +CD8 − and CD4 −CD8 + peripheral blood and splenic T cells. Spleens from engrafted NOD- scid IL2Rγ null mice contain human Ig + B cells and lower numbers of human CD3 + T cells. These human cells include B cells, NK cells, myeloid cells, plasmacytoid dendritic cells, and HSC. Engraftment of NOD- scid IL2Rγ null mice with human HSC generate 6-fold higher percentages of human CD45 + cells in host bone marrow than with similarly treated NOD- scid mice. NOD- scid IL2Rγ null mice are deficient in mature lymphocytes and NK cells, survive beyond 16 mo of age, and even after sublethal irradiation resist lymphoma development. We report the development and characterization of a new genetic stock of IL-2R common γ-chain deficient NOD/LtSz- scid (NOD- scid IL2Rγ null) mice and document their ability to support human mobilized blood HSC engraftment and multilineage differentiation. To overcome this limitation, small animal models of human HSC engraftment have been used. In general, Prkdc scid leakiness is low on the NOD/ShiLtSz genetic background.Ethical considerations constrain the in vivo study of human hemopoietic stem cells (HSC). ![]() Prkdc scid mice accept allogeneic and xenogeneic grafts making them an ideal model for cell transfer experiments. Mice homozygous for the severe combined immune deficiency spontaneous mutation Prkdc scid, commonly referred to as scid, are characterized by an absence of functional T cells and B cells, lymphopenia, hypogammaglobulinemia, and a normal hematopoietic microenvironment.
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