Limits...
Improved B cell development in humanized NOD ‐ scid IL2R γ mice transgenically expressing human stem cell factor, granulocyte ‐ macrophage colony ‐ stimulating factor and interleukin ‐ 3

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Immunodeficient mice engrafted with human immune systems support studies of human hematopoiesis and the immune response to human‐specific pathogens. A significant limitation of these humanized mouse models is, however, a severely restricted ability of human B cells to undergo class switching and produce antigen‐specific IgG after infection or immunization.

Methods: In this study, we have characterized the development and function of human B cells in NOD‐scid IL2Rγ (NSG) mice transgenically expressing human stem cell factor (SCF), granulocyte macrophage colony‐stimulating factor (GM‐CSF), and IL‐3 (NSG‐SGM3) following engraftment with human hematopoietic stem cells, autologous fetal liver, and thymic tissues (bone marrow, liver, thymus or BLT model). The NSG‐SGM3 BLT mice engraft rapidly with human immune cells and develop T cells, B cells, and myeloid cells.

Results: A higher proportion of human B cells developing in NSG‐SGM3 BLT mice had a mature/naive phenotype with a corresponding decrease in immature/transitional human B cells as compared to NSG BLT mice. In addition, NSG‐SGM3 BLT mice have higher basal levels of human IgM and IgG as compared with NSG BLT mice. Moreover, dengue virus infection of NSG‐SGM3 BLT mice generated higher levels of antigen‐specific IgM and IgG, a result not observed in NSG BLT mice.

Conclusions: Our studies suggest that NSG‐SGM3 BLT mice show improved human B cell development and permit the generation of antigen‐specific antibody responses to viral infection.

No MeSH data available.


Human CD33+ myeloid cell engraftment kinetics in the peripheral blood, spleen, and bone marrow of NSG BLT mice and NSG‐SGM3 BLT mice. The peripheral blood of the NSG BLT and NSG‐SGM3 BLT mice was screened for total human CD33+ myeloid cell engraftment at 6‐week (A), 9‐week (B), and 12‐week (C) post‐transplantation of human fetal tissues. The spleen (D and E) and bone marrow (F and G) of NSG BLT and NSG‐SGM3 BLT mice were screened for human CD33+ myeloid cell engraftment 12 weeks after transplantation of human fetal tissues. Engraftment results are represented as a percentage of total human CD45+ cells or as total numbers in the spleen (D and E) and in the bone marrow (F and G). In (B), data points shown for NSG‐SGM3 BLT are a combination of 8 and 9 week time points. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. Each symbol indicates an individual BLT mouse. The results for peripheral blood are from four independent experiments and for spleen and bone marrow are from two independent experiments.
© Copyright Policy - creativeCommonsBy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5134721&req=5

iid3124-fig-0004: Human CD33+ myeloid cell engraftment kinetics in the peripheral blood, spleen, and bone marrow of NSG BLT mice and NSG‐SGM3 BLT mice. The peripheral blood of the NSG BLT and NSG‐SGM3 BLT mice was screened for total human CD33+ myeloid cell engraftment at 6‐week (A), 9‐week (B), and 12‐week (C) post‐transplantation of human fetal tissues. The spleen (D and E) and bone marrow (F and G) of NSG BLT and NSG‐SGM3 BLT mice were screened for human CD33+ myeloid cell engraftment 12 weeks after transplantation of human fetal tissues. Engraftment results are represented as a percentage of total human CD45+ cells or as total numbers in the spleen (D and E) and in the bone marrow (F and G). In (B), data points shown for NSG‐SGM3 BLT are a combination of 8 and 9 week time points. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. Each symbol indicates an individual BLT mouse. The results for peripheral blood are from four independent experiments and for spleen and bone marrow are from two independent experiments.

Mentions: Previous studies have shown that NSG‐SGM3 mice engrafted with human HSC have significantly improved myeloid cell development 18, 19, 20, 21. Human CD33+ myeloid cell development in NSG‐SGM3 BLT and NSG BLT mice was monitored in the blood at 6, 9, and 12 weeks post‐implantation and in spleen and bone marrow at week 12 (Fig. 4). At all time points tested significantly higher levels of human CD33+ cells were detected in the blood of NSG‐SGM3 BLT mice as compared to NSG BLT mice (Fig. 4A–C). In the spleen, the percentages and total numbers of human CD33+ cells were significantly higher in NSG‐SGM3 mice at 12 weeks post‐implantation compared to NSG mice (Fig. 4D and E). The percentages and total numbers of human CD45+ cells in the bone marrow were similar between NSG and NSG‐SGM3 mice at 12 weeks (Fig. 4F and G). Together, these data show that NSG‐SGM3 BLT mice show a heightened development of human myeloid development as has been found in HSC‐engrafted NSG‐SGM3 mice 21.


Improved B cell development in humanized NOD ‐ scid IL2R γ mice transgenically expressing human stem cell factor, granulocyte ‐ macrophage colony ‐ stimulating factor and interleukin ‐ 3
Human CD33+ myeloid cell engraftment kinetics in the peripheral blood, spleen, and bone marrow of NSG BLT mice and NSG‐SGM3 BLT mice. The peripheral blood of the NSG BLT and NSG‐SGM3 BLT mice was screened for total human CD33+ myeloid cell engraftment at 6‐week (A), 9‐week (B), and 12‐week (C) post‐transplantation of human fetal tissues. The spleen (D and E) and bone marrow (F and G) of NSG BLT and NSG‐SGM3 BLT mice were screened for human CD33+ myeloid cell engraftment 12 weeks after transplantation of human fetal tissues. Engraftment results are represented as a percentage of total human CD45+ cells or as total numbers in the spleen (D and E) and in the bone marrow (F and G). In (B), data points shown for NSG‐SGM3 BLT are a combination of 8 and 9 week time points. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. Each symbol indicates an individual BLT mouse. The results for peripheral blood are from four independent experiments and for spleen and bone marrow are from two independent experiments.
© Copyright Policy - creativeCommonsBy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5134721&req=5

iid3124-fig-0004: Human CD33+ myeloid cell engraftment kinetics in the peripheral blood, spleen, and bone marrow of NSG BLT mice and NSG‐SGM3 BLT mice. The peripheral blood of the NSG BLT and NSG‐SGM3 BLT mice was screened for total human CD33+ myeloid cell engraftment at 6‐week (A), 9‐week (B), and 12‐week (C) post‐transplantation of human fetal tissues. The spleen (D and E) and bone marrow (F and G) of NSG BLT and NSG‐SGM3 BLT mice were screened for human CD33+ myeloid cell engraftment 12 weeks after transplantation of human fetal tissues. Engraftment results are represented as a percentage of total human CD45+ cells or as total numbers in the spleen (D and E) and in the bone marrow (F and G). In (B), data points shown for NSG‐SGM3 BLT are a combination of 8 and 9 week time points. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. Each symbol indicates an individual BLT mouse. The results for peripheral blood are from four independent experiments and for spleen and bone marrow are from two independent experiments.
Mentions: Previous studies have shown that NSG‐SGM3 mice engrafted with human HSC have significantly improved myeloid cell development 18, 19, 20, 21. Human CD33+ myeloid cell development in NSG‐SGM3 BLT and NSG BLT mice was monitored in the blood at 6, 9, and 12 weeks post‐implantation and in spleen and bone marrow at week 12 (Fig. 4). At all time points tested significantly higher levels of human CD33+ cells were detected in the blood of NSG‐SGM3 BLT mice as compared to NSG BLT mice (Fig. 4A–C). In the spleen, the percentages and total numbers of human CD33+ cells were significantly higher in NSG‐SGM3 mice at 12 weeks post‐implantation compared to NSG mice (Fig. 4D and E). The percentages and total numbers of human CD45+ cells in the bone marrow were similar between NSG and NSG‐SGM3 mice at 12 weeks (Fig. 4F and G). Together, these data show that NSG‐SGM3 BLT mice show a heightened development of human myeloid development as has been found in HSC‐engrafted NSG‐SGM3 mice 21.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Immunodeficient mice engrafted with human immune systems support studies of human hematopoiesis and the immune response to human&#8208;specific pathogens. A significant limitation of these humanized mouse models is, however, a severely restricted ability of human B cells to undergo class switching and produce antigen&#8208;specific IgG after infection or immunization.

Methods: In this study, we have characterized the development and function of human B cells in NOD&#8208;scid IL2R&gamma; (NSG) mice transgenically expressing human stem cell factor (SCF), granulocyte macrophage colony&#8208;stimulating factor (GM&#8208;CSF), and IL&#8208;3 (NSG&#8208;SGM3) following engraftment with human hematopoietic stem cells, autologous fetal liver, and thymic tissues (bone marrow, liver, thymus or BLT model). The NSG&#8208;SGM3 BLT mice engraft rapidly with human immune cells and develop T cells, B cells, and myeloid cells.

Results: A higher proportion of human B cells developing in NSG&#8208;SGM3 BLT mice had a mature/naive phenotype with a corresponding decrease in immature/transitional human B cells as compared to NSG BLT mice. In addition, NSG&#8208;SGM3 BLT mice have higher basal levels of human IgM and IgG as compared with NSG BLT mice. Moreover, dengue virus infection of NSG&#8208;SGM3 BLT mice generated higher levels of antigen&#8208;specific IgM and IgG, a result not observed in NSG BLT mice.

Conclusions: Our studies suggest that NSG&#8208;SGM3 BLT mice show improved human B cell development and permit the generation of antigen&#8208;specific antibody responses to viral infection.

No MeSH data available.