Dataset Information

Improved B cell development in humanized NOD-scid IL2R?^null mice transgenically expressing human stem cell factor, granulocyte-macrophage colony-stimulating factor and interleukin-3.

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 IL2R?^null (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.

SUBMITTER: Jangalwe S

PROVIDER: S-EPMC5134721 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Improved B cell development in humanized NOD<i>-scid IL2Rγ<sup>null</sup></i> mice transgenically expressing human stem cell factor, granulocyte-macrophage colony-stimulating factor and interleukin-3.

Jangalwe Sonal S Shultz Leonard D LD Mathew Anuja A Brehm Michael A MA

Immunity, inflammation and disease 20160828 4

<h4>Introduction</h4>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.<h4>Methods</h4>In this study, we have characterized the development and function of human B cells in NOD-<i>scid IL2Rγ<s ...[more]

PMID: 27980777

Similar Datasets

Project description:Immunodeficient mice reconstituted with human hematopoietic stem cells enable the in vivo study of human hematopoiesis. In particular, NOD-scid-IL2R?(null) engrafted mice have been shown to have reasonable levels of T and B cell repopulation and can mount T-cell dependent responses; however, antigen-specific B-cell responses in this model are generally poor. We explored whether developmental defects in the immunoglobulin gene repertoire might be partly responsible for the low level of antibody responses in this model. Roche 454 sequencing was used to obtain over 685,000 reads from cDNA encoding immunoglobulin heavy (IGH) and light (IGK and IGL) genes isolated from immature, naïve, or total splenic B cells in engrafted NOD-scid-IL2R?(null) mice, and compared with over 940,000 reads from peripheral B cells of two healthy volunteers. We find that while naïve B-cell repertoires in humanized mice are chiefly indistinguishable from those in human blood B cells, and display highly correlated patterns of immunoglobulin gene segment use, the complementarity-determining region H3 (CDR-H3) repertoires are nevertheless extremely diverse and are specific for each individual. Despite this diversity, preferential D(H)-J(H) pairings repeatedly occur within the CDR-H3 interval that are strikingly similar across all repertoires examined, implying a genetic constraint imposed on repertoire generation. Moreover, CDR-H3 length, charged amino-acid content, and hydropathy are indistinguishable between humans and humanized mice, with no evidence of global autoimmune signatures. Importantly, however, a statistically greater usage of the inherently autoreactive IGHV4-34 and IGKV4-1 genes was observed in the newly formed immature B cells relative to naïve B or total splenic B cells in the humanized mice, a finding consistent with the deletion of autoreactive B cells in humans. Overall, our results provide evidence that key features of the primary repertoire are shaped by genetic factors intrinsic to human B cells and are principally unaltered by differences between mouse and human stromal microenvironments.

Dataset Information

Improved B cell development in humanized NOD-scid IL2R?^null mice transgenically expressing human stem cell factor, granulocyte-macrophage colony-stimulating factor and interleukin-3.

Introduction

Methods

Results

Conclusions

Publications

Improved B cell development in humanized NOD<i>-scid IL2Rγ<sup>null</sup></i> mice transgenically expressing human stem cell factor, granulocyte-macrophage colony-stimulating factor and interleukin-3.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Introduction

Methods

Results

Conclusions

Publications

Improved B cell development in humanized NOD<i>-scid IL2Rγ<sup>null</sup></i> mice transgenically expressing human stem cell factor, granulocyte-macrophage colony-stimulating factor and interleukin-3.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Improved B cell development in humanized NOD-scid IL2R?^null mice transgenically expressing human stem cell factor, granulocyte-macrophage colony-stimulating factor and interleukin-3.