Replacing mouse BAFF with human BAFF does not improve B-cell maturation in hematopoietic humanized mice

Lang, Julie; Zhang, Bicheng; Kelly, Margot; Peterson, Jacob N.; Barbee, Jacob; Freed, Brian M.; Santo, James P. Di; Matsuda, Jennifer L.; Torres, Raul M.; Pelanda, Roberta

doi:10.1182/bloodadvances.2017010090

Cited by 23 publications

(22 citation statements)

References 55 publications

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“…BRGS humanized mice. For this study, we utilized BALB/c Rag2 null Il2r␥ null Sirpa NOD (BRGS) mice that are immunodeficient, devoid of murine T, B, and NK cells, and highly permissive to xenograft transplantation as previously described (42,43). CB CD34 ϩ cells were prepared using a CD34-positive selection kit (Miltenyi Biotec, Bergisch Gladbach, Germany) and expanded in culture as previously described (40).…”

Section: Methodsmentioning

confidence: 99%

“…Human chimerism is defined as the percentage of human (hCD45 ϩ ) hematopoietic cells in the total population (human and mouse) of hematopoietic (hCD45 ϩ and mCD45 ϩ ) cells. Abs used in flow cytometric analyses were as described previously (40,41,43) and purchased from BioLegend (San Diego, CA). Cells were incubated with Abs in staining buffer (PBS, 1% bovine serum albumin [BSA], 0.1% sodium azide) for 15 min at 4°C and washed two times with the same buffer.…”

Section: Methodsmentioning

confidence: 99%

“…Both CD4 ϩ and CD8 ϩ T cell subsets are observed in BRG hu-mice along with normal thymic CD4/CD8 expression patterns. The BRG strain was further modified with the introduction of the NOD-derived Sirpa allele (referred to from this point as the BRGS strain), which improves human chimerism (42,43). A significant advantage of the BRGS hu-mouse model is the combination of B cell maturation and robust IgG production as well as significant thymic engraftment and T cell generation without the need for human thymus cotransplantation, as required in other models (44).…”

mentioning

confidence: 99%

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Epstein-Barr Virus Type 2 Infects T Cells and Induces B Cell Lymphomagenesis in Humanized Mice

Coleman

Lang

Sweet

et al. 2018

J Virol

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Epstein-Barr virus (EBV) has been classified into two strains, EBV type 1 (EBV-1) and EBV type 2 (EBV-2) based on genetic variances and differences in transforming capacity. EBV-1 readily transforms B cells in culture while EBV-2 is poorly transforming. The differing abilities to immortalize B cellsin vitrosuggest thatin vivothese viruses likely use alternative approaches to establish latency. Indeed, we recently reported that EBV-2 has a unique cell tropism for T cells, infecting T cells in culture and in healthy Kenyan infants, strongly suggesting that EBV-2 infection of T cells is a natural part of the EBV-2 life cycle. However, limitations of human studies hamper further investigation into how EBV-2 utilizes T cells. Therefore, BALB/c Rag2nullIL2rγnullSIRPα humanized mice were utilized to develop an EBV-2in vivomodel. Infection of humanized mice with EBV-2 led to infection of both T and B cells, unlike infection with EBV-1, in which only B cells were infected. Gene expression analysis demonstrated that EBV-2 established a latency III infection with evidence of ongoing viral reactivation in both B and T cells. Importantly, EBV-2-infected mice developed tumors resembling diffuse large B cell lymphoma (DLBCL). These lymphomas had morphological features comparable to those of EBV-1-induced DLBCLs, developed at similar rates with equivalent frequencies, and expressed a latency III gene profile. Thus, despite the impaired ability of EBV-2 to immortalize B cellsin vitro, EBV-2 efficiently induces lymphomagenesis in humanized mice. Further research utilizing this model will enhance our understanding of EBV-2 biology, the consequence of EBV infection of T cells, and the capacity of EBV-2 to drive lymphomagenesis.IMPORTANCEEBV is a well-established B cell-tropic virus. However, we have recently shown that the EBV type 2 (EBV-2) strain also infects primary T cells in culture and in healthy Kenyan children. This finding suggests that EBV-2, unlike the well-studied EBV-1 strain, utilizes the T cell compartment to persist. As EBV is human specific, studies to understand the role of T cells in EBV-2 persistence require anin vivomodel. Thus, we developed an EBV-2 humanized mouse model, utilizing immunodeficient mice engrafted with human cord blood CD34+stem cells. Characterization of the EBV-2-infected humanized mice established that both T cells and B cells are infected by EBV-2 and that the majority of infected mice develop a B cell lymphoma resembling diffuse large B cell lymphoma. This newin vivomodel can be utilized for studies to enhance our understanding of how EBV-2 infection of T cells contributes to persistence and lymphomagenesis.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Epstein-Barr Virus Type 2 Infects T Cells and Induces B Cell Lymphomagenesis in Humanized Mice

Coleman

Lang

Sweet

et al. 2018

J Virol

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“…Our group has spent significant effort investigating the development and function of human B cells in HIS hu-mice. Using the model generated by transplanting human HSCs from umbilical cord blood into BRG and BRGS neonates, we have shown that human B cells are robustly produced in these animals and that their bone marrow development is largely normal [ 109 , 110 ]. Once exported outside the bone marrow, however, newly generated human B cells are impaired from developing into fully mature cells, and we have found that their maturation is aided by the accumulation of T cells [ 109 ] but not by the addition of human BAFF [ 110 ].…”

Section: Using His Mice To Study Tolerance and Autoimmunitymentioning

confidence: 99%

The development of human immune system mice and their use to study tolerance and autoimmunity

Costa

Lang

Torres

et al. 2019

Journal of Translational Autoimmunity

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Autoimmune diseases evolve from complex interactions between the immune system and self-antigens and involve several genetic attributes, environmental triggers and diverse cell types. Research using experimental mouse models has contributed key knowledge on the mechanisms that underlie these diseases in humans, but differences between the mouse and human immune systems can and, at times, do undermine the translational significance of these findings. The use of human immune system (HIS) mice enables the utility of mouse models with greater relevance for human diseases. As the name conveys, these mice are reconstituted with mature human immune cells transferred directly from peripheral blood or via transplantation of human hematopoietic stem cells that nucleate the generation of a complex human immune system. The function of the human immune system in HIS mice has improved over the years with the stepwise development of better models. HIS mice exhibit key benefits of the murine animal model, such as small size, robust and rapid reproduction and ease of experimental manipulation. Importantly, HIS mice also provide an applicable in vivo setting that permit the investigation of the physiological and pathological functions of the human immune system and its response to novel treatments. With the gaining popularity of HIS mice in the last decade, the potential of this model has been exploited for research in basic science, infectious diseases, cancer, and autoimmunity. In this review we focus on the use of HIS mice in autoimmune studies to stimulate further development of these valuable models.

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“…Indeed, in experimental models, T cells are both necessary and sufficient for the rejection of most allografts. 46 , 47 Whereas recreation of these features is important, a caveat of PBMC-humanization is that reconstitution is heavily lymphoid-biased: over 90% of human cells are T cells and the majority express an activated or memory phenotype. 48 The disproportionately large fraction of the human leukocyte repertoire (usually ~5%–20%) may misrepresent the global immunologic reaction to transplantation, potentially limiting the relatability of experimental findings to the true human alloresponse.…”

Section: Micementioning

confidence: 99%

Humanization of Immunodeficient Animals for the Modeling of Transplantation, Graft Versus Host Disease, and Regenerative Medicine

et al. 2020

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The humanization of animals is a powerful tool for the exploration of human disease pathogenesis in biomedical research, as well as for the development of therapeutic interventions with enhanced translational potential. Humanized models enable us to overcome biologic differences that exist between humans and other species, while giving us a platform to study human processes in vivo. To become humanized, an immune-deficient recipient is engrafted with cells, tissues, or organoids. The mouse is the most well studied of these hosts, with a variety of immunodeficient strains available for various specific uses. More recently, efforts have turned to the humanization of other animal species such as the rat, which offers some technical and immunologic advantages over mice. These advances, together with ongoing developments in the incorporation of human transgenes and additional mutations in humanized mouse models, have expanded our opportunities to replicate aspects of human allotransplantation and to assist in the development of immunotherapies. In this review, the immune and tissue humanization of various species is presented with an emphasis on their potential for use as models for allotransplantation, graft versus host disease, and regenerative medicine.

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Replacing mouse BAFF with human BAFF does not improve B-cell maturation in hematopoietic humanized mice

Abstract: Key Points• Expression of full-length hBAFF from cDNA in the endogenous murine locus does not improve maturation of human B cells in hu-mice.• mBAFF is not limiting the maturation of human B cells in hu-mice.

Cited by 23 publications

References 55 publications

Epstein-Barr Virus Type 2 Infects T Cells and Induces B Cell Lymphomagenesis in Humanized Mice

Epstein-Barr Virus Type 2 Infects T Cells and Induces B Cell Lymphomagenesis in Humanized Mice

The development of human immune system mice and their use to study tolerance and autoimmunity

Humanization of Immunodeficient Animals for the Modeling of Transplantation, Graft Versus Host Disease, and Regenerative Medicine

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