Dataset Information

Building the Next Generation of Humanized Hemato-Lymphoid System Mice.

ABSTRACT: Since the late 1980s, mice have been repopulated with human hematopoietic cells to study the fundamental biology of human hematopoiesis and immunity, as well as a broad range of human diseases in vivo. Multiple mouse recipient strains have been developed and protocols optimized to efficiently generate these "humanized" mice. Here, we review three guiding principles that have been applied to the development of the currently available models: (1) establishing tolerance of the mouse host for the human graft; (2) opening hematopoietic niches so that they can be occupied by human cells; and (3) providing necessary support for human hematopoiesis. We then discuss four remaining challenges: (1) human hematopoietic lineages that poorly develop in mice; (2) limited antigen-specific adaptive immunity; (3) absent tolerance of the human immune system for its mouse host; and (4) sub-functional interactions between human immune effectors and target mouse tissues. While major advances are still needed, the current models can already be used to answer specific, clinically-relevant questions and hopefully inform the development of new, life-saving therapies.

SUBMITTER: Martinov T

PROVIDER: S-EPMC7938325 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Building the Next Generation of Humanized Hemato-Lymphoid System Mice.

Martinov Tijana T McKenna Kelly M KM Tan Wei Hong WH Collins Emily J EJ Kehret Allie R AR Linton Jonathan D JD Olsen Tayla M TM Shobaki Nour N Rongvaux Anthony A

Frontiers in immunology 20210222

Since the late 1980s, mice have been repopulated with human hematopoietic cells to study the fundamental biology of human hematopoiesis and immunity, as well as a broad range of human diseases <i>in vivo</i>. Multiple mouse recipient strains have been developed and protocols optimized to efficiently generate these "humanized" mice. Here, we review three guiding principles that have been applied to the development of the currently available models: (1) establishing tolerance of the mouse host for ...[more]

PMID: 33692812

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Project description:Humanized hemato-lymphoid system mice, or humanized mice, emerged in recent years as a promising model to study the course of infection of human-adapted or human-specific pathogens. Though Staphylococcus aureus infects and colonizes a variety of species, it has nonetheless become one of the most successful human pathogens of our time with a wide armory of human-adapted virulence factors. Humanized mice showed increased vulnerability to S. aureus compared to wild type mice in a variety of clinically relevant disease models. Most of these studies employed humanized NSG (NOD-scid IL2Rgnull) mice which are widely used in the scientific community, but show poor human myeloid cell reconstitution. Since this immune cell compartment plays a decisive role in the defense of the human immune system against S. aureus, we asked whether next-generation humanized mice, like NSG-SGM3 (NOD-scid IL2Rgnull-3/GM/SF) with improved myeloid reconstitution, would prove to be more resistant to infection. To our surprise, we found the contrary when we infected humanized NSG-SGM3 (huSGM3) mice with S. aureus: although they had stronger human immune cell engraftment than humanized NSG mice, particularly in the myeloid compartment, they displayed even more pronounced vulnerability to S. aureus infection. HuSGM3 mice had overall higher numbers of human T cells, B cells, neutrophils and monocytes in the blood and the spleen. This was accompanied by elevated levels of pro-inflammatory human cytokines in the blood of huSGM3 mice. We further identified that the impaired survival of huSGM3 mice was not linked to higher bacterial burden nor to differences in the murine immune cell repertoire. Conversely, we could demonstrate a correlation of the rate of humanization and the severity of infection. Collectively, this study suggests a detrimental effect of the human immune system in humanized mice upon encounter with S. aureus which might help to guide future therapy approaches and analysis of virulence mechanisms.

Project description:ProblemDissemination and implementation (D&I) science provides the tools needed to close the gap between known intervention strategies and their effective application. The authors report on the Mentored Training for Dissemination and Implementation Research in Cancer (MT-DIRC) program-a D&I training program for postdoctoral or early-career cancer prevention and control scholars.ApproachMT-DIRC was a 2-year training institute in which fellows attended 2 annual Summer Institutes and other conferences and received didactic, group, and individual instruction; individualized mentoring; and other supports (e.g., pilot funding). A quasi-experimental design compared changes in 3 areas: mentoring, skills, and network composition. To evaluate mentoring and D&I skills, data from fellows on their mentors' mentoring competencies, their perspectives on the importance of and satisfaction with mentoring priority areas, and their self-rated skills in D&I competency domains were collected. Network composition data were collected from faculty and fellows for 3 core social network domains: contact, mentoring, and collaboration. Paired t tests (mentoring), linear mixed models (skills), and descriptive analyses (network composition) were performed.OutcomesMentors were rated as highly competent across all mentoring competencies, and each mentoring priority area showed reductions in gaps between satisfaction and importance between the 6 and 18 months post-first Summer Institute. Fellows' self-rated skills in D&I competencies improved significantly in all domains over time (range: 42.5%-52.9% increase from baseline to 18 months post-first Summer Institute). Mentorship and collaboration networks grew over time, with the highest number of collaboration network ties for scholarly manuscripts (n = 199) in 2018 and for research projects (n = 160) in 2019.Next stepsBuilding on study findings and existing literature, mentored training of scholars is an important approach for building D&I skills and networks, and thus to better applying the vast amount of available intervention evidence to benefit cancer control.

Dataset Information

Building the Next Generation of Humanized Hemato-Lymphoid System Mice.

Publications

Building the Next Generation of Humanized Hemato-Lymphoid System Mice.

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