Human immune system development and survival of non-obese diabetic (NOD)-scid IL2rγnull(NSG) mice engrafted with human thymus and autologous haematopoietic stem cells

Identifying critical windows in immune system development is crucial for determination of either safety or vulnerability to exposure to specific agents during rapidly changing phases of ontogeny. These phases in the human range from postconception early gestation through adolescence. A detailed understanding of these windows will facilitate avoidance of environmental toxins as well as allow improved planning for unavoidable exposures. Critical windows of immune development will be influenced by concomitant development, maturation and growth of other organ systems, thus the influence of potentially toxic exposures must be determined within a co-ordinated multisystem and multidisciplinary approach.

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Overview of immune system development in the dog: comparison with humans

Human & Experimental Toxicology ◽

10.1191/0960327102ht286oa ◽

2002 ◽

Vol 21 (9-10) ◽

pp. 487-492 ◽

Cited By ~ 63

Author(s):

P J Felsburg

Keyword(s):

Immune System ◽

System Development ◽

Postnatal Period ◽

Large Animal ◽

Human Immune System ◽

Potential Toxicity ◽

Clinical Model ◽

Investigational Drugs ◽

Immune System Development ◽

Human Immune

Dogs play an important role in toxicology because of their importance as a large animal, pre-clinical model for evaluating potential toxicity in human drug development including the effects of investigational drugs on the immune system. The purpose of this paper is to review the development of the canine immune system during the fetal, neonatal and postnatal periods and to compare it with that of the human immune system. Unlike rodents, the development of the canine immune system shares many similarities to that of the human. In both dogs and humans, the immune system, including the mucosal immune system, is fully developed before birth although the maturity of the immune response may continue into the postnatal period.

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Human-like NSG mouse glycoproteins sialylation pattern changes the phenotype of human lymphocytes and sensitivity to HIV-1 infection

10.1101/404905 ◽

2018 ◽

Author(s):

Raghubendra Singh Dagur ◽

Amanda Branch Woods ◽

Saumi Mathews ◽

Poonam S. Joshi ◽

Rolen M. Quadros ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

System Development ◽

Human Immune System ◽

Hematopoietic Stem ◽

Acetylneuraminic Acid ◽

Immune System Development ◽

Human Immune ◽

Nsg Mouse ◽

Hiv 1

AbstractBackgroundThe use of immunodeficient mice transplanted with human hematopoietic stem cells is an accepted approach to study human-specific infectious diseases, like HIV-1, and to investigate multiple aspects of human immune system development. However, mouse and human are different in sialylation patterns of proteins due to evolutionary mutations of the CMP-N-acetylneuraminic acid hydroxylase (CMAH) gene that prevent formation of N-glycolylneuraminic acid from N-acetylneuraminic acid. How changes of mouse glycoproteins chemistry will affect phenotype and function of transplanted human hematopoietic stem cells and mature human immune cells in the course of HIV-1 infection is not known.ResultsWe mutated mouseCMAHon the most widely human cells transplantation strain NOD/scid-IL2Rγc-/-(NSG) mouse background using the CRISPR/Cas9 system. The new strain provides a better environment for human immune cells. Transplantation of human hematopoietic stem cells leads to broad B cells repertoire, higher sensitivity to HIV-1 infection, and enhanced proliferation of transplanted peripheral blood lymphocytes. The mice showed low effects on the clearance of human immunoglobulins and enhanced transduction efficiency of recombinant adeno-associated viral vector rAAV2/DJ8.ConclusionNSG-cmah-/-mice expand the mouse models suitable for human cells transplantation and this new model has advantages in generating a human B cell repertoire. This strain is suitable to study different aspects of the human immune system development, might provide advantages in patient-derived tissue and cell transplantation, and could allow studies of viral vectors and infectious agents that are sensitive to human-like sialylation of mouse glycoproteins.

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Evaluation of the efficiency of human immune system reconstitution in NSG mice and NSG mice containing a human HLA.A2 transgene using hematopoietic stem cells purified from different sources

Journal of Immunological Methods ◽

10.1016/j.jim.2015.02.007 ◽

2015 ◽

Vol 422 ◽

pp. 13-21 ◽

Cited By ~ 14

Author(s):

John Patton ◽

Raja Vuyyuru ◽

Amanda Siglin ◽

Michael Root ◽

Tim Manser

Keyword(s):

Stem Cells ◽

Immune System ◽

Hematopoietic Stem Cells ◽

Human Immune System ◽

Hematopoietic Stem ◽

Nsg Mice ◽

Human Immune ◽

Different Sources

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Acceptive Immunity: The Role of Fucosylated Glycans in Human Host–Microbiome Interactions

International Journal of Molecular Sciences ◽

10.3390/ijms22083854 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3854

Author(s):

Svetlana Kononova ◽

Ekaterina Litvinova ◽

Timur Vakhitov ◽

Maria Skalinskaya ◽

Stanislav Sitkin

Keyword(s):

Immune System ◽

System Development ◽

Bacterial Colonization ◽

Past Century ◽

Human Immune System ◽

Immune System Development ◽

Human Immune ◽

The Relationship ◽

Symbiotic Microbiota

The growth in the number of chronic non-communicable diseases in the second half of the past century and in the first two decades of the new century is largely due to the disruption of the relationship between the human body and its symbiotic microbiota, and not pathogens. The interaction of the human immune system with symbionts is not accompanied by inflammation, but is a physiological norm. This is achieved via microbiota control by the immune system through a complex balance of pro-inflammatory and suppressive responses, and only a disturbance of this balance can trigger pathophysiological mechanisms. This review discusses the establishment of homeostatic relationships during immune system development and intestinal bacterial colonization through the interaction of milk glycans, mucins, and secretory immunoglobulins. In particular, the role of fucose and fucosylated glycans in the mechanism of interactions between host epithelial and immune cells is discussed.

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Mesenchymal Stem Cells in COVID-19: A Journey from Bench to Bedside

Laboratory Medicine ◽

10.1093/labmed/lmaa049 ◽

2020 ◽

Vol 52 (1) ◽

pp. 24-35

Author(s):

Kamal Kant Sahu ◽

Ahmad Daniyal Siddiqui ◽

Jan Cerny

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Immune System ◽

Therapeutic Option ◽

Antiviral Agent ◽

In Vitro Models ◽

Human Immune System ◽

Economic Sectors ◽

Human Immune

Abstract The COVID-19 pandemic has led to a major setback in both the health and economic sectors across the globe. The scale of the problem is enormous because we still do not have any specific anti-SARS-CoV-2 antiviral agent or vaccine. The human immune system has never been exposed to this novel virus, so the viral interactions with the human immune system are completely naive. New approaches are being studied at various levels, including animal in vitro models and human-based studies, to contain the COVID-19 pandemic as soon as possible. Many drugs are being tested for repurposing, but so far only remdesivir has shown some positive benefits based on preliminary reports, but these results also need further confirmation via ongoing trials. Otherwise, no other agents have shown an impactful response against COVID-19. Recently, research exploring the therapeutic application of mesenchymal stem cells (MSCs) in critically ill patients suffering from COVID-19 has gained momentum. The patients belonging to this subset are most likely beyond the point where they could benefit from an antiviral therapy because most of their illness at this stage of disease is driven by inflammatory (over)response of the immune system. In this review, we discuss the potential of MSCs as a therapeutic option for patients with COVID-19, based on the encouraging results from the preliminary data showing improved outcomes in the progression of COVID-19 disease.

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Engraftment of human HSCs in nonirradiated newborn NOD-scid IL2rγnull mice is enhanced by transgenic expression of membrane-bound human SCF

Blood ◽

10.1182/blood-2011-05-353243 ◽

2012 ◽

Vol 119 (12) ◽

pp. 2778-2788 ◽

Cited By ~ 54

Author(s):

Michael A. Brehm ◽

Waldemar J. Racki ◽

Jean Leif ◽

Lisa Burzenski ◽

Vishnu Hosur ◽

...

Keyword(s):

Stem Cell ◽

Immune System ◽

Stem Cell Factor ◽

Human Immune System ◽

Transgenic Expression ◽

Immunodeficient Mice ◽

Nsg Mice ◽

Immune System Development ◽

Membrane Bound ◽

Human Hscs

Abstract Immunodeficient mice engrafted with human HSCs support multidisciplinary translational experimentation, including the study of human hematopoiesis. Heightened levels of human HSC engraftment are observed in immunodeficient mice expressing mutations in the IL2-receptor common γ chain (IL2rg) gene, including NOD-scid IL2rγnull (NSG) mice. Engraftment of human HSC requires preconditioning of immunodeficient recipients, usually with irradiation. Such preconditioning increases the expression of stem cell factor (SCF), which is critical for HSC engraftment, proliferation, and survival. We hypothesized that transgenic expression of human membrane-bound stem cell factor Tg(hu-mSCF)] would increase levels of human HSC engraftment in nonirradiated NSG mice and eliminate complications associated with irradiation. Surprisingly, detectable levels of human CD45+ cell chimerism were observed after transplantation of cord blood–derived human HSCs into nonirradiated adult as well as newborn NSG mice. However, transgenic expression of human mSCF enabled heightened levels of human hematopoietic cell chimerism in the absence of irradiation. Moreover, nonirradiated NSG-Tg(hu-mSCF) mice engrafted as newborns with human HSCs rejected human skin grafts from a histoincompatible donor, indicating the development of a functional human immune system. These data provide a new immunodeficient mouse model that does not require irradiation preconditioning for human HSC engraftment and immune system development.

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Advances in Human Immune System Mouse Models for Personalized Treg-Based Immunotherapies

Frontiers in Immunology ◽

10.3389/fimmu.2021.643544 ◽

2021 ◽

Vol 12 ◽

Author(s):

Isabelle Serr ◽

Maria Kral ◽

Martin G. Scherm ◽

Carolin Daniel

Keyword(s):

Stem Cells ◽

Immune System ◽

Personalized Medicine ◽

Peripheral Blood ◽

Human Immune System ◽

Hematopoietic Stem ◽

Immunodeficient Mice ◽

Central Target ◽

Human Immune ◽

Cancer Immunotherapies

Immunodeficient mice engrafted with a functional human immune system [Human immune system (HIS) mice] have paved the way to major advances for personalized medicine and translation of immune-based therapies. One prerequisite for advancing personalized medicine is modeling the immune system of individuals or disease groups in a preclinical setting. HIS mice engrafted with peripheral blood mononuclear cells have provided fundamental insights in underlying mechanisms guiding immune activation vs. regulation in several diseases including cancer. However, the development of Graft-vs.-host disease restrains relevant long-term studies in HIS mice. Alternatively, engraftment with hematopoietic stem cells (HSCs) enables mimicking different disease stages, however, low frequencies of HSCs in peripheral blood of adults impede engraftment efficacy. One possibility to overcome those limitations is the use of patient-derived induced pluripotent stem cells (iPSCs) reprogrammed into HSCs, a challenging process which has recently seen major advances. Personalized HIS mice bridge research in mice and human diseases thereby facilitating the translation of immunomodulatory therapies. Regulatory T cells (Tregs) are important mediators of immune suppression and thereby contribute to tumor immune evasion, which has made them a central target for cancer immunotherapies. Importantly, studying Tregs in the human immune system in vivo in HIS mice will help to determine requirements for efficient Treg-targeting. In this review article, we discuss advances on personalized HIS models using reprogrammed iPSCs and review the use of HIS mice to study requirements for efficient targeting of human Tregs for personalized cancer immunotherapies.

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