scholarly journals A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production

Blood ◽  
2017 ◽  
Vol 129 (8) ◽  
pp. 959-969 ◽  
Author(s):  
Hua Yu ◽  
Chiara Borsotti ◽  
Jean-Nicolas Schickel ◽  
Shu Zhu ◽  
Till Strowig ◽  
...  
Keyword(s):  
Mouse Model ◽  
High Specificity ◽  
Memory B Cells ◽  
Humanized Mice ◽  
Antibody Repertoire ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Cell Engraftment ◽  
Key Points ◽  
Specific Antibody Production

Key Points Human IL-6 improves T-cell engraftment and serum IgG production in humanized mice. IgG-switched memory B cells in IL-6 knock-in mice displayed a diverse antibody repertoire and high specificity against immunized antigen.

scholarly journals A functional DC cross talk promotes human ILC homeostasis in humanized mice

2017 ◽  
Vol 1 (10) ◽  
pp. 601-614 ◽  
Author(s):  
Silvia Lopez-Lastra ◽  
Guillemette Masse-Ranson ◽  
Oriane Fiquet ◽  
Sylvie Darche ◽  
Nicolas Serafini ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cross Talk ◽  
Humanized Mice ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Key Points

Key Points A novel humanized mouse model to study human ILC biology. Human DC cross talk with ILCs in vivo.

scholarly journals Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model

2020 ◽  
Vol 8 (2) ◽  
pp. e001513
Author(s):  
Nahee Park ◽  
Kamal Pandey ◽  
Sei Kyung Chang ◽  
Ah-Young Kwon ◽  
Young Bin Cho ◽  
...  
Keyword(s):  
Mouse Model ◽  
Humanized Mice ◽  
Preclinical Models ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Durable Response ◽  
Term Efficacy ◽  
Nsg Mice ◽  
Oncology Research

BackgroundWell-characterized preclinical models are essential for immune-oncology research. We investigated the feasibility of our humanized mouse model for evaluating the long-term efficacy of immunotherapy and biomarkers.MethodsHumanized mice were generated by injecting human fetal cord blood-derived CD34+ hematopoietic stem cells to NOD-scid IL2rγnull (NSG) mice myeloablated with irradiation or busulfan. The humanization success was defined as a 25% or higher ratio of human CD45+ cells to mice peripheral blood mononuclear cells.ResultsBusulfan was ultimately selected as the appropriate myeloablative method because it provided a higher success rate of humanization (approximately 80%) and longer survival time (45 weeks). We proved the development of functional T cells by demonstrating the anticancer effect of the programmed cell death-1 (PD-1) inhibitor in our humanized mice but not in non-humanized NSG mice. After confirming the long-lasting humanization state (45 weeks), we further investigated the response durability of the PD-1 inhibitor and biomarkers in our humanized mice. Early increase in serum tumor necrosis factor α levels, late increase in serum interleukin 6 levels and increase in tumor-infiltrating CD8+ T lymphocytes correlated more with a durable response over 60 days than with a non-durable response.ConclusionsOur CD34+ humanized mouse model is the first in vivo platform for testing the long-term efficacy of anticancer immunotherapies and biomarkers, given that none of the preclinical models has ever been evaluated for such a long duration.

scholarly journals Natural Killer Cells Improve Hematopoietic Stem Cell Engraftment by Increasing Stem Cell Clonogenicity In Vitro and in a Humanized Mouse Model

PLoS ONE ◽  
2015 ◽  
Vol 10 (10) ◽  
pp. e0138623 ◽  
Author(s):  
Michelle Escobedo-Cousin ◽  
Nicola Jackson ◽  
Raquel Laza-Briviesca ◽  
Linda Ariza-McNaughton ◽  
Martha Luevano ◽  
...  
Keyword(s):  
Stem Cell ◽  
Natural Killer Cells ◽  
Mouse Model ◽  
Natural Killer ◽  
Hematopoietic Stem Cell ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Hematopoietic Stem ◽  
Cell Engraftment

An Innovative Humanized Mouse Model of Multiple Myeloma (MM) for Studying MM in Its Natural Environment Using Multi-Color Light Sheet Fluorescence Microscopy (LSFM)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1809-1809
Author(s):  
Sabrina Kraus ◽  
Martin Chopra ◽  
Christian Brede ◽  
Simone S Riedel ◽  
Mike Friedrich ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mouse Model ◽  
Single Cell ◽  
Bioluminescence Imaging ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Cell Engraftment ◽  
Intact Bone ◽  
In Vivo Bioluminescence Imaging

Abstract Abstract 1809 Various imaging platforms are well established in hematology research. Nevertheless, the three-dimensional architecture of the bone marrow and tumor growth within this microenvironment remain largely uncharacterized. To date the major hindrance to microscopically image tumor engraftment and the immune response in the bone marrow on a single cell level is the compact structure of the bone that is almost impossible to image through. Therefore, we developed a novel bioluminescent mouse model that recapitulates the clinical characteristics of MM using the new human UMM3 cell line (CD38+, CD56+, CD138+, CD19−, CD20−), from the pleural effusion of a patient with an IgG lambda myeloma (ISS stage I) as well as the well-characterized RPMI8226 cell line transduced to express eGFP and firefly luciferase (UMM3eGFPluc and RPMIeGFPluc). 1×106 MM cells were injected intravenously into NOD.Cg-Prkdcscid IL2rg (NSG) mice and disease progression and bone marrow (BM) engraftment were monitored twice weekly by in vivo bioluminescence imaging. Both cell lines homed to the BM compartment, reflecting MM pathophysiology. Histological analysis confirmed BM engraftment and showed multiple osteolytic lesions for both UMM3 and RPMI cells. Since we were interested in imaging the interactions between human MM cells and the bone marrow microenvironment on a single cell level, we employed the multi-color LSFM after decalcification, specific deep-tissue antibody staining and clearing of the bone structures. With this innovative microscopy technique, we were able to establish a novel tool to display tumor cell engraftment in the bone marrow compartment in three dimensions through the intact bone. We recorded 1500 optical sections for three individual channels each (488, 532, and 647 nm) with an increment of 5μm which allows scanning the whole bone marrow compartment of the sternum within minutes in single-cell resolution. Using higher magnification enabled us to even visualize subcellular components within the bone marrow. Moreover, tissue autofluorescene, recorded mainly in the 488 nm channel, displayed detailed microanatomical structures which allowed for the localization of individual cells within their anatomical context. We could establish protocols for various fluorophore-coupled antibodies and successfully stained CD138+ cells in relation to CD3+ cells and to the microenvironment in the bone marrow. The CD138-positive cells infiltrated the bone marrow in a number of small clusters and comprising about 15% of cellular elements in total. Ex vivo bioluminescence imaging of the sternum from UMM3 tumor-bearing mice revealed massive infiltration of luciferase-expressing cells into the bone marrow compartment. This could also be confirmed by flow cytometrical analysis of bone marrow cells which showed eGFP+hCD138+ cells. We have successfully introduced a novel technique to study MM cell engraftment and progression in a humanized mouse model. We were able to track the tumor cells both in the living animal by in vivo bioluminescence imaging and on single-cell resolution by multi-color LSFM within the intact bone. Our model may lead to better insights into the pathogenesis of MM and could serve as a model for preclinical testing of new therapeutic approaches for the treatment of MM patients. Disclosures: No relevant conflicts of interest to declare.

Soluble GARP has potent antiinflammatory and immunomodulatory impact on human CD4+ T cells

Blood ◽  
2013 ◽  
Vol 122 (7) ◽  
pp. 1182-1191 ◽  
Author(s):  
Susanne A. Hahn ◽  
Heiko F. Stahl ◽  
Christian Becker ◽  
Anita Correll ◽  
Franz-Joseph Schneider ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Mouse Model ◽  
Cd4 T Cells ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Key Points ◽  
Destructive Inflammation

Key Points GARP efficiently represses proliferation of naïve and resting CD4+ T cells and is involved in the induction of adaptive regulatory T cells. In vivo, GARP prevents T cell–mediated destructive inflammation in a preclinical humanized mouse model of GVHD.

scholarly journals 14 Novel CD3 epsilon humanized N-terminal epitope model for assessment of efficacy of T-cell engagers

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A14-A14
Author(s):  
Gaëlle Martin ◽  
Fabiane Sônego ◽  
Audrey Beringer ◽  
Chloé Beuraud ◽  
Yacine Cherifi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Mouse Model ◽  
Humanized Mice ◽  
Dependent Manner ◽  
Salt Bridges ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Concentration Dependent Manner

BackgroundT-cell engagers have proved to be a promising therapeutic strategy in immunotherapy, for redirecting T cells activity against tumor cells. To facilitate the preclinical assessment of novel T-cell engagers and their translatability, we have developed an immunocompetent CD3 epsilon N-terminal epitope humanized mouse model.MethodsThis model was developed to express the human epitope of the CD3 epsilon chain, which is recognized by approximately 70% of the T-cell engagers (clone SP34). The rest of the extracellular domain was kept from mouse origin to preserve the amino acids involved in the interaction with CD3 gamma and delta. Similarly, the transmembrane domains and the intracellular domains where kept murine to enable salt bridges interaction, interaction with the CD3 zeta and the signaling into mouse cells.ResultsT cells from CD3 epsilon epitope humanized mice are found in comparable frequency in spleen, blood and bone marrow from WT mice. B cells, monocytes, dendritic cells and NK frequencies are also similar to the frequencies of these cell types in WT mice, suggesting that the humanization of the epitope of CD3 epsilon did not alter the immune cells distribution in these mice. Activation of T cells with antibodies targeting human CD3 (clone SP34) induced CD4 and CD8 T cell proliferation, as well as production of IL-2 and IFN-gamma. The CD3 functionality was demonstrated in vitro by the ability of B cells to produce IgM upon activation of T cells, suggesting a proper cooperation between T and B cells. Additionally, a first class of T-cell engagers targeting both human CD3 and a tumoral antigen, induced tumor cell lysis of MC38-Ag in a concentration-dependent manner. A second class of T cell engagers, also targeting CD3 and a tumoral antigen, showed an anti-tumor effect in vivo, and this effect was also shown to be dose-dependent.ConclusionsThese data suggest that the CD3 epsilon N-terminal epitope humanized mouse model enables the assessment of efficacy and mechanism of action of T-cell engagers.This model is currently being intercrossed with immunostimulatory humanized mouse models to provide new opportunities for assessment of bi-specific antibodies targeting the CD3 and immunostimulatory molecules. This model is the first generation of a broader program aiming at developping a Pan CD3 humanized model, where the gamma, delta and epsilon chains of the CD3 complex will be humanized. The Pan CD3 humanized mice are currently being investigated for immune responses and would provide a broader tool for assessment of T-cell engagers.

scholarly journals Experimental adaptive evolution of SIVcpz to pandemic HIV-1 using a humanized mouse model

2017 ◽  
pp. JVI.01905-17 ◽  
Author(s):  
Kei Sato ◽  
Naoko Misawa ◽  
Junko S Takeuchi ◽  
Tomoko Kobayashi ◽  
Taisuke Izumi ◽  
...  
Keyword(s):  
Mouse Model ◽  
Causative Agent ◽  
Humanized Mice ◽  
Humanized Mouse ◽  
Gain Of Function ◽  
Humanized Mouse Model ◽  
Hematopoietic Stem ◽  
Human Virus ◽  
The Cross ◽  
Hiv 1

HIV-1, the causative agent of AIDS, is originated from SIVcpz, the chimpanzee precursor of the human virus, approximately 100 years ago. This indicates that HIV-1 has emerged through the cross-species transmission of SIVcpz from chimpanzees to humans. However, it remains unclear how SIVcpz has evolved into pandemic HIV-1 in humans. To address this question, we inoculated three SIVcpz (MB897, EK505, and MT145), four pandemic HIV-1 (NL4-3, NLCSFV3, JRCSF and AD8) and 2 non-pandemic HIV-1 (YBF30 and DJO0131) strains. Humanized mice infected with SIVcpz strain MB897, a virus phylogenetically similar to pandemic HIV-1, exhibited a comparable peak viral load to that of mice infected with pandemic HIV-1, while peak viral loads of mice infected with SIVcpz strains EK505 or MT145 as well as non-pandemic HIV-1 strains were significantly lower. These results suggest that SIVcpz strain MB897 is pre-adapted to humans when compared to the other SIVcpz strains. Moreover, viral RNA sequencing of MB897-infected humanized mice identified a nonsynonymous mutation inenv, G413R substitution in gp120. The infectivity of the gp120 G413R mutant of MB897 was significantly higher than that of parental MB897. Furthermore, we demonstrated that the gp120 G413R mutant of MB897 augments the capacity for viral replication in bothin vitrocell cultures and humanized mice. Taken together, this is the first experimental investigation to use an animal model to demonstrate a gain-of-function evolution of SIVcpz into pandemic HIV-1.ImportanceFrom the mid-20th century, humans are exposed to the menace of viral infectious diseases such as SARS coronavirus, Ebola virus and Zika virus. These outbreaks of emerging/re-emerging viruses can be triggered by cross-species viral transmission from wild animals to humans or zoonoses. HIV-1, the causative agent of AIDS, was emerged by the cross-species transmission of SIVcpz, the HIV-1 precursor in chimpanzee, around 100 years ago. However, the process by which SIVcpz evolved to become HIV-1 in humans remains unclear. By using a hematopoietic stem cell-transplanted humanized mouse model, here we experimentally recapitulate the evolutionary process of SIVcpz to become HIV-1. We provide evidence suggesting that a strain of SIVcpz, MB897, has pre-adapted to infect humans comparing to other SIVcpz strains. We further demonstrate a gain-of-function evolution of SIVcpz in infected humanized mice. Our study reveals that pandemic HIV-1 has emerged through at least two steps: preadaptation and subsequent gain-of-function mutations.

scholarly journals Activation of the erythroid K-Cl cotransporter Kcc1 enhances sickle cell disease pathology in a humanized mouse model

Blood ◽  
2015 ◽  
Vol 126 (26) ◽  
pp. 2863-2870 ◽  
Author(s):  
Fiona C. Brown ◽  
Ashlee J. Conway ◽  
Loretta Cerruti ◽  
Janelle E. Collinge ◽  
Catriona McLean ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Mouse Model ◽  
Missense Mutation ◽  
Sickle Cell ◽  
Cytoplasmic Tail ◽  
Cell Disease ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Key Points

Key Points A missense mutation in the cytoplasmic tail of Kcc1 activates K-Cl cotransporter activity by impairing phosphorylation of nearby threonines. In vivo evidence shows that activation of Kcc1 directly contributes to the pathogenesis of sickle cell disease.

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