scholarly journals A Double Humanized BLT-mice Model Featuring a Stable Human-Like Gut Microbiome and Human Immune System

10.3791/59773 ◽  
2019 ◽  
Author(s):  
Lance Daharsh ◽  
Jianshui Zhang ◽  
Amanda Ramer-Tait ◽  
Qingsheng Li
Keyword(s):  
Immune System ◽  
Gut Microbiome ◽  
Mice Model ◽  
Human Immune System ◽  
Human Immune ◽  
Blt Mice

scholarly journals Stable Engraftment of a Human Gut Bacterial Microbiome in Double Humanized BLT-mice

2019 ◽  
Author(s):  
Lance Daharsh ◽  
Amanda E. Ramer-Tait ◽  
Qingsheng Li
Keyword(s):  
Immune System ◽  
Gut Microbiome ◽  
Human Disease ◽  
Humanized Mice ◽  
Rrna Gene ◽  
Human Immune System ◽  
Human Gut ◽  
Healthy Human ◽  
Human Immune

AbstractBackgroundHumanized mice featuring a functional human immune system are an important pre-clinical model for examining immune responses to human-specific pathogens. This model has been widely utilized to study human diseases that are otherwise impossible or difficult to investigate in humans or with other animal models. However, one limitation of using humanized mice is their native murine gut microbiome, which significantly differs from the one found in humans. These differences may be even greater for mice housed and bred in specific pathogen free conditions. Given the importance of the gut microbiome to human health and disease, these differences may profoundly impact the ability to translate the results from humanized mice studies to human disease. Further, there is a critical need for improved pre-clinical models to study the complex in vivo relationships of the gut microbiome, immune system, and human disease. We therefore created double humanized mice with both a functional human immune system and stable human-like gut microbiome.ResultsSurgery was performed on NOD.Cg-PrkdcscidII2rgtm1Wjl/SzJ (NSG) mice to create bone-marrow, liver, thymus (BLT) humanized mice. After immune reconstitution, mice were treated with broad spectrum antibiotics to deplete murine gut bacteria and then transplanted with fecal material from healthy human donors. Characterization of 173 fecal samples obtained from 45 humanized mice revealed that double humanized mice had unique 16S rRNA gene profiles consistent with those of the individual human donor samples. Importantly, transplanted human-like gut microbiomes were stable in mice for the duration of the study, up to 14.5 weeks post-transplant. Microbiomes of double humanized mice also harbored predicted functional capacities that more closely resembled those of the human donors compared to humanized mice.ConclusionsHere, we describe successful engraftment of a stable human microbiome in BLT humanized mice to further improve this preclinical humanized mouse model. These double humanized mice represent a unique and tractable new model to study the complex relationships between the human gut microbiome, human immune system, and human disease in vivo.

scholarly journals Alterations in the gut microbiome by HIV-1 infection or a high-fat diet associates with systemic immune activation and inflammation in double humanized-BLT mice

2020 ◽  
Author(s):  
Lance Daharsh ◽  
Amanda E. Ramer-Tait ◽  
Qingsheng Li
Keyword(s):  
Immune System ◽  
Systemic Inflammation ◽  
Immune Activation ◽  
Gut Microbiome ◽  
High Fat Diet ◽  
Human Immune System ◽  
Systemic Immune Activation ◽  
Human Immune ◽  
Hiv 1

AbstractBackgroundWhile the translatability of gut microbiome studies utilizing animal models to humans has proven difficult, studying the gut microbiome directly in humans is also challenging due to the existence of many confounding variables. Therefore, we utilized double humanized mice, which have both an engrafted stable human-like gut microbiome and functional human immune system. With this model, we were able to determine the in vivo impact of HIV-1 infection or a high-fat diet (HFD) on gut human microbiome composition, and its relationship with human immune cell activation and systemic inflammation.ResultsSurgery was performed on NSG mice to create humanized bone-marrow, liver, thymus mice (hu-mice). In order to create double hu-mice, the hu-mice were treated with broad spectrum antibiotics to deplete murine gut bacteria and subsequently transplanted with human fecal material from healthy human donors. We characterized 262 fecal samples from hu-mice, double hu-mice, and human fecal donors to determine the impact of HIV-1 infection or HFD on the gut microbiome and systemic immune activation and inflammation. We found that HIV-1 infection altered the human-like gut microbiome of double hu-mice, which was associated with decreased human CD4 T cells and increased systemic inflammation and immune activation. Further, using a HFD we induced gut microbial dysbiosis in double hu-mice which corresponded with increased systemic immune activation and inflammation.ConclusionsHere, we describe the changes in the human gut microbiome and human immune system due to HIV-1 infection or HFD using our double hu-mice model. HIV-1 infection led to changes in the composition of the human-like gut microbiome that was associated with human CD4 T cell loss and high levels of inflammation and immune activation. The HFD quickly changed the composition of the gut microbiome and led to systemic immune activation and inflammation. We further identified a subset of gut bacteria in HIV-1 infected and HFD fed double hu-mice that was closely associated with systemic inflammation and immune activation. This study demonstrated how double humanized mice can be used to study the complex in vivo interactions of the gut microbiome and human immune system in the context of both disease and diet.

721 AT1412, a patient-derived CD9 antibody in preclinical development promoting tumor immune infiltration and inducing tumor rejection

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A763-A763
Author(s):  
Remko Schotte ◽  
Julien Villaudy ◽  
Martijn Kedde ◽  
Wouter Pos ◽  
Daniel Go ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Tumor Cells ◽  
Tumor Rejection ◽  
Human Immune System ◽  
Preclinical Development ◽  
High Affinity ◽  
Human Immune ◽  
A375 Melanoma

BackgroundAdaptive immunity to cancer cells forms a crucial part of cancer immunotherapy. Recently, the importance of tumor B-cell signatures were shown to correlate with melanoma survival. We investigated whether tumor-targeting antibodies could be isolated from a patient that cured (now 13 years tumor-free) metastatic melanoma following adoptive transfer of ex vivo expanded autologous T cells.MethodsPatient‘s peripheral blood B cells were isolated and tested for the presence of tumor-reactive B cells using AIMM’s immmortalisation technology. Antibody AT1412 was identified by virtue of its differential binding to melanoma cells as compared to healthy melanocytes. AT1412 binds the tetraspanin CD9, a broadly expressed protein involved in multiple cellular activities in cancer and induces ADCC and ADCP by effector cells.ResultsSpontaneous immune rejection of tumors was observed in human immune system (HIS) mouse models implanted with CD9 genetically-disrupted A375 melanoma (A375-CD9KO) tumor cells, while A375wt cells were not cleared. Most notably, no tumor rejection of A375-CD9KO tumors was observed in NSG mice, indicating that blockade of CD9 makes tumor cells susceptible to immune rejection.CD9 has been described to regulate integrin signaling, e.g. LFA-1, VLA-4, VCAM-1 and ICAM-1. AT1412 was shown to modulate CD9 function by enhancing adhesion and transmigration of T cells to endothelial (HUVEC) cells. AT1412 was most potently enhancing transendothelial T-cell migration, in contrast to a high affinity version of AT1412 or other high affinity anti-CD9 reference antibodies (e.g. ALB6). Enhanced immune cell infiltration is also observed in immunodeficient mice harbouring a human immune system (HIS). AT1412 strongly enhanced CD8 T-cell and macrophage infiltration resulting in tumor rejection (A375 melanoma). PD-1 checkpoint blockade is further sustaining this effect. In a second melanoma model carrying a PD-1 resistant and highly aggressive tumor (SK-MEL5) AT1412 together with nivolumab was inducing full tumor rejection, while either one of the antibodies alone did not.ConclusionsThe safety of AT1412 has been assessed in preclinical development and is well tolerated up to 10 mg/kg (highest dose tested) by non human primates. AT1412 demonstrated a half-life of 8.5 days, supporting 2–3 weekly administration in humans. Besides transient thrombocytopenia no other pathological deviations were observed. No effect on coagulation parameters, bruising or bleeding were observed macro- or microscopically. The thrombocytopenia is reversible, and its recovery accelerated in those animals developing anti-drug antibodies. First in Human clinical study is planned to start early 2021.Ethics ApprovalStudy protocols were approved by the Medical Ethical Committee of the Leiden University Medical Center (Leiden, Netherlands).ConsentBlood was obtained after written informed consent by the patient.

scholarly journals Transplacental priming of the human immune system with environmental allergens can occur early in gestation

2000 ◽  
Vol 106 (3) ◽  
pp. 530-536 ◽  
Author(s):  
Zsolt Szépfalusi ◽  
Josefa Pichler ◽  
Stefan Elsässer ◽  
Katalin van Duren ◽  
Christof Ebner ◽  
...  
Keyword(s):  
Immune System ◽  
Human Immune System ◽  
Human Immune

scholarly journals Antimicrobial peptides: The ancient arm of the human immune system

Virulence ◽  
2010 ◽  
Vol 1 (5) ◽  
pp. 440-464 ◽  
Author(s):  
Jochen Wiesner ◽  
Andreas Vilcinskas
Keyword(s):  
Immune System ◽  
Antimicrobial Peptides ◽  
Human Immune System ◽  
Human Immune

On the use of multiple heterogeneous devices to speedup the execution of a computational model of the Human Immune System

2015 ◽  
Vol 267 ◽  
pp. 304-313 ◽  
Author(s):  
T.M. do Nascimento ◽  
J.M. de Oliveira ◽  
M.P. Xavier ◽  
A.B. Pigozzo ◽  
R.W. dos Santos ◽  
...  
Keyword(s):  
Immune System ◽  
Computational Model ◽  
Human Immune System ◽  
Heterogeneous Devices ◽  
Human Immune

Al-Muddaththir of the Quran Linked to the Covid-19 and Spanish Flu Pandemics: Circumstantial Evidence

2021 ◽  
Vol 02 (02) ◽  
Author(s):  
Baback Khodadoost ◽  
Keyword(s):  
Immune System ◽  
Circumstantial Evidence ◽  
The Moon ◽  
Human Immune System ◽  
Main Emphasis ◽  
Spanish Flu ◽  
Human Immune

Recently there have been speculations concerning a possible link between the covid-19 pandemic and al-Muddaththir, the 74th chapter of the Quran. An examination of this chapter presented in this article shows further evidences in support of these speculations. It is shown that indications of not only the current Covid-19 pandemic, but also the horrific 1918 Spanish flu can be detected in chapter 74. The main emphasis of this article will be to demonstrate the timings of the pandemic events as they appear to have been encoded in four of the chapter verses. The concept of Translational-Coding and in particular, its use in decoding one of the time-informing verses will be explained. A remarkable scheme of al-Muddaththir to announce the exact occurring years of the two major pandemics, will also be exposed. Coincidences of the Super Moon occurrences with major events of both, Covid-19 and Spanish flu pandemics, will be shown as the possible reason for “by the moon” swearing in verse 74:32. In connection with these observed coincidences, possible effect of the moon’s differential gravity on suppression of the human immune system during a Super Moon occurrence will be addressed. Some other verses in al-Muddaththir with possible relevance to the pandemic perspective of this chapter will also be discussed.

What did we learn from CTLA-4 insufficiency on the human immune system?

2018 ◽  
Vol 287 (1) ◽  
pp. 33-49 ◽  
Author(s):  
Noriko Mitsuiki ◽  
Charlotte Schwab ◽  
Bodo Grimbacher
Keyword(s):  
Immune System ◽  
Human Immune System ◽  
Human Immune
Sign in / Sign up

Export Citation Format

Share Document