scholarly journals Testing Cancer Immunotherapy in a Human Immune System Mouse Model: Correlating Treatment Responses to Human Chimerism, Therapeutic Variables and Immune Cell Phenotypes

2021 ◽  
Vol 12 ◽  
Author(s):  
Juan A. Marín-Jiménez ◽  
Anna Capasso ◽  
Matthew S. Lewis ◽  
Stacey M. Bagby ◽  
Sarah J. Hartman ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Immune System ◽  
Mouse Model ◽  
Immune Cell ◽  
Receptor Expression ◽  
Human Immune System ◽  
Combination Drug ◽  
Hematopoietic Stem ◽  
Human Immune ◽  
Treatment Responses

Over the past decade, immunotherapies have revolutionized the treatment of cancer. Although the success of immunotherapy is remarkable, it is still limited to a subset of patients. More than 1500 clinical trials are currently ongoing with a goal of improving the efficacy of immunotherapy through co-administration of other agents. Preclinical, small-animal models are strongly desired to increase the pace of scientific discovery, while reducing the cost of combination drug testing in humans. Human immune system (HIS) mice are highly immune-deficient mouse recipients rtpeconstituted with human hematopoietic stem cells. These HIS-mice are capable of growing human tumor cell lines and patient-derived tumor xenografts. This model allows rapid testing of multiple, immune-related therapeutics for tumors originating from unique clinical samples. Using a cord blood-derived HIS-BALB/c-Rag2nullIl2rγnullSIRPαNOD (BRGS) mouse model, we summarize our experiments testing immune checkpoint blockade combinations in these mice bearing a variety of human tumors, including breast, colorectal, pancreatic, lung, adrenocortical, melanoma and hematological malignancies. We present in-depth characterization of the kinetics and subsets of the HIS in lymph and non-lymph organs and relate these to protocol development and immune-related treatment responses. Furthermore, we compare the phenotype of the HIS in lymph tissues and tumors. We show that the immunotype and amount of tumor infiltrating leukocytes are widely-variable and that this phenotype is tumor-dependent in the HIS-BRGS model. We further present flow cytometric analyses of immune cell subsets, activation state, cytokine production and inhibitory receptor expression in peripheral lymph organs and tumors. We show that responding tumors bear human infiltrating T cells with a more inflammatory signature compared to non-responding tumors, similar to reports of “responding” patients in human immunotherapy clinical trials. Collectively these data support the use of HIS mice as a preclinical model to test combination immunotherapies for human cancers, if careful attention is taken to both protocol details and data analysis.

scholarly journals A Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2. HLA-DR4. Rag1 KO.IL-2Rγc KO. NOD) for COVID-19

2021 ◽  
Author(s):  
Teodor-Doru Brumeanu ◽  
Pooja Vir ◽  
Ahmad Faisal Karim ◽  
Swagata Kar ◽  
Dalia Benetiene ◽  
...  
Keyword(s):  
Immune System ◽  
T Cell ◽  
Mouse Model ◽  
Human Model ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
Human Immune

Abstract We report the first Human Immune System (HIS)-humanized mouse model (“DRAGA”: HLA-A2.HLA-DR4.Rag1KO.IL-2RgcKO.NOD) for COVID-19 research. This mouse is reconstituted with human cord blood-derived, HLA-matched hematopoietic stem cells. It engrafts human epi/endothelial cells expressing the human ACE2 receptor for SARS-CoV-2 and TMPRSS2 serine protease co-localized on lung epithelia. HIS-DRAGA mice sustained SARS-CoV-2 infection, showing deteriorated clinical condition, replicating virus in the lungs, and human-like lung immunopathology including T-cell infiltrates, microthrombi and pulmonary sequelae. Among T-cell infiltrates, lung-resident (CD103+) CD8+ T cells were sequestered in epithelial (CD326+) lung niches and secreted granzyme B and perforin, indicating cytotoxic potential. Infected mice also developed antibodies against the SARS-CoV-2 viral proteins. Hence, HIS-DRAGA mice showed unique advantages as a surrogate in vivo human model for studying SARS-CoV-2 immunopathology and for testing the safety and efficacy of candidate vaccines and therapeutics.

scholarly journals A Human-Immune-System (HIS) humanized mouse model for COVID-19 research (DRAGA: HLA-A2.HLA-DR4.Rag1KO.IL-2Rγc KO.NOD)

2020 ◽  
Author(s):  
Teodor-Doru Brumeanu ◽  
Pooja Vir ◽  
Ahmad Faisal Karim ◽  
Swagata Kar ◽  
Kevin K. Chung ◽  
...  
Keyword(s):  
Immune System ◽  
T Cell ◽  
Mouse Model ◽  
Human Model ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Hematopoietic Stem ◽  
Human Immune

We report the first Human Immune System (HIS)-humanized mouse model (DRAGA: HLA-A2.HLA-DR4.Rag1KO.IL-2RgammacKO.NOD) for SARS-CoV-2 infection and COVID-19 research. This mouse is reconstituted with HLA-matched human hematopoietic stem cells from cord blood, thereby avoiding use of fetal tissue. It engrafts human epi/endothelial cells expressing the human ACE2 receptor for SARS-CoV-2 and the TMPRSS2 serine protease, which co-localize on lung epithelia. HIS-DRAGA mice sustained SARS-CoV-2 infection, showing abrupt weight loss, ruffed fur, hunched back and reduced mobility. Infected mice developed human-like lung immunopathology including T-cell infiltrates, microthrombi, hemorrhage, and pulmonary sequelae. Among T-cell infiltrates, lung-resident (CD103+)CD8+ T cells were sequestered in epithelial (CD326+) lung niches and secreted granzyme B and perforin, indicating cytotoxic potential. Infected mice developed antibodies against the SARS-CoV-2 S protein. Hence, HIS-DRAGA mice show unique advantages as a surrogate in vivo human model for studying SARS-CoV-2 immunopathology and for testing the safety and efficacy of candidate vaccines and therapeutics.

scholarly journals Functional Human CD141+ Dendritic Cells in Human Immune System Mice

2019 ◽  
Vol 221 (2) ◽  
pp. 201-213 ◽  
Author(s):  
Jordana G A Coelho-Dos-Reis ◽  
Ryota Funakoshi ◽  
Jing Huang ◽  
Felipe Valença Pereira ◽  
Sho Iketani ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune System ◽  
Mouse Model ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Hematopoietic Stem ◽  
Virus Serotype ◽  
Human Immune

Abstract Background For the purpose of studying functional human dendritic cells (DCs) in a humanized mouse model that mimics the human immune system (HIS), a model referred to as HIS mice was established. Methods Human immune system mice were made by engrafting NOD/SCID/IL2Rgammanull (NSG) mice with human hematopoietic stem cells (HSCs) following the transduction of genes encoding human cytokines and human leukocyte antigen (HLA)-A2.1 by adeno-associated virus serotype 9 (AAV9) vectors. Results Our results indicate that human DC subsets, such as CD141+CD11c+ and CD1c+CD11c+ myeloid DCs, distribute throughout several organs in HIS mice including blood, bone marrow, spleen, and draining lymph nodes. The CD141+CD11c+ and CD1c+CD11c+ human DCs isolated from HIS mice immunized with adenoviruses expressing malaria/human immunodeficiency virus (HIV) epitopes were able to induce the proliferation of malaria/HIV epitopes-specific human CD8+ T cells in vitro. Upregulation of CD1c was also observed in human CD141+ DCs 1 day after immunization with the adenovirus-based vaccines. Conclusions Establishment of such a humanized mouse model that mounts functional human DCs enables preclinical assessment of the immunogenicity of human vaccines in vivo.

scholarly journals P06.07 In vivo studies of immunomodulatory a-CTLA-4 antibody in a humanized mouse model

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A22.1-A22
Author(s):  
C Reitinger ◽  
F Nimmerjahn
Keyword(s):  
Immune System ◽  
Mouse Model ◽  
Cancer Immunotherapy ◽  
Model Systems ◽  
Checkpoint Control ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Human Immune

BackgroundRecent findings in cancer immunotherapy have reinforced the hypothesis that the immune system is able to control most cancers. Immunomodulatory antibodies can enhance immune responses, having the potential to generate anti-cancer immunity.1–4Materials and MethodsMost current studies addressing this question are performed in murine mouse model systems or use in vitro culture systems, which do not reflect the human in vivo situation, potentially leading to results that cannot be fully translated into human cancer therapy. Therefore, it is necessary to establish a new mouse model, which allows the study of cancer immunotherapy in the context of a human immune system. We focused on the establishment of a humanized mouse model, in which different immunomodulatory antibodies can be tested in the presence of a human immune system.ResultsFirst experiments concerning the suitability to test immunomodulatory antibodies in the humanized mouse model, revealed that effects of checkpoint-control antibody a-CTLA-4 were similar to the effects seen in patients of clinical studies. To analyse the anti-tumor activities of immunomodulatory antibodies in vivo we are establishing a human melanoma-like tumor model in humanized mice.ConclusionsThis enables us to test the efficacy of immunomodulatory agonistic antibodies (such as CP-870,893) and checkpoint control antibodies (such as anti-CTLA-4) in eliminating a melanoma-like tumor. Furthermore, parameters like tumor infiltrating human cells und cytokine/chemokine production can be analysed.ReferencesSchuster M, Nechansky A, Loibner H. Cancer immunotherapy. Biotechnol J 2006;1:138–147.Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature rev 2011;480:480–489.Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Annals of Oncology 2012;23:vii6–vii9.Langer LF, Clay TM, Morse MA. Update on anti-CTLA-4 in clinical trials. Expert Opin Biol Ther 2007;8:1245–1256.Disclosure InformationC. Reitinger: None. F. Nimmerjahn: None.

scholarly journals Human immune system variation during one year

2020 ◽  
Author(s):  
Tadepally Lakshmikanth ◽  
Sayyed Auwn Muhammad ◽  
Axel Olin ◽  
Yang Chen ◽  
Jaromir Mikes ◽  
...  
Keyword(s):  
Immune System ◽  
Individual Variation ◽  
Immune Cell ◽  
Metabolic Health ◽  
Individual Feature ◽  
Human Immune System ◽  
Principal Curve ◽  
Human Immune ◽  
One Year ◽  
Over Time

SUMMARYThe human immune system varies extensively between individuals, but variation within individuals over time has not been well characterized. Systems-level analyses allow for simultaneous quantification of many interacting immune system components, and the inference of global regulatory principles. Here we present a longitudinal, systems-level analysis in 99 healthy adults, 50 to 65 years of age and sampled every 3rd month during one year. We describe the structure of inter-individual variation and characterize extreme phenotypes along a principal curve. From coordinated measurement fluctuations, we infer relationships between 115 immune cell populations and 750 plasma proteins constituting the blood immune system. While most individuals have stable immune systems, the degree of longitudinal variability is an individual feature. The most variable individuals, in the absence of overt infections, exhibited markers of poor metabolic health suggestive of a functional link between metabolic and immunologic homeostatic regulation.HIGHLIGHTSLongitudinal variation in immune cell composition during one yearInter-individual variation can be described along a principal curveImmune cell and protein relationships are inferredVariability over time is an individual feature correlating with markers of poor metabolic health

scholarly journals Recent Advancements and Applications of Human Immune System Mice in Preclinical Immuno-Oncology

2019 ◽  
Vol 48 (2) ◽  
pp. 302-316 ◽  
Author(s):  
Michelle Curran ◽  
Maelle Mairesse ◽  
Alba Matas-Céspedes ◽  
Bethany Bareham ◽  
Giovanni Pellegrini ◽  
...  
Keyword(s):  
Immune System ◽  
New Technologies ◽  
Immune Cell ◽  
Human Immune System ◽  
Immunodeficient Mice ◽  
Graft Versus Host ◽  
Human Immune ◽  
And Function ◽  
Human Cytokines

Significant advances in immunotherapies have resulted in the increasing need of predictive preclinical models to improve immunotherapeutic drug development, treatment combination, and to prevent or minimize toxicity in clinical trials. Immunodeficient mice reconstituted with human immune system (HIS), termed humanized mice or HIS mice, permit detailed analysis of human immune biology, development, and function. Although this model constitutes a great translational model, some aspects need to be improved as the incomplete engraftment of immune cells, graft versus host disease and the lack of human cytokines and growth factors. In this review, we discuss current HIS platforms, their pathology, and recent advances in their development to improve the quality of human immune cell reconstitution. We also highlight new technologies that can be used to better understand these models and how improved characterization is needed for their application in immuno-oncology safety, efficacy, and new modalities therapy development.

A human immune system mouse model with robust lymph node development

2018 ◽  
Vol 15 (8) ◽  
pp. 623-630 ◽  
Author(s):  
Yan Li ◽  
Guillemette Masse-Ranson ◽  
Zacarias Garcia ◽  
Timothée Bruel ◽  
Ayrin Kök ◽  
...  
Keyword(s):  
Lymph Node ◽  
Immune System ◽  
Mouse Model ◽  
Human Immune System ◽  
Human Immune ◽  
Node Development

scholarly journals Evaluation of safety and efficacy of RNAi against HIV-1 in the human immune system (Rag-2-/-γc-/-) mouse model

Gene Therapy ◽  
2008 ◽  
Vol 16 (1) ◽  
pp. 148-153 ◽  
Author(s):  
O ter Brake ◽  
N Legrand ◽  
K J von Eije ◽  
M Centlivre ◽  
H Spits ◽  
...  
Keyword(s):  
Immune System ◽  
Mouse Model ◽  
Human Immune System ◽  
Safety And Efficacy ◽  
Human Immune ◽  
Hiv 1

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

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.

scholarly journals Comprehensive multi-omics single-cell data integration reveals greater heterogeneity in the human immune system

2021 ◽  
Author(s):  
Congmin Xu ◽  
Junkai Yang ◽  
Astrid Kosters ◽  
Benjamin R Babcock ◽  
Peng Qiu ◽  
...  
Keyword(s):  
Immune System ◽  
Single Cell ◽  
Immune Cell ◽  
Cell Types ◽  
Cell Receptor ◽  
Surface Proteins ◽  
Cell Type ◽  
Human Immune System ◽  
Receptor Repertoire ◽  
Human Immune

Single-cell transcriptomics enables the definition of diverse human immune cell types across multiple tissue and disease contexts. Still, deeper biological understanding requires comprehensive integration of multiple single-cell omics (transcriptomic, proteomic, and cell receptor repertoire). To improve the identification of diverse cell types and the accuracy of cell-type classification in our multi-omics single-cell datasets, we developed SuPERR-seq, a novel analysis workflow to increase the resolution and accuracy of clustering and allow for the discovery and characterization of previously hidden cell subsets. We show that by incorporating information from cell-surface proteins and immunoglobulin transcript counts, we accurately remove cell doublets and prevent widespread cell-type misclassification. This approach uniquely improves the identification of heterogeneous cell types in the human immune system, including a novel subset of antibody-secreting cells in the bone marrow.

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