Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation

Blood ◽  
2006 ◽  
Vol 108 (2) ◽  
pp. 487-492 ◽  
Author(s):  
Ping Lan ◽  
Noriko Tonomura ◽  
Akira Shimizu ◽  
Shumei Wang ◽  
Yong-Guang Yang
Keyword(s):  
Immune System ◽  
Scid Mice ◽  
In Vivo Model ◽  
Human Immune System ◽  
Hematopoietic Stem ◽  
Fetal Thymus ◽  
Xenograft Rejection ◽  
Immunodeficient Mice ◽  
Human Immune

Studies of the human immune system have been limited by the lack of an appropriate in vivo model. For this reason, efforts have been made to develop murine models with a functional human immune system. We report here that cotransplantation of human fetal thymus/liver tissues and CD34+ hematopoietic stem/progenitor cells led to the development of sustained human hematopoiesis and a functional human immune system in immunodeficient NOD/SCID mice. The humanized mice showed systemic repopulation with a comprehensive array of human lymphohematopoietic cells, including T cells, B cells, and dendritic cells, and the formation of secondary lymphoid organs. Furthermore, these mice produce high levels of human IgM and IgG antibodies and mediate strong immune responses in vivo as demonstrated by skin xenograft rejection. Thus, the humanized NOD/SCID mice described in this paper provide a powerful model system to study human immune function.

scholarly journals Antigen-specific human T-cell responses and T cell–dependent production of human antibodies in a humanized mouse model

Blood ◽  
2008 ◽  
Vol 111 (8) ◽  
pp. 4293-4296 ◽  
Author(s):  
Noriko Tonomura ◽  
Katsuyoshi Habiro ◽  
Akira Shimizu ◽  
Megan Sykes ◽  
Yong-Guang Yang
Keyword(s):  
Immune System ◽  
T Cell ◽  
Humanized Mice ◽  
Human Immune System ◽  
Hematopoietic Stem ◽  
Fetal Thymus ◽  
Human Antibodies ◽  
Human Immune ◽  
Liver Tissues

Abstract Humanized mice with a functional human immune system would be very useful for in vivo studies of human immunobiology. We have previously shown that cotransplantation of human fetal thymus/liver tissues and CD34+ fetal liver cells into immunodeficient nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice leads to the development of multiple lineages of human lymphohematopoietic cells and formation of secondary lymphoid organs with normal architecture. Here, we evaluated the ability of these humanized mice to develop antigen-specific, T cell–dependent antibody responses after in vivo immunization with T-dependent antigen, 2,4-dinitrophenyl hapten-keyhole limpet hemocyanin (DNP23-KLH). Human T cells from DNP23-KLH–immunized mice showed strong proliferation in response to KLH in vitro. Furthermore, T cell–dependent production of DNP-specific human antibodies (mainly IgG1 and IgG2) was detected in all immunized mice. These results confirm that a functional human immune system can be established in immunodeficient mice through cotransplantation of human fetal thymus/liver tissues and CD34+ hematopoietic stem/progenitor cells.

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 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 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 The Utility of Human Immune System Mice for High-Containment Viral Hemorrhagic Fever Research

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 98
Author(s):  
David M. Wozniak ◽  
Kerry J. Lavender ◽  
Joseph Prescott ◽  
Jessica R. Spengler
Keyword(s):  
Immune System ◽  
Mouse Models ◽  
Severe Disease ◽  
Case Fatality ◽  
Hemorrhagic Fever ◽  
Human Immune System ◽  
Immunodeficient Mice ◽  
Hemorrhagic Fevers ◽  
Laboratory Facilities ◽  
Human Immune

Human immune system (HIS) mice are a subset of humanized mice that are generated by xenoengraftment of human immune cells or tissues and/or their progenitors into immunodeficient mice. Viral hemorrhagic fevers (VHFs) cause severe disease in humans, typically with high case fatality rates. HIS mouse studies have been performed to investigate the pathogenesis and immune responses to VHFs that must be handled in high-containment laboratory facilities. Here, we summarize studies on filoviruses, nairoviruses, phenuiviruses, and hantaviruses, and discuss the knowledge gained from using various HIS mouse models. Furthermore, we discuss the complexities of designing and interpreting studies utilizing HIS mice while highlighting additional questions about VHFs that can still be addressed using HIS mouse models.

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.

scholarly journals Human NK cells of mice with reconstituted human immune system components require preactivation to acquire functional competence

Blood ◽  
2010 ◽  
Vol 116 (20) ◽  
pp. 4158-4167 ◽  
Author(s):  
Till Strowig ◽  
Obinna Chijioke ◽  
Paolo Carrega ◽  
Frida Arrey ◽  
Sonja Meixlsperger ◽  
...  
Keyword(s):  
Immune System ◽  
Cord Blood ◽  
Nk Cells ◽  
Nk Cell ◽  
Human Immune System ◽  
Hematopoietic Progenitor ◽  
Human Adult ◽  
System Components ◽  
Human Immune

Abstract To investigate human natural killer (NK)–cell reactivity in vivo we have reconstituted human immune system components by transplantation of human hematopoietic progenitor cells into NOD-scid IL2Rγnull mice. We demonstrate here that this model allows the development of all NK-cell subsets that are also found in human adult peripheral and cord blood, including NKp46+CD56− NK cells. Similar to human cord blood, NK cells from these reconstituted mice require preactivation by interleukin-15 to reach the functional competence of human adult NK cells. Mainly the terminally differentiated CD16+ NK cells demonstrate lower reactivity without this stimulation. After preactivation, both CD16+ and CD16− NK cells efficiently produce interferon-γ and degranulate in response to stimulation with NK cell–susceptible targets, including K562 erythroleukemia cells. NK-cell lines, established from reconstituted mice, demonstrate cytotoxicity against this tumor cell line. Importantly, preactivation can as well be achieved by bystander cell maturation via poly I:C stimulation in vitro and injection of this maturation stimulus in vivo. Preactivation in vivo enhances killing of human leukocyte antigen class I negative tumor cells after their adoptive transfer. These data suggest that a functional, but resting, NK-cell compartment can be established in immune-compromised mice after human hematopoietic progenitor cell transfer.

scholarly journals Human innate responses and adjuvant activity of TLR ligands in vivo in mice reconstituted with a human immune system

Vaccine ◽  
2017 ◽  
Vol 35 (45) ◽  
pp. 6143-6153 ◽  
Author(s):  
Liang Cheng ◽  
Zheng Zhang ◽  
Guangming Li ◽  
Feng Li ◽  
Li Wang ◽  
...  
Keyword(s):  
Immune System ◽  
Human Immune System ◽  
Adjuvant Activity ◽  
Human Immune

Macrophages Prevent Human Red Blood Cell Reconstitution In NOD/SCID and NOD/SCID/γc−/− Mice.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3723-3723
Author(s):  
Zheng Hu ◽  
Yong-Guang Yang
Keyword(s):  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Embryonic Stem ◽  
Humanized Mice ◽  
In Vivo Model ◽  
Recipient Mouse ◽  
Hematopoietic Stem ◽  
Immunodeficient Mice ◽  
Human Rbcs

Abstract Abstract 3723 An animal model supporting human erythropoiesis will be highly valuable for assessing the biological function of human RBCs under physiological and disease settings, and for evaluating protocols of in vitro RBC differentiation from human embryonic stem cells. Although immunodeficient mice on the NOD background have been widely used to study human hematopoietic stem cell function in vivo, the successful use of these mice in the study of human erythropoiesis and RBC function has not been reported. We have previously shown that co-transplantation of human fetal thymic tissue (under renal capsule) and CD34+ fetal liver cells (FLCs; i.v.) in NOD/SCID or NOD/SCID/γc−/− mice results in the development of multilineage human hematopoietic cells. Here, we analyzed human RBC reconstitution in these humanized mice. Although a large number of human erythrocytes, which consisted predominantly of immature nucleated erythrocytes, were detected in the bone marrow of human fetal thymus/CD34+ FLC-grafted mice, human RBCs were undetectable in blood of these mice, even in those with nearly full human chimerism in peripheral blood mononuclear cells (PBMCs). Recipient mouse macrophage-mediated rejection is, at least, one of the major mechanisms responsible for the lack of human RBCs in these mice, as human RBCs became detectable in blood following macrophage depletion and disappeared again after withdrawal of treatment. Furthermore, treatment with human erythropoietin (EPO) and human IL-3 significantly increased human RBC reconstitution in mice that were depleted of macrophages. Like the human RBCs developed in the humanized mice, exogenously injected normal human RBCs were also rapidly rejected by macrophages in NOD/SCID mice. Taken together, our data demonstrate that human RBCs are highly susceptible to rejection by macrophages in immunodeficient mice. Thus, strategies for preventing human RBC rejection by macrophages are required for using immunodeficient mice as an in vivo model to study human erythropoiesis and RBC function. Disclosures: No relevant conflicts of interest to declare.

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