Immunodeficient mice engrafted with CD34+ hematopoietic stem/progenitor cells (HSPCs) are an attractive humanized mouse model for immuno-oncology efficacy studies, as they are a validated platform that provides bone marrow engraftment with development of multi-lineage human immune cells in the peripheral blood.
For many studies, such as those with engineered cells (e.g. HSPCs and CAR-T), it may be preferential that the study sponsor dictates the donor for CD34+ humanized mice. Hera has demonstrated through effective recipient conditioning, transplantation and flow cytometric (FC) analysis efficient engraftment of engineered CD34+ HSPCs as indicated by high levels of human CD45+ chimerism in the blood and bone marrow. We offer custom donor as well as standardized donor humanized mouse studies for preclinical immuno-oncology.
Immuno-Oncology Services
Our team of experienced scientists provide immuno-oncology services utilizing humanized immune system mouse models with CD34+ cells. Humanized mouse models are designed to closely mimic the human immune system, enabling us to evaluate the efficacy and safety of novel immuno-oncology therapies in a preclinical setting.
- Immune cell profiling and characterization
- In vivo tumor growth and tumor infiltration
- Efficacy and toxicity studies of immuno-oncology therapies
- Mechanistic studies of immune response to cancer
Advantages for Immuno-Oncology Research
Mice with a humanized immune system offers several advantages over immunodeficient preclinical models, including:
- Replication of human immune responses and tumor immune cell infiltration.
- Ability to evaluate drug efficacy and toxicity in the context of a human immune system.
- More reliable prediction of clinical outcomes in humans.
At Hera, we are committed to advancing Immuno-Oncology research and helping our clients achieve their goals. Contact us today to learn more about our services and how we can help accelerate your research.
Humanized Immune System in Mice
FC analysis of peripheral blood for human CD45+ at 8 weeks.
Blood collected at 8 weeks post-transplant of G-CSF mobilized peripheral blood CD34+ cells was subjected to FC analysis for human and mouse CD45. Left panel: group 1 (vehicle control); center two panels: group 2; right two panels: group 3.
FC analysis of bone marrow for human CD45+ at 8 weeks.
Bone marrow collected at 8 weeks post-transplant of G-CSF mobilized peripheral blood CD34+ cells was subjected to FC analysis for human and mouse CD45. Left panel: group 1 (vehicle control); center two panels: group 2; right two panels: group 3.
Frequently Asked Questions
Current pre-clinical animal models have been- useful to study the many aspects of mammalian biological systems, however translating discoveries in rodents into clinical applications often falls short due to species related differences in biology, leading to the failure of drug candidates. In order to overcome these limitations “humanized” rodent models haven been developed, and they are becoming a crucial tool for researchers.
There are two approaches for creating humanized models: tissue and cellular humanization and genetic humanization. Tissue or cellular humanization involves replacing cells or entire organs with human cells in order to develop a functioning human liver or immune system within the model organism. Genetic humanization uses genetic modification to replace a particular endogenous gene or genes, such as the Cyp2d, which are is involved in drug metabolism, with their human orthologs.
Yes, the SRG rats are highly immunodeficient and tolerate engraftment of human immune cells (PBMCs). Although cancer xenograft models such as the SRG rat and SCID mice which lack a rodent immune system can effectively engraft and grow human cancer cells, humanized mice and rats engrafted with components of the human immune system may be ideal for answering human-specific questions on therapeutic immune responses and the tumor immune system environment. Humanized rodents are also beneficial for human-specific efficacy and safety studies as well as the discovery of novel therapeutics. Therefore, humanized models are often desired over more traditional syngeneic mouse models.
Hera has the unique ability to take a complementary approach for immuno-oncology studies, utilizing SRG rats humanized with peripheral blood mononuclear cells, NOD SCID mice, or NSG mice. Among other advantages, the SRG rat often has a higher tumor take rate and more favorable growth kinetics for cancer cell line xenografts and PDX models. Conversely, Hematopoietic stem cell (HSC) engraftment, ideal for longer term studies, still in development in the SRG rat but is well established in SCID mice such as NOD SCID and NSG mice.
SRG rat: humanization with PBMCs
Human PBMCs were collected and injected into SRG rats for engraftment. By 4 weeks post-transplant, recipients had an average of 29% circulating human CD45+ cells. As of 10 weeks post-transplant, recipients have up to 46% human CD45+ cells and remain healthy. Download the AACR Poster on Humanization for full data.
- Humanized mice for immune system investigation: progress, promise and challenges
Abstract: Significant advances in our understanding of the in vivo functions of human cells and tissues and the human immune system have resulted from the development of ‘humanized’ mouse strains that are based on severely immunodeficient mice with mutations in the interleukin-2 receptor common γ-chain locus. These mouse strains support the engraftment of a functional human immune system and permit detailed analyses of human immune biology, development and functions. In this Review, recent advances in the development and utilization of humanized mice, the lessons learnt, the remaining challenges and the promise of using humanized mice for the in vivo study of human immunology are discussed.
Shultz, et al. Nature Reviews Immunology. 2012 November. 12(11), 786–798. - Immunodeficient mouse model for human hematopoietic stem cell engraftment and immune system development.
Summary: Immunodeficient mice engrafted with human immune systems provide an exciting model to study human immunobiology in an in vivo setting without placing patients at risk. The essential parameter for creation of these “humanized models” is engraftment of human hematopoietic stem cells (HSC) that will allow optimal development of human immune systems. This paper describes a protocol for the co-implantation of human HSC with autologous fetal liver and thymic tissues into immunodeficient mice to create a humanized model with optimal human T cell development. This model, often referred to as the Thy/Liv or BLT (bone marrow, liver, thymus) mouse, develops a functional human immune system, including HLA-restricted human T cells, B cells and innate immune cells.
Aryee, et al. Methods in Molecular Biology. 2015 June. 1185, 267–278. - Humanized Mice Reveal Differential Immunogenicity of Cells Derived from Autologous Induced Pluripotent Stem Cells
Summary: Induced pluripotent stem cells (iPSCs) could become a renewable source of autologous cells for transplantation into human patients. While it has been assumed that the immune rejection problem challenging hESCs could be mitigated by the development of patient-specific hiPSCs without the concern of immune rejection, recent studies have shown that certain cell types derived from mouse iPSCs such as cardiomyocytes are immunogenic in syngeneic recipients. Therefore, as an integral part of the effort to develop hiPSCs into human cell therapy, it is important to evaluate the immunogenicity of hiPSC-derived cells in the context of an autologous human immune system. To address this bottleneck, we established humanized mouse models that are efficiently reconstituted with both T and B cells as well as macrophages and dendritic cells required for antigen presentation. Differential immunogenicity and T-cell response to human iPS derived smooth muscle cells (SMCs) and retinal pigment epithelial (RPE) cell treatment where shown. Humanized mice can mount vigorous immune rejection of allogeneic cells derived from hESCs. Therefore, the humanized mice provide a unique opportunity to examine the immunogenicity of autologous cells derived from hiPSCs.
Zhao, et al. Cell Stem Cell. 2015 September. 17;3 (353–359).