Comparison of Myeloid-Enhanced HIS Mouse Models:
Advantages and Disadvantages
Traditional human immune system (HIS) mouse models, such as BRG, NOG, and NSG, harbor immune systems primarily composed of lymphocytes, including T cells and B cells. These models have become indispensable in vivo platforms for developing clinical therapeutics targeting lymphoid cells, such as PD-1 blockade antibodies, immune checkpoint inhibitors (ICIs), T cell engagers, and adoptive immunotherapies like CAR-T. However, due to limited homology between certain human and murine cytokines, these models exhibit impaired human myeloid cell differentiation. This limitation restricts their utility in studying innovative immunity-based therapies, including human-specific antibody-dependent cellular phagocytosis (ADCP), myeloid-derived suppressor cells (MDSCs), and antigen-specific immune responses.
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To address this challenge, myeloid-enhanced HIS mouse models have been developed by genetically engineering human cytokines—such as M-CSF, GM-CSF, IL-3, and SCF—into immunodeficient mouse strains. These cytokines are expressed at varying levels using different techniques, enabling improved human myeloid cell differentiation and function. Below, we highlight the characteristics of several myeloid-enhanced HIS mouse models, emphasizing their advantages and disadvantages.​
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Potential features of popular myeloid-enhanced HIS mouse models from literatures
Key Considerations and Limitations
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While myeloid-enhanced HIS mouse models address the shortcomings of traditional HIS models, they are not without limitations. Key disadvantages include:
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Non-Controlled Cytokine Expression:
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Human cytokines are often expressed constitutively or at non-physiological levels, leading to abnormal immune cell development and function.
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This lack of temporal or spatial control over cytokine expression can skew experimental results.
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Artificial Immune Activation:
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Overexpression of cytokines creates an artificial environment that may overactivate human immune cells, causing hyperinflammatory responses or immune exhaustion.
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This can confound studies of immunotherapies, such as immune checkpoint inhibitors or adoptive cell therapies.
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Limited Lifespan:
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HIS mice, including myeloid-enhanced models, often have a limited lifespan due to graft-versus-host disease (GVHD) or other complications.
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This restricts the duration of experiments and prevents long-term studies of immune responses or therapeutic efficacy.
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Incomplete Recapitulation of the Human Immune System:
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While these models improve myeloid cell development, they still lack a fully functional human immune system, including lymphoid-myeloid interactions and tissue-specific immunity.
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This limits their translational relevance, as immune responses may not fully mirror those in humans.
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Donor-Dependent Variability:
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Engraftment efficiency and immune cell functionality can vary significantly depending on the donor source (e.g., cord blood, peripheral blood mononuclear cells).
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This variability affects reproducibility and complicates data interpretation.
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References:
1.Blood. 2011 ; 117(11): 3076–3086.
2.J Immunol , 2013, 191 (6) 2890-2899
3.Nat Biotechnol. 2014; 32(4): 364–372.
4.PLoS One. 2018; 13(12): e0209034
5.Blood Adv. 2019 Feb 12; 3(3): 268–274
6.Front Immunol. 2020; 11: 2082