Humanized mice are specialized laboratory animals engineered to carry functional components of the human biological system. These models are created by transplanting human genes, cells, tissues, or organs into a mouse host to better mimic human physiology and disease progression. They provide a unique platform for researchers to study human-specific biological processes within a living system before moving to clinical trials. These indispensable tools bridge the gap between standard animal models and the complexities of the human body.
The Necessity of Immunodeficient Hosts
Creating a humanized mouse requires bypassing the host’s natural defense mechanisms. A typical mouse possesses a fully functional immune system that would immediately recognize and destroy implanted human cells or tissues as foreign material. This powerful rejection response, called xenograft rejection, prevents the successful establishment of human components within a standard mouse.
To solve this problem, scientists utilize genetically modified mice that are profoundly immunodeficient, meaning they lack a functional immune system. Modern humanized mouse models are often based on strains like the NOD-scid IL2rγ null (NSG) mice, which have genetic defects that eliminate mature T and B lymphocytes, as well as natural killer (NK) cells. This triple deficiency provides an environment where transplanted human cells can survive and engraft without being attacked by the host.
The process of “humanization” involves introducing human cells into this immunodeficient host through various methods. One common approach is the transplantation of human hematopoietic stem cells (HSCs), often sourced from umbilical cord blood, into the mouse. These CD34+ cells are the precursors to all human blood and immune cells, allowing a human-like immune system to develop and mature long-term within the mouse’s bone marrow. Alternatively, for shorter-term studies, mature human peripheral blood mononuclear cells (PBMCs) can be directly injected, providing a rapid source of human T-cells and other immune cells.
Diverse Applications in Human Disease Modeling
Humanized mouse models allow for the study of human-specific diseases that cannot infect or progress in standard mouse models. In infectious disease research, these models were initially developed to study the Human Immunodeficiency Virus (HIV), which requires human immune cells to replicate. Mice infected with HIV enable researchers to investigate viral pathogenesis and test new antiretroviral therapies in a living system.
Similar models study other human-tropic pathogens, such as Hepatitis B and C viruses, which require human liver components to establish infection. Mice humanized with human liver cells allow for the study of viral replication and the long-term effects of chronic infection. This provides a platform for evaluating novel antiviral compounds and vaccine candidates with a higher predictive value for human outcomes.
In oncology, humanized mice are essential for testing advanced cancer immunotherapies, such as checkpoint inhibitors, which engage the human immune system against tumors. By engrafting human tumors—a process known as patient-derived xenograft (PDX)—into a mouse that also possesses a human immune system, researchers can observe the complex interaction between the tumor, the immune cells, and the therapeutic agent. This allows for personalized medicine research, testing drug efficacy on a patient’s own tumor cells in a living model.
These models are also valuable in predicting how the human body processes drugs. Mice humanized with functional human liver cells can accurately predict drug metabolism and potential toxicity before compounds enter clinical trials. This liver humanization model accounts for the human-specific enzymes responsible for breaking down drug compounds, offering a reliable assessment of pharmacokinetics.
Current Limitations and Scientific Challenges
Despite their utility, humanized mouse models present several scientific constraints. One limitation is that the human immune system components developed in the mouse are often incomplete or functionally impaired. For example, human T-cells that develop within the mouse are restricted by the mouse’s own Major Histocompatibility Complex (MHC) molecules, which limits their functional capacity and interaction with other human cells.
The mouse’s environment also poses a challenge, as its body temperature, metabolism, and lifespan differ significantly from a human’s, influencing the long-term development and behavior of the human cells. A common issue in models using mature human cells, such as PBMCs, is the development of xenogeneic graft-versus-host disease (GVHD). In GVHD, the transplanted human immune cells attack the mouse host’s tissues, which shortens the model’s lifespan and limits its use to short-term studies.
The adaptive immune response, particularly the ability to generate a sustained antibody response (humoral immunity), remains weak in many humanized models. Scientists also face difficulty in achieving full reconstitution of certain cell lineages, which are crucial components of the innate immune system. Researchers are working to overcome these challenges by genetically modifying the mouse host to express human signaling molecules, or cytokines, necessary for the complete maturation and function of the human immune cells.