For decades, one of the most prominent tools in preclinical research— ranging from drug testing to understanding fundamental science and mechanisms of disease— has been the laboratory mouse. Many major breakthroughs in immunology and medicine are owed to early experiments performed in mice. While other animal models do exist, the mouse has been the gold standard in immunology for several reasons. For one, the mouse immune system is strikingly similar to our own: many immune cell types, signaling pathways, and functions closely resemble those of humans. Combined with the feasibility of housing, breeding, and genetic manipulation, mice have long been strong candidates for studying immunology outside of human subjects.
That said, human and mouse immunology do not directly mirror one another. Laboratory mice are also nearly genetically identical to one another as a result of inbreeding, which contrasts with the genetic diversity seen across human populations. Furthermore, laboratory mice are typically housed in sterile, pathogen-free environments, meaning they lack the lifelong exposure to bacteria, viruses, and other microbes that continuously shape the human immune system. These collective limitations help explain why so many treatments succeed in preclinical mouse models but fall short in human trials, and they highlight the need for research tools that better reflect human immunology. To address this, researchers have developed modified mouse models that better approximate the human immune system. One example includes “humanized” mice, which are engineered to carry human rather than mouse immune cells. Another example includes “dirty” mice, which possess more diverse communities of microorganisms to better reflect the human microbiome.
But is there a better alternative? Recent efforts in biotechnology and bioengineering have been searching for the next best thing, of which, organoids have taken center stage. As its name suggests, an organoid is essentially a miniature organ-like structure, albeit substantially less complex and incapable of fully recapitulating the function of human organs (at least not yet). Still, organoids offer an exciting opportunity for immunologists to study immune responses in systems that more closely resemble human biology.
Organoids can be grown from stem cells, which are essentially like blank canvases that, under certain conditions, can be “instructed” to develop into a specific cell type that composes a tissue of interest. Alternatively, organoids can be derived from human tissue samples, where small pieces of tissue obtained during surgeries or biopsies can be placed in specialized conditions where they continue to grow while maintaining many of the structural features of the original organ. In both cases, the goal is the same: to create an effective model of human tissue that can be studied in highly controlled laboratory settings rather than in the body.
Organoids have been explored in various contexts, ranging from drug testing to understanding basic principles of human immunology. One particularly creative application with organoids
involves tonsils. Typically thought of as an inconvenience to be removed, excised tonsils that would otherwise be discarded after surgery are proving to be surprisingly useful for research. Tonsils are densely populated with immune cells and maintain their structure remarkably well in laboratory conditions. A 2021 study leveraged tonsil organoids to study immune responses to vaccines, successfully identifying the components needed to produce influenza-specific immunity. These results offer a compelling proof of concept for using organoid models to model complex immune processes.
Another application for human organoids is to better understand the function of tissue resident immune cells. These cells, which live inside the tissue, can functionally differ from the immune cells that circulate throughout the blood. While understanding their function provides insights into their role in disease and potential treatments, studying these cells in humans continues to be a challenge. One study investigated this by creating an intestinal organoid that encapsulates immune cells as well. This model allowed the researchers to understand how cancer treatments triggered inflammation in the gut and identified new pathways that could be targeted to overcome this side effect.
Perhaps one of the most rapidly growing applications of organoids lies in cancer research, particularly in the study of immunotherapy. Immunotherapies work by harnessing the immune system to recognize and destroy cancer cells. While these treatments have shown remarkable success in some patients, they are not successful in all cases, and predicting who may respond to certain treatments remains a challenge. Tumour organoids can be grown directly from patient tumour samples obtained during surgery or biopsy, and they often retain many of the genetic mutations and characteristics of the original tumour when cultured in the laboratory. Researchers introduce immune cells into these systems to observe how they interact with the cancer cells. By testing different therapies on tumour organoids, scientists can study why some cancers respond to immunotherapy while others resist treatment. In the future, this approach may be revolutionary for personalized medicine, where doctors could potentially test treatments on a patient’s tumour organoid to determine which therapy is most likely to work before administering it. Researchers are also using organoid systems to better model human immune responses in ways that are difficult to achieve in traditional animal models. For instance, former University of Toronto trainee Lisa Wagar, now at University of California, Irvine, has pioneered the use of human organoid- and tissue-based systems to study vaccine responses and human immunology in more physiologically relevant settings.
Despite their exciting potential, organoids are not a perfect substitute for animal models. The human body is extraordinarily complex, and we are not yet at the stage where we can mimic its function entirely in a petri dish. Furthermore, organoids are not suitable for studying connections between multiple organs (e.g. the gut-brain axis). For this reason, animal models still play an important role. While organoids cannot currently replace animal models entirely, they still serve as a valuable complementary approach. It’s possible that with time, these tiny organoids may one day have a tremendous impact on the future of immunology research.
Milea DiPonzio
