Immunologist Creates Humanized Mouse Model to Study New-Onset Celiac Disease with Human Neutrophils

The Celiac Disease Foundation, the nation’s leading patient advocacy organization for celiac disease, and Takeda Development Center Americas (Takeda), a global biopharmaceutical leader, announce Dr. Esen Sefik, PhD as the recipient of the Celiac Disease Foundation–Takeda Early Career Research Award, an award designed to support promising early-career researchers working toward independent and productive research careers in celiac disease.  

Dr. Sefik, an immunologist and an Associate Research Scientist in the Flavell Lab at Yale School of Medicine, will use the grant to investigate how human neutrophils contribute to the development of celiac disease. She will use a humanized mouse model to study the role of neutrophils in new-onset celiac disease. 

Dr. Sefik’s research will help shed light on the complex immune response involved in celiac disease and may lead to new insights and potential treatments. The Celiac Disease Foundation and Takeda are proud to support her important work and look forward to the findings that will result from her research. 

Celiac disease is an autoimmune disorder in which the ingestion of gluten leads to damage of the small intestine and other complications. Despite being one of the most common chronic diseases, there is still much to learn about the underlying mechanisms and potential therapies. 

This award is part of the Foundation’s ongoing efforts to support research and improve the lives of those affected by celiac disease. Through initiatives like this, the Foundation is helping to advance the understanding and treatment of this complex disease, ultimately bringing us closer to a cure. 

Hear Dr. Sefik explain her research and read on as she answers a few questions for our community. 

CDF: Please tell us about yourself and your background. What drew you to the field of celiac disease research?   

Dr. Sefik: I have extensive experience and training in immunological research in the context of autoimmune and inflammatory diseases. Various immune and non-immune cells interact to form a coherent system in tissues. I first became interested in how this system fails in chronic diseases as an undergraduate student studying immunological memory at Yale University. During my doctoral training with Drs. Christophe Benoist, Diane Mathis, and Dennis Kasper at Harvard University, I explored how microbial interactions ensure tissue integrity in intestines. More specifically, I studied how gut microbes help the host immune system mature and how dysregulation in this microbial balance drives inflammatory intestinal disease via its effect on immune cells. My findings challenged some earlier work on seemingly antagonistic mechanisms and, instead, suggested a collaborative rather than competitive regulation, potentiated by gut microbes. For my postdoctoral training, I returned to Yale and joined Dr. Richard Flavell’s laboratory. 

Since then, I have dedicated my efforts to utilizing humanized mice—mice with a human immune system—to model chronic human diseases. Humanized mice generated by the transplantation of human stem and progenitor cells into various strains of immune-compromised mice allow a human immune system to develop in mice. These mice have greatly expanded our knowledge of how the human immune system works. More recently, I used these mice to model severe COVID-19, a disease that has shaped all our lives in the last four years. Humanized mice when infected with SARS-COV-2 exhibited severe, persistent lung disease reminiscent of human patients, features lacking in other animal models. Mechanistic study of our model defined the unique ways that human immune cells contribute causally to the lung pathology in real time. In a way, every step of my career armored me with the tools, skills, and training to tackle challenges posed by the study of celiac disease. While I am relatively new to celiac disease research, I hope to bring a fresh perspective and introduce new tools to the field.

CDF: Can you share an overview of your current research project? What question or challenge are you setting out to address? What is innovative or essential about your research? Do you have an analogy to help people understand your work?   

Dr. Sefik: Celiac disease is a complex disease with a strong genetic predisposition, but our mechanistic understating is still limited. Producing effective public health countermeasures demands suitable tools and expertise. Genomic technologies and computational tools have improved our ability to analyze large-scale biological datasets, commonly referred to as “-omics data.” However, the application of these advancements to gain mechanistic insights and establish causality in diseases has been limited.   

The establishment of cause-and-effect in human diseases is an essential step in the path which leads from clinical observations to disease mechanisms to treatment. To identify cause-and-effect, perturbation of the human components is required. Human investigation is limited by ethical constraints. In other words, we can’t easily and safely use genetic or cellular interventions in patients.   

So, we rely on animal models that faithfully represent the human disease. This is essential to establish cause-and-effect. For decades, scientists have relied on multiple small animal models, particularly mice, to study human disease, but standard laboratory mice simply do not get celiac disease in response to gluten. My proposed research comes into play here. In the Flavell Laboratory, we have pioneered the development of a re-engineered mouse that facilitates the development of a patient’s immune system in mice. We are using these special mice and modifying them further to enable the development of a celiac disease–susceptible human immune system in mice. This humanized mouse model of celiac disease will incorporate essential cellular and molecular mechanisms linked to celiac disease, testing their role in celiac disease development. This model will also facilitate the development and testing of new therapies. We endeavor to integrate the “-omics” data from patients, as mentioned earlier, with a more advanced celiac disease humanized mouse model to better understand the path to the disease and, ultimately, work towards finding a cure.   

CDF: What is the potential impact of your research on celiac disease understanding, treatment, and patient quality of life?   

Dr. Sefik: Currently, the only approved therapy for celiac disease is avoiding gluten in diet. This is very difficult to achieve. Nearly one-third of patients still encounter difficulties with dietary management. The absence of real-time understanding of disease activity hampers both assessment and the development of new therapeutic approaches. My research on understanding celiac disease aims to pave the way for therapeutics that can effectively manage disease symptoms and, ideally, contribute to finding a cure.   

CDF: What message would you like to convey to individuals and families affected by celiac disease?   

Dr. Sefik: As a mother, witnessing the struggles of children with celiac disease breaks my heart. Simultaneously, as a scientist, I recognize the complexity and heterogeneity of celiac disease. Our research commences with an examination of the human immune system, leading to a mouse model that renders susceptibility to celiac disease in the mouse host. Our approach holds the potential to provide precise and non-invasive methods for real-time comprehension of the disease within a “personalized” system utilizing patient cells. This strategy seeks to propel pre-clinical and clinical studies, paving the way for personalized patient management in the future.