My research involves manipulating the immune system to prevent and treat immune mediated diseases such as allergies and autoimmune diseases. We try to specifically change the way a person’s immune system responds to challenges like food allergens or viruses using vaccines. There are three different areas that we work on.

The first approach alters the immune response to viral infection. This involves generating mucosal immunity to the infection in a way that provides better protection against infection and does not lead to autoimmune disease. This was particularly important during COVID-19 when infections with the virus acutely cause severe disability and death while at the same time leading to chronic autoimmune and inflammatory diseases (long COVID). We are making new vaccines based on this approach.

A second area involves suppressing the Vitamin A dependent immune system responses that result in exaggerated responses to viral infections leading to asthma. This is seen in respiratory syncytial virus (RSV) infection in young children, which often leads to long term asthma. We have been able to alter the immune response in mice by blocking Vitamin A based immunity in a way that provides better protection while preventing the development of allergic asthma.

Finally, we are interested in treating people with food allergies by altering their allergic immune response to food. This involves immunizing with food allergens in different formulations that induced protective immunity rather than allergies. We have already achieved this in mice. Importantly, we have shown that this change is long lived, providing the first potential approach to potentially cure food allergies.

Hogan Lab

The Hogan Lab had an excellent 2024, making significant advancements in our understanding of molecular regulation of anaphylaxis severity, and also underlying immune signals that contribute to esophageal remodeling in eosinophilic esophagitis.

In one study, postdoctoral fellow Dr. James Krempski spearheaded a research project defining the underlying molecular mechanisms that exacerbate histamine-induced vascular endothelial dysfunction and hypovolemic shock. During severe food allergic reactions, blood fluid is thought to extravasate through vascular endothelial cells into tissues, leading to cardiovascular collapse and life-threatening anaphylactic symptoms. We have previously demonstrated that the fluid extravasation is mediated by mast cell-derived histamine, and that the histamine-induced fluid extravasation can be amplified by the cytokine IL-4. 

In this new study, Dr. Krempski demonstrated that IL-4 signals through the transcription factor STAT6 to enhance histamine-induced fluid extravasation. Dr. Krempski and the team demonstrated that pharmacologic knockdown of STAT6 abrogated IL-4–mediated amplification of histamine-induced hypovolemia. These studies unveil a novel role of the IL-4/STAT6 signaling axis in the priming of vascular endothelial cells predisposing to exacerbation of histamine-induced anaphylaxis.

Our lab is investigating the interplay between the environment, microbiome, nervous system and immune system as it relates to food allergy and other allergic manifestations.  

This is a highly topical area in clinical food allergy research; however, the ability to piece together the connections between these complex systems is difficult in human subjects.  Thus, we rely on using a mouse model of food allergy to identify targets and connections in this disease, with the goal ultimately being validation in human subjects.  

Using these models, we have mapped out the immune response in food allergic mice from the stomach through the colon and identified specific regions of the intestinal tract, along with microbiome and inflammatory changes, that correlate strongly with the development of severe food allergic responses (anaphylaxis). 

We are currently in the direct hypothesis-testing stages for these new disease pathways to provide the necessary pre-clinical data that can be used by investigators to move this toward clinical studies.  Our goal is the development of prognostic indicators for the severity of food allergy, as well as identifying potential targets and therapies for mitigating the severity of disease.

We have made progress in several projects investigating both basic and preclinical aspects of immune regulation by vitamin and gut microbial metabolites. 

One set of projects is studying the impact of vitamin A in regulating food allergy and respiratory syncytial virus immune responses. The current progress indicates that Vitamin A metabolites play important regulatory functions in developing inflammatory and allergy immune responses. Further studies are needed to validate the findings and provide mechanistic information that would foster the development of useful intervention ideas. 

We also made a significant progress in regulation of antibody production during general and allergic immune responses. We are focusing on a key molecular regulator in B cells. We also made significant progress in identifying biologically active gut microbial metabolites in immune regulation. The current plan is to apply these findings broadly to control several diseases, including allergic immune responses. 

Moreover, collaborative efforts with other principal investigators led to important discoveries and publications on regulation of mucosal barrier and inflammatory responses. We have published several articles including one in the journal Cell Reports that circadian signals regulate the movement of immune cell progenitors out of the bone marrow to seed various peripheral tissues. In this work, we identified several circadian signals that control the innate immunity. The research findings highlight the importance of maintaining the proper circadian rhythm for optimal functions of the immune system to prevent pathological conditions, such as infection, cancer, and allergic responses.

In 2024, the O’Konek lab continued its commitment to team science, with multiple collaborations with industry and other academic labs. The two major areas of research in the O’Konek lab are investigating the mechanisms of action of vaccine adjuvants and the development of novel therapeutics for food allergies.

The O’Konek lab collaborates on research on the pre-clinical development of multiple novel therapies for food allergies. The lab presented research at national and international scientific meetings on novel technologies including nanoparticles, modified allergens and allergen-specific antibodies. Much of this work was published in high-impact journals.  

Two works to highlight are as follows: In collaboration with other labs at the University of Michigan and the University of Virginia, we published one of the first manuscripts showing a preclinical efficacy of a therapeutic for alpha-gal syndrome, an allergy to red meat that is induced by tick bites. The O’Konek lab performed preclinical mouse modeling to demonstrate efficacy of an antibody developed by IgGenix to prevent allergic reactions to peanut, which was published in the Journal of Allergy and Clinical Immunology. 

The O’Konek lab has extended their research on the immune effects of vaccine adjuvants to study specific immune effects of immunization in early life. This work was led by veterinary resident Taylor Simmons and undergraduate student Cecilia Chen. Cecilia presented her work at the national meeting for the Society of Leukocyte Biology and was awarded best talk in her category. 

Dr. O’Shea’s research primarily focuses on the early-life factors and genetic signatures that contribute to the development of food allergies, as well as exploring novel therapeutic approaches to treat them. She is the lead investigator of the M-SIBS longitudinal birth cohort, launched in May 2024, which aims to investigate the genetic and environmental influences on food allergy development. Her research is dedicated to advancing the understanding of food allergy progression and identifying key factors that shape its onset.

In addition, she is the lead investigator and co-investigator on numerous clinical trials evaluating new therapeutic options for food allergy.  Dr. O’Shea continues to lead the Food Allergy Therapy Program within the University of Michigan Division of Allergy and Clinical Immunology, where she directs the oral immunotherapy program. Her research also extends to advocacy efforts around oral immunotherapy and examining healthcare disparities in food allergy treatment.

Dr. O’Shea is also the President-Elect for the Michigan Allergy and Asthma Society. She has served on the Board of the Michigan Allergy and Asthma Society for three years. 

Over the last year, my research has been focused on two areas of food allergy. 

First, we are continuing to look at the role of the intestinal epithelial barrier in the development of severe food allergy. We are looking at how a breakdown of that barrier may lead to severe reactions in food allergy, whereby food proteins inappropriately move from the lumen and activate immune cells in the lamina propria and enhancing anaphylaxis. 

Using an animal model, we were able to delete one of the critical proteins that creates this epithelial barrier, thereby allowing greater protein detection by the immune cells. We found that mice lacking this barrier protein have more severe anaphylactic responses and an altered immune profile. We are using this model to better understand how disruption of barrier function, whether genetically or due to environmental factors, may lead to worse outcomes in food allergic individuals. We are also looking at how barrier function might be improved, whether through environmental changes such as in the microbiome, or through potential treatments such as molecules that modulate inflammation.

The second, recent aspect of my research has been on skin barrier function as a mechanism for allergic sensitization. Data in patients with food allergy suggest that many of them may first be exposed through the skin, and we are investigating ways that cells in the skin and intestine may communicate to initiate food allergy through this remote site. We are also looking at how anaphylactic responses might be anticipated through measuring skin barrier function. This too has been observed in patients, and we are using our mouse models to understand how this works, hopefully leading to improved diagnostics.

Schuler Lab 

The 2023-2024 academic year was a busy one for our group. On the laboratory side, Allison Wang (PhD student in the Immunology Program), Melanie Donahue, MD (clinical fellow in the Allergy/Immunology Fellowship), and Judy Hines, PhD (laboratory manager for the Schuler lab) all joined the research group. 

On the clinical discovery side, Lea Franco (project manager), and Anjali Sundar, MD (clinical fellow in the Allergy/Immunology Fellowship) joined the group. The Consortium of Food Allergy Research U01 grant, the Immunology T32 grant, institutional, and generous donor support all provided pivotal roles in supporting this growth.

Our project using transepidermal water loss in predicting food anaphylaxis continues to generate results, including publications and presentations. The project using machine learning to predict food challenge outcomes generated its first manuscript this year. The laboratory projects supported collaborative publications this year, with primary manuscripts expected in the coming year. 

In the year ahead, we expect to consolidate our strengths, focus on publishing additional studies, continue training the next generation of food allergy experts, and contribute to the food allergy field.