Novel and Emerging Therapies for Food Allergy
Alexander S. Zhovmer, PhD
Office of Vaccines Research and Review
Division of Bacterial, Parasitic, and Allergenic Products
Laboratory of Immunobiochemistry
Biosketch
Dr. Alexander S. Zhovmer serves as a Principal Investigator in the Laboratory of Immunobiochemistry studying the immunology of food allergy. He received a master’s degree in medical biology at the Novosibirsk State University, working on the immunology of breast cancer at the Institute of Clinical Immunology in Novosibirsk, Russia. During his Ph.D. training at the University of Strasbourg, he worked with Drs. Frederic Coin and Jean-Marc Egly at the Institute of Genetics and Molecular and Cellular Biology in Illkirch, France, on discovering novel mechanisms of DNA damage detection and repair. During his postdoctoral training with Dr. Xiaohui Qu at the Memorial Sloan Kettering Cancer Center in New York, he developed new methods for quantitative single-molecule analysis of eukaryotic transcription. Working with Dr. Robert Adelstein at the National Heart, Lung, and Blood Institute, NIH, he combined human and mouse genetics, super-resolution imaging, and bioengineering to uncover cytoskeletal mechanisms that regulate immune cell motility and control cell shape established through interactions with the extracellular matrix.
Currently, Dr. Alexander Zhovmer is developing projects studying allergenic imprinting of the immune system, including immunotherapies for food allergy as well as the biophysics, therapeutic implications, and reverse-engineering of lymphocyte trafficking in tissues.
General Overview
Allergies are common in the industrialized countries, where up to half of school-age children have at least one allergy. In the United States, allergies affect an estimated 40 to 50 million people, with more than half allergic to common foods. Food allergy typically manifests via local inflammation in tissues, e.g., in gastrointestinal tract, lungs or skin, but sometimes allergic reactions progress to a fatal anaphylaxis. Along with venom and drug allergies, food allergies rank among the top three causes of anaphylaxis.
Statistics show that prevalence and severity of food allergies are on the rise. In the U.S., the prevalence of food allergies in children increased by 50% between 1997 and 2011 and more than tripled for peanut and tree nut allergies between 1997 and 2008. The severity of food allergies, e.g., childhood hospitalizations for food allergy, tripled between the late 1990s and the mid-2000s. Anaphylactic reactions resulting from food allergy increased by 377% between 2007 and 2016. The cost of living with food allergies has become a financial burden, both on affected individuals and on the public health system. Childhood food allergies alone cost the U.S. $24.8 billion annually, including $5.5 billion in out-of-pocket costs to families.
Since current options for treatment of food allergy are limited, interest in developing new technologies and clinical products for treatment of allergic diseases is strong. Options include allergen immunotherapy, cell therapy with gene-modified immune cells, and DNA or viral-like particle vaccines. In our research program, we aim to develop advanced in vitro platforms and animal allergy models for accurate and rapid characterization of novel allergenic products, vaccines, and immunotherapies. Further, we are evaluating emerging applications of cell therapy for safety and efficacy.
Scientific Overview
Food allergy is caused by the IgE-mediated immune system sensitivity to common food allergens such as cow's milk, eggs, peanuts, shellfish, fish, tree nuts, soy, wheat, rice, sesame seeds, and fruits. Typically imprinting of the immune system by a pathogen or a vaccine generates mature memory cells that protect against a disease and provide long-term effectiveness. Occasionally, imprinting may go wrong and result in the generation of pathogenic memory cells that react to usually harmless consumed substances, resulting in the development of food allergies.
Pathogenic memory cells can mediate abnormal immune responses to foods indefinitely, by lifelong production of allergen-reactive immunoglobulin E (IgE) and sensitization of mast cells. IgE antibodies are produced by plasma cells that are supported by allergen-specific memory B and T cells. Pathogenic memory B, T, and plasma cells can circulate in the blood, can infiltrate various allergy-prone tissues such as the gut and the skin, or can reside within the lymphatic organs for years.
Current treatments for food allergy are limited to avoidance of allergenic foods and epinephrine injections for anaphylaxis. While oral desensitization is becoming more common, no evidence to date suggests that desensitization deletes IgE-producing memory B cells or pathogenic T cells to induce true tolerance. We hypothesize that chimeric antigen receptor (CAR)-based cell therapy can be used to target these pathogenic cells, thus having the potential to provide true immunologic tolerance to food-allergic patients. In short, cytotoxic immune cells can be gene-modified to express a chimeric antigen receptor that helps them to specifically recognize and eliminate antigen-specific diseased cells.
However, CAR therapy is limited by at least two impediments. First, the severe inflammatory toxicity, i.e., cytokine storm associated with killing the tumor burden, is often life-threatening. Since the cell burden of antigen specific B, T, and plasma cells is expected to be much lower than that of cancer cells, we predict that that our animal models will demonstrate that the physiologic consequences of CAR therapy for allergic disease will be comparatively mild. We further aim to solve the second impediment, that CAR cells often do not traffic towards their tissue-embedded target cells, as a component of the research program.
In our research program, we combine animal allergy models and advanced in vitro platforms, such as functionalized elastic hydrogels, microchannels, modular DNA nano- and micro-patterns, for studying: (a) allergenic imprinting and trafficking of leukocytes in tissues; (b) allergenic remodeling of tissues and its therapeutic implications; (c) the possibility for establishment of permanent immunologic tolerance following depletion of allergen-specific memory B, T and plasma cells; and (d) potential adverse reactions of cell therapy for food allergy, such as mast cell degranulation, cytokine release syndrome and off-target activities of cytotoxic CAR cells.
Important Links
- ORCID ID: 0000-0003-3465-4953
Publications
- Nanomedicine 2021 Oct;37:102442
Programmable DNA-augmented hydrogels for controlled activation of human lymphocytes.
Zhovmer AS, Chandler M, Manning A, Afonin KA, Tabdanov E - Nat Commun 2021 May 14;12(1):2815
Engineering T cells to enhance 3D migration through structurally and mechanically complex tumor microenvironments.
Tabdanov ED, Rodríguez-Merced NJ, Cartagena-Rivera AX, Puram VV, Callaway MK, Ensminger EA, Pomeroy EJ, Yamamoto K, Lahr WS, Webber BR, Moriarity BS, Zhovmer AS, Provenzano PP