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  1. Biologics Research Projects

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

Alexander.Zhovmer@fda.hhs.gov


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

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


Publications

  1. Proc Winter Simul Conf 2019 Dec;2019:1008-1019
    Multi-objective model exploration of hepatitis C elimination in an agent-based model of people who inject drugs.
    Tatara E, Collier NT, Ozik J, Gutfraind A, Cotler SJ, Dahari H, Major M, Boodram B
  2. Vaccine 2019 May 1;37(19):2608-16
    Modeling indicates efficient vaccine-based interventions for the elimination of hepatitis C virus among persons who inject drugs in metropolitan Chicago.
    Echevarria D, Gutfraind A, Boodram B, Layden J, Ozik J, Page K, Cotler SJ, Major M, Dahari H
  3. Methods Mol Biol 2019;1911:421-32
    Detection of antibodies to HCV E1E2 by lectin-capture ELISA.
    Major M, Law M
  4. Sci Transl Med 2018 Jul 11;10(449):eaao4496
    Modeling of patient virus titers suggests that availability of a vaccine could reduce hepatitis C virus transmission among injecting drug users.
    Major M, Gutfraind A, Shekhtman L, Cui Q, Kachko A, Cotler SJ, Hajarizadeh B, Sacks-Davis R, Page K, Boodram B, Dahari H
  5. J Virol 2018 Mar;92(6):e01742-17
    Determinants in the IgV domain of human HAVCR1 (TIM-1) are required to enhance hepatitis C virus entry.
    Kachko A, Costafreda MI, Zubkova I, Jacques J, Takeda K, Wells F, Kaplan G, Major ME
  6. Antiviral Res 2017 Aug;144:281-5
    Modeling HCV cure after an ultra-short duration of therapy with direct acting agents.
    Goyal A, Lurie Y, Meissner EG, Major M, Sansone N, Uprichard SL, Cotler SJ, Dahari H
  7. PLoS One 2017 Jul 21;12(7):e0181578
    Qualitative differences in cellular immunogenicity elicited by hepatitis C virus T-Cell vaccines employing prime-boost regimens.
    Tan WG, Zubkova I, Kachko A, Wells F, Adler H, Sutter G, Major ME
  8. Gut 2016 Jan;65(1):4-5
    Hepatitis C: new clues to better vaccines?
    Major ME
  9. Hepatology 2015 Dec;62(6):1670-82
    Antibodies to an interfering epitope in hepatitis C Virus E2 can mask vaccine-induced neutralizing activity.
    Kachko A, Frey SE, Sirota L, Ray R, Wells F, Zubkova I, Zhang P, Major ME
  10. PLoS One 2015 Sep 30;10(9):e0137993
    Agent-based model forecasts aging of the population of people who inject drugs in metropolitan Chicago and changing prevalence of hepatitis C infections.
    Gutfraind A, Boodram B, Prachand N, Hailegiorgis A, Dahari H, Major ME
  11. PLoS One 2015 Aug 21;10(8):e0135901
    Mathematical modeling of hepatitis C prevalence reduction with antiviral treatment scale-up in persons who inject drugs in metropolitan Chicago.
    Echevarria D, Gutfraind A, Boodram B, Major M, Del Valle S, Cotler SJ, Dahari H
  12. EBioMedicine 2015 Jun 30;2(8):857-65
    Reverse engineering of vaccine antigens using high throughput sequencing-enhanced mRNA display.
    Guo N, Duan H, Kachko A, Krause BW, Major ME, Krause PR
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