The long-term goal of this grant project is to understand the mechanisms of eosinophilic inflammation in human diseases. Airway inflammation in patients with asthma is characterized by airway eosinophilia and increased numbers of lymphocytes producing Th2-type cytokines. However, the immunological mechanisms to explain the associations among genes, environment and Th2-type inflammation in asthma are not well understood. We recently found that when mice are exposed to an environmental allergen, IL-33 is released quickly to the airways. Administration of exogenous IL-33 promotes airway eosinophilia and development of antigen- specific Th2 CD4+ T cells. We have also identified in mouse lungs a novel lymphoid cell that expresses no lineage markers, but distinctly expresses CD25, CD44, IL-7R, and Sca-1. This cell responds quickly and vigorously to IL-33 and produces large quantities of IL-5, IL-9 and IL-13. Therefore, we hypothesize that when the respiratory tract is exposed to airborne environmental allergens, this novel lymphoid cell in the lungs [referred herein as the lung innate helper (LIH) cell] is involvedin both innate and adaptive Th2 immune responses and airway pathologic changes. Our renewal application will test this hypothesis.
In Aim 1, we will determine the proliferation and functions of LIH cells in response to lung-derived cytokines, such as IL-33, TSLP, and IL-25. We will investigate the regulation of LIH cells and how IL-33- stimulated LIH cells are involved in innate Th2-type airway inflammation and in the development of antigen- specific Th2 CD4+ T cells.
In Aim 2, we will determine the roles of IL-33, TSLP and LIH cells in allergen- induced Th2-type airway inflammation. We will investigate the roles of these molecules and cells in acute and chronic asthma models in mice exposed to environmental allergens.
In Aim 3, we will investigate the frequency and functions of the innate lymphoid cells that are analogous to the LIH cell in human asthma. We will collect peripheral blood specimens from severe asthma patients and from control individuals and examine whether IL-33-responsive LIH-like cells are increased and/or functionally activated in patients with asthma. We have developed robust mouse models to dissect the innate and adaptive Th2-type immune responses to environmental allergens. All the tools necessary to accomplish the project, including gene- deficient mice and adoptive cell transfer model, are currently available in our laboratory. An outstanding group of investigators, including an asthma specialist, will also participate. Therefore, the proposed studies are likely to provide fundamental information regarding the mechanisms by which Th2-type immune responses and airway inflammation develop after exposure to environmental allergens. They will provide a new understanding of the pathogenesis of asthma and will lead to the development of novel treatments and prevention strategies for asthma and other Th2-type airway inflammatory disorders.

Public Health Relevance

Patients with asthma have persistent respiratory problems because of inflammation in their airways. This research will investigate how the interaction of immune cells and environmental allergens causes the immune responses and inflammation in the airways. Successful completion of this project will provide new prevention and therapeutic strategies for asthma and related airway diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Minnicozzi, Michael
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Mayo Clinic, Rochester
United States
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Anderson, E L; Kobayashi, T; Iijima, K et al. (2016) IL-33 mediates reactive eosinophilopoiesis in response to airborne allergen exposure. Allergy 71:977-88
Kobayashi, Takehito; Soma, Tomoyuki; Noguchi, Toru et al. (2015) ATP drives eosinophil effector responses through P2 purinergic receptors. Allergol Int 64 Suppl:S30-6
Bartemes, Kathleen R; Kephart, Gail M; Fox, Stephanie J et al. (2014) Enhanced innate type 2 immune response in peripheral blood from patients with asthma. J Allergy Clin Immunol 134:671-678.e4
Fujisawa, Daisuke; Kashiwakura, Jun-Ichi; Kita, Hirohito et al. (2014) Expression of Mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticaria. J Allergy Clin Immunol 134:622-633.e9
Drake, L Y; Iijima, K; Kita, H (2014) Group 2 innate lymphoid cells and CD4+ T cells cooperate to mediate type 2 immune response in mice. Allergy 69:1300-7
Kita, Hirohito (2013) Eosinophils: multifunctional and distinctive properties. Int Arch Allergy Immunol 161 Suppl 2:3-9
Bartemes, Kathleen R; Iijima, Koji; Kobayashi, Takao et al. (2012) IL-33-responsive lineage- CD25+ CD44(hi) lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J Immunol 188:1503-13
Matsuwaki, Yoshinori; Wada, Kota; White, Thomas et al. (2012) Alternaria fungus induces the production of GM-CSF, interleukin-6 and interleukin-8 and calcium signaling in human airway epithelium through protease-activated receptor 2. Int Arch Allergy Immunol 158 Suppl 1:19-29
Kouzaki, Hideaki; Iijima, Koji; Kobayashi, Takao et al. (2011) The danger signal, extracellular ATP, is a sensor for an airborne allergen and triggers IL-33 release and innate Th2-type responses. J Immunol 186:4375-87
Kephart, Gail M; Alexander, Jeffrey A; Arora, Amindra S et al. (2010) Marked deposition of eosinophil-derived neurotoxin in adult patients with eosinophilic esophagitis. Am J Gastroenterol 105:298-307

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