The long-term goal of this project is to better understand the immunologic mechanisms of asthma and allergic diseases. These diseases are generally thought to result from dysregulated immune responses to environmental proteins and organisms, which are mediated by Th2 cells. However, several fundamental questions still remain. How do patients develop such maladaptive T cell responses? Why don't all patients who have detectable serum IgE antibodies (e.g. patients with allergic rhinoconjunctivitis) develop asthma? By using the Alternaria fungus, which has been implicated in human asthma, we have been studying how allergen-specific CD4+ T cells develop and which allergen molecules are critically involved. We now hypothesize that the so-called """"""""Th2-type immune response"""""""" to airborne allergens is mediated by two distinct CD4+ T cell subsets, namely Th2 cells and follicular T (Tfh) cells, which are critically involved in eosinophilic inflammation and gE antibody production, respectively. We also hypothesize that exogenous and endogenous ribonucleases (RNases) are involved in development of pathologic Th2 cells.
In Aim 1, we will use mouse models and determine the roles of Th2 cells and Tfh cells in Th2-type airway immune responses to Alternaria and other airborne allergens. We will leverage cytokine reporter mice and gene-deficient mice and investigate the compartmentalized development of Th2 cells and Tfh cells.
In Aim 2, we will investigate the roles of Tfh cells in human airway disease. We will characterize blood CXCR5+CD4+ T cells, a human counterpart of Tfh cells, in a cohort of patients with short ragweed hay fever and examine the dynamic changes in these cells during the hay fever season.
In Aim 3, we will determine the roles of Alternaria-derived RNases and endogenous RNases, such as eosinophil-derived neurotoxin, in development and exacerbation of Th2 type immune responses. We will integrate data obtained from in vitro experiments and in vivo mouse models. Recombinant Alternaria RNases and the fungi deficient in these RNases will be examined. The technical expertise required for these three Aims is readily available in the laboratories of Dr. Kita and his collaborator, Dr. Lawrence, a fungal functional genomics expert. The proposed studies are likely to provide a better understanding of the fundamental mechanisms underlying the development of Th2-type immunity to airborne allergens and will provide an explanation for the dissociation between robust airway inflammation and IgE antibody production in certain patients with allergic airway disorders. The study will also likely identify potential key environmental and endogenous molecules that participate in the development of pathologic T cell responses in asthma. Ultimately, these studies will significantly enhance our understanding of the key cellular pathway(s) and molecule(s) involved in allergen- induced airway inflammation, allowing for identification of critical targets for development of novel therapeutic strategies to treat or to prevent asthma and related airway disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI071106-06A1
Application #
8581934
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Minnicozzi, Michael
Project Start
2013-05-20
Project End
2018-04-30
Budget Start
2013-05-20
Budget End
2014-04-30
Support Year
6
Fiscal Year
2013
Total Cost
$380,030
Indirect Cost
$133,028
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Dolence, Joseph J; Kobayashi, Takao; Iijima, Koji et al. (2018) Airway exposure initiates peanut allergy by involving the IL-1 pathway and T follicular helper cells in mice. J Allergy Clin Immunol 142:1144-1158.e8
Hayes, Tristan; Rumore, Amanda; Howard, Brad et al. (2018) Innate Immunity Induced by the Major Allergen Alt a 1 From the Fungus Alternaria Is Dependent Upon Toll-Like Receptors 2/4 in Human Lung Epithelial Cells. Front Immunol 9:1507
Bartemes, Kathleen R; Kita, Hirohito (2018) Innate and adaptive immune responses to fungi in the airway. J Allergy Clin Immunol 142:353-363
Bartemes, Kathleen; Chen, Chien-Chang; Iijima, Koji et al. (2018) IL-33-Responsive Group 2 Innate Lymphoid Cells Are Regulated by Female Sex Hormones in the Uterus. J Immunol 200:229-236
Drake, Li Yin; Kita, Hirohito (2017) IL-33: biological properties, functions, and roles in airway disease. Immunol Rev 278:173-184
Kobayashi, Takao; Iijima, Koji; Dent, Alexander L et al. (2017) Follicular helper T cells mediate IgE antibody response to airborne allergens. J Allergy Clin Immunol 139:300-313.e7
Chen, Chien-Chang; Kobayashi, Takao; Iijima, Koji et al. (2017) IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs. J Allergy Clin Immunol 140:1351-1363.e7
Uchida, M; Anderson, E L; Squillace, D L et al. (2017) Oxidative stress serves as a key checkpoint for IL-33 release by airway epithelium. Allergy 72:1521-1531
Kouzaki, Hideaki; Matsumoto, Koji; Kikuoka, Hirotaka et al. (2017) Endogenous Protease Inhibitors in Airway Epithelial Cells Contribute to Eosinophilic Chronic Rhinosinusitis. Am J Respir Crit Care Med 195:737-747
Kita, Hirohito (2015) ILC2s and fungal allergy. Allergol Int 64:219-26

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