Type 2 Innate Lymphoid Cells and Asthma

Project: Research project

Description

PROJECT SUMMARY/ABSTRACT The long-term goal of this grant project is to understand the immunological mechanisms of asthma.
Airway inflammation in patients with asthma is generally characterized by increased numbers of eosinophils
and lymphocytes producing Th2 cytokines. However, the mechanisms involved in development of Th2-type
CD4+ T cells and persistent and/or recurrent production of Th2 cytokines in the airways are not fully
understood. Recently, we and other investigators have identified in mouse lungs novel type 2 innate lymphoid cells
(ILC2s) that are responsive to IL-33. Airway exposure to aeroallergens induces IL-33 production in the lungs,
and administration of exogenous IL-33 promotes development of antigen-specific Th2-type CD4+ T cells.
Furthermore, ILC2s and conventional CD4+ T cells work together synergistically, resulting in production of
large quantities of Th2 cytokines in vitro. Therefore, we hypothesize that ILC2s are involved in the
development of robust Th2-type immune responses and persistent inflammation in respiratory tract exposed
to airborne allergens, leading to chronic airway diseases such as asthma. In Aim 1, we will determine the roles of ILC2s in development of antigen-specific Th2-type CD4+ T
cells. By using in vitro experiments and IL-33-driven mouse airway sensitization models, we will investigate
how ILC2s are involved in the development and/or maintenance of antigen-specific Th2-type CD4+ T cells in
the lungs. In Aim 2, we will determine the roles of ILC2s and conventional Th2-type CD4+ T cells in asthma.
By using a mouse model of chronic asthma (i.e. mice exposed repeatedly to environmental allergens), we will
dissect the roles for synergistic interactions between ILC2s and CD4+ T cells in persistent airway
inflammation and lung pathology. In Aim 3, we will investigate the roles of ILC2s in human asthma. We will
collect peripheral blood specimens from allergic asthma patients and from control individuals and examine
whether IL-33-responsive ILC2s are increased and/or functionally activated in patients with asthma. We have developed several robust mouse models to dissect the Th2-type immune responses and
airway inflammation to airborne allergens. All of the tools necessary to accomplish this project, including
gene-deficient mice, cytokine reporter mice and adoptive cell transfer models, are currently available in our
laboratory. An outstanding group of investigators, including an asthma specialist, will participate in this
project. Therefore, the proposed studies are likely to provide fundamental information regarding the
mechanisms by which Th2-type immune responses and airway inflammation develop and persist 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.
StatusFinished
Effective start/end date1/15/1412/31/17

Funding

  • National Institutes of Health: $388,770.00
  • National Institutes of Health: $394,691.00
  • National Institutes of Health: $395,813.00

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Asthma
Lymphocytes
T-Lymphocytes
Allergens
Cytokines
Inflammation
Lung
Antigens
Research Personnel
Adoptive Transfer
Organized Financing
Lymphocyte Count
Respiratory System
Chronic Disease
Maintenance
Interleukin-33
Environmental Exposure
Pathology
Eosinophils
Pneumonia

ASJC

  • Medicine(all)