The role of IL-33 in the innate and adaptive immune responses in asthma
Lead Research Organisation:
University of Glasgow
Department Name: Inst of Immunology Infection & Inflam
Abstract
Asthma affects over 5 million people in the U.K and the incidence is increasing. This disorder is characterised by breathlessness and cough with occasional deteriorations in symptoms, often requiring hospitalisation. Asthma is caused when the body‘s immune system responds inappropriately within the lungs. Many different types of immune cells are involved in asthma and these cells communicate with each other by releasing messenger molecules. When these messages are too strong, this can lead to inflammation and subsequent asthma.
Recent work suggests that a new messenger molecule called IL-33 causes worsening inflammation in the airways and may act on a number of different immune cells to cause damage. I intend to investigate how IL-33 works and it‘s role in asthma by studying a mouse model and examining samples from human asthmatics.
Developing new treatments for asthma is important as current treatments options are limited and can often carry undesirable side effects. In addition to improving our understanding of this significant condition, studying IL-33 could lead to a novel target for new treatments acting to block it‘s effects.
Recent work suggests that a new messenger molecule called IL-33 causes worsening inflammation in the airways and may act on a number of different immune cells to cause damage. I intend to investigate how IL-33 works and it‘s role in asthma by studying a mouse model and examining samples from human asthmatics.
Developing new treatments for asthma is important as current treatments options are limited and can often carry undesirable side effects. In addition to improving our understanding of this significant condition, studying IL-33 could lead to a novel target for new treatments acting to block it‘s effects.
Technical Summary
Asthma continues to be a cause of significant morbidity and mortality and prove a considerable economic and social burden. Airway inflammation is key in the pathogenesis of asthma and hence, corticosteroids remain the most important anti-inflammatory treatment. Therefore, there is a drive to develop novel, more specific and safer therapies.
Asthma pathophysiology involves complex interactions between a diverse group of cells in the innate and adaptive immune systems and is mediated by a range of cytokines and inflammatory mediators. Interleukin (IL)-33 is a recently discovered pro-inflammatory cytokine which signals through the receptor ST2L. My preliminary data show that IL-33 administered intranasally (i.n.) to mice caused severe airway inflammation as demonstrated by increased eosinophilia in the bronchoalveolar lavage fluid (BALF). Furthermore, IL-33 administered to antigen-specific murine asthma model, worsened the inflammation. These results have led to my hypothesis that IL-33 exacerbates the innate and adaptive arms of the immune responses in airway inflammation and asthma.
I therefore propose to (i) characterize the cell types induced by IL-33 in airways inflammation in mice, (ii) determine the contribution of IL-33 to chronic T cell-mediated airway inflammation in OVA-induced murine asthma, and (iii) investigate the presence of IL-33 in different grades of asthma.
Using an in vivo mouse model of airway inflammation, IL-33 will be introduced i.n. at various time points. Cell characterization in the BALF will be analysed and quantified using flow cytometry. Immunhistochemistry of lung tissues will be performed to further assess the type and extent of cellular infiltration in the inflammatory site. To assess the contribution of the adaptive immune system to airway inflammation, similar analysis on the BALF will be performed using RAG-/- mice which completely lack B and T cells. Subsequent transfer of OVA-specific Th2 cells to RAG-/- recipients preceding intranasal IL-33 administration will identify the contribution of the Th2 cells to the inflammatory response to IL-33. In addition, the consequences of neutralising IL-33 by anti-IL-33 antibody administration will be assessed in a well-established OVA-specific murine model using wild type and IL-33-/- mice. Finally, the presence of IL-33 will be sought in sputum and peripheral blood samples from different grades of asthmatics using quantitative PCR and ELISA. These experiments should demonstrate the relationship between IL-33 and clinical asthma.
Thus understanding how IL-33 functions and the effects of IL-33 neutralisation on airway inflammation, may lead to the development of novel therapeutic strategies against inflammation in general and asthma in particular.
Asthma pathophysiology involves complex interactions between a diverse group of cells in the innate and adaptive immune systems and is mediated by a range of cytokines and inflammatory mediators. Interleukin (IL)-33 is a recently discovered pro-inflammatory cytokine which signals through the receptor ST2L. My preliminary data show that IL-33 administered intranasally (i.n.) to mice caused severe airway inflammation as demonstrated by increased eosinophilia in the bronchoalveolar lavage fluid (BALF). Furthermore, IL-33 administered to antigen-specific murine asthma model, worsened the inflammation. These results have led to my hypothesis that IL-33 exacerbates the innate and adaptive arms of the immune responses in airway inflammation and asthma.
I therefore propose to (i) characterize the cell types induced by IL-33 in airways inflammation in mice, (ii) determine the contribution of IL-33 to chronic T cell-mediated airway inflammation in OVA-induced murine asthma, and (iii) investigate the presence of IL-33 in different grades of asthma.
Using an in vivo mouse model of airway inflammation, IL-33 will be introduced i.n. at various time points. Cell characterization in the BALF will be analysed and quantified using flow cytometry. Immunhistochemistry of lung tissues will be performed to further assess the type and extent of cellular infiltration in the inflammatory site. To assess the contribution of the adaptive immune system to airway inflammation, similar analysis on the BALF will be performed using RAG-/- mice which completely lack B and T cells. Subsequent transfer of OVA-specific Th2 cells to RAG-/- recipients preceding intranasal IL-33 administration will identify the contribution of the Th2 cells to the inflammatory response to IL-33. In addition, the consequences of neutralising IL-33 by anti-IL-33 antibody administration will be assessed in a well-established OVA-specific murine model using wild type and IL-33-/- mice. Finally, the presence of IL-33 will be sought in sputum and peripheral blood samples from different grades of asthmatics using quantitative PCR and ELISA. These experiments should demonstrate the relationship between IL-33 and clinical asthma.
Thus understanding how IL-33 functions and the effects of IL-33 neutralisation on airway inflammation, may lead to the development of novel therapeutic strategies against inflammation in general and asthma in particular.