IL-33 is a recently discovered member of the IL-1 family of cytokines. Administration of recombinant IL-33 has been shown to have profound effects on a diverse range of diseases, including arthritis, infection and allergy that are mediate though its receptor ST2. Several different cell types have been shown to express IL-33 and we, and others, have shown that epithelial cells have a high constitutive expression and release it during damage. Consequently, IL-33 has been coined an alarmin, important for the communication between tissue cells and the immune response. However, we have demonstrated that inflammatory cells, such as mast cells [and dendritic cells], have low levels at rest but are induced to express IL-33 upon their activation. The functional consequences of these different sources of IL-33 have not been studied and determining these is the basis for our study. Our preliminary data establishes that ST2 is necessary for both the sensitization to allergens, as well as efficiently mounting an inflammatory response when sensitization in bypassed. Interestingly, our findings show that ST2 is only required for sensitization through the intestine and that, by injecting the same antigen, ST2 KO mice are capable of becoming allergic. We hypothesize that epithelial cells are the necessary source of IL-33 that drives allergic sensitization while mast cell-derived IL-33 is the critical signal for inflammation after sensitization has occurred. We will examine this hypothesis using murine models of food allergy and anaphylaxis that we have developed. Since food allergy is increasing in prevalence and there are very few therapeutic options available at this time, our work has the potential to facilitate new therapies for these patients. We propose to test our hypothesis with two distinct specific aims that address the overall theme of 1) sensitization and 2) elicitation of allergic responses.
These aims are:
Specific Aim 1 : Determine the role of cell-specific IL-33 expression in the generation of peanut-specific antibody and T cell responses.
Specific Aim 2 : Determine the mechanisms through which IL-33 regulates the generation of tissue inflammation to allergens.

Public Health Relevance

IL-33 is a recently identified cytokine that influences allergic-like responses. Several cells express IL-33 but some, such as epithelial cells, possess constitutive expression while others, such as mast cells, are induced to express it. The functional role of these different sources is unknown and we aim to determine the roles IL-33 in allergen-associated sensitization and inflammation the setting of food allergy and anaphylaxis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI105839-02
Application #
8803737
Study Section
Special Emphasis Panel (ZRG1-HAI-D (08))
Program Officer
Davidson, Wendy F
Project Start
2014-02-11
Project End
2019-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
2
Fiscal Year
2015
Total Cost
$386,250
Indirect Cost
$136,250
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Robida, Piper A; Puzzovio, Pier Giorgio; Pahima, Hadas et al. (2018) Human eosinophils and mast cells: Birds of a feather flock together. Immunol Rev 282:151-167
Khoury, Paneez; Akuthota, Praveen; Ackerman, Steven J et al. (2018) Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD). J Leukoc Biol 104:69-83
Han, H; Roan, F; Johnston, L K et al. (2018) IL-33 promotes gastrointestinal allergy in a TSLP-independent manner. Mucosal Immunol 11:578
Wei, Yadong; Chhiba, Krishan D; Zhang, Fengrui et al. (2018) Mast Cell-Specific Expression of Human Siglec-8 in Conditional Knock-in Mice. Int J Mol Sci 20:
Johnston, Laura K; Bryce, Paul J (2017) Understanding Interleukin 33 and Its Roles in Eosinophil Development. Front Med (Lausanne) 4:51
Chhiba, Krishan D; Hsu, Chia-Lin; Berdnikovs, Sergejs et al. (2017) Transcriptional Heterogeneity of Mast Cells and Basophils upon Activation. J Immunol 198:4868-4878
Johnston, Laura K; Hsu, Chia-Lin; Krier-Burris, Rebecca A et al. (2016) IL-33 Precedes IL-5 in Regulating Eosinophil Commitment and Is Required for Eosinophil Homeostasis. J Immunol 197:3445-3453
Bryce, Paul J (2016) Balancing Tolerance or Allergy to Food Proteins. Trends Immunol 37:659-667
Bryce, Paul J; Falahati, Rustom; Kenney, Laurie L et al. (2016) Humanized mouse model of mast cell-mediated passive cutaneous anaphylaxis and passive systemic anaphylaxis. J Allergy Clin Immunol 138:769-779
Kamdar, Toral A; Peterson, Sarah; Lau, Claudia H et al. (2015) Prevalence and characteristics of adult-onset food allergy. J Allergy Clin Immunol Pract 3:114-5.e1

Showing the most recent 10 out of 14 publications