Chronic Rhinosinusitis (CRS) is the most frequently reported chronic disease in the U.S. The etiology of CRS is not well understood. CRS patients are often difficult to treat effectively; even with aggressive medical and surgical therapies, many patients continue to have persistent or recurrent disease. The long-term goal of this project is to understand the causes and pathophysiologic mechanisms of CRS through both clinical and basic research. The specific objective is to delineate the mechanisms causing chronic antigenic stimulation and eosinophilic inflammation in sinus and nasal cavities of CRS patients. The underlying hypothesis to be tested is that immune cells in CRS patients respond to fungi colonized in nasal and sinus cavities and produce large amounts of IL-5 and other inflammatory cytokines, resulting in persistent eosinophilic inflammation of the upper airways.
In Aim 1, the altered immunologic responses of CRS patients to fungal antigens are defined. We will examine whether CRS patients' lymphocytes produce more IL-5 and IFN-gamma compared to normal subjects or atopic controls when exposed to fungal antigen(s). The clinical correlation of eosinophil mediators with sinus inflammation and disease severity in patients will be determined.
In Aim 2, we will ask why and how eosinophil degranulation occurs in sinus cavities of patients with CRS. We will test the hypothesis that fungal antigen(s) activate and induce eosinophil degranulation through protease-activated receptors (PARs) expressed on eosinophils. The observations in Aim 1 and Aim 2 will be culminated in Aim 3. We will directly ask whether fungal organisms colonized in nasal and sinus cavities cause or exacerbate the disease in CRS patients. By instillation of an antifungal agent, we will remove the colonized fungi from the nasal/sinus cavities of patients and will examine eosinophilic inflammation and clinical outcomes. We believe these studies will lead to a better understanding of the pathophysiologic mechanisms of CRS, especially the underlying causes of antigenic stimulation of immune cells in patients. Elucidation of the causes and mechanisms of inflammation may help to develop specific and effective therapies for this common, costly, and incapacitating disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI049235-01
Application #
6316358
Study Section
Special Emphasis Panel (ZRG1-IMB (03))
Program Officer
Plaut, Marshall
Project Start
2001-03-01
Project End
2006-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
1
Fiscal Year
2001
Total Cost
$403,339
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Divekar, Rohit; Hagan, John; Rank, Matthew et al. (2016) Diagnostic Utility of Urinary LTE4 in Asthma, Allergic Rhinitis, Chronic Rhinosinusitis, Nasal Polyps, and Aspirin Sensitivity. J Allergy Clin Immunol Pract 4:665-70
Ponikau, Jens U; Winter, Laurie A; Kephart, Gail M et al. (2015) An immunologic test for chronic rhinosinusitis based on free intranasal eosinophilic major basic protein. Int Forum Allergy Rhinol 5:28-35
Divekar, Rohit; Kita, Hirohito (2015) Recent advances in epithelium-derived cytokines (IL-33, IL-25, and thymic stromal lymphopoietin) and allergic inflammation. Curr Opin Allergy Clin Immunol 15:98-103
Kobayashi, Takehito; Soma, Tomoyuki; Noguchi, Toru et al. (2015) ATP drives eosinophil effector responses through P2 purinergic receptors. Allergol Int 64 Suppl:S30-6
Drake, Li Yin; Iijima, Koji; Hara, Kenichiro et al. (2015) B cells play key roles in th2-type airway immune responses in mice exposed to natural airborne allergens. PLoS One 10:e0121660
Divekar, R D; Samant, S; Rank, M A et al. (2015) Immunological profiling in chronic rhinosinusitis with nasal polyps reveals distinct VEGF and GM-CSF signatures during symptomatic exacerbations. Clin Exp Allergy 45:767-78
Hara, Kenichiro; Iijima, Koji; Elias, Martha K et al. (2014) Airway uric acid is a sensor of inhaled protease allergens and initiates type 2 immune responses in respiratory mucosa. J Immunol 192:4032-42
Iijima, Koji; Kobayashi, Takao; Hara, Kenichiro et al. (2014) IL-33 and thymic stromal lymphopoietin mediate immune pathology in response to chronic airborne allergen exposure. J Immunol 193:1549-59
Likness, Micah M; Pallanch, John F; Sherris, David A et al. (2014) Computed tomography scans as an objective measure of disease severity in chronic rhinosinusitis. Otolaryngol Head Neck Surg 150:305-11
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

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