Project Details
Description
Project Summary
Aspirin-exacerbated respiratory disease (AERD) is a subset of asthma, characterized by nasal polyposis and
respiratory reactions to all medications that inhibit cyclooxygenase 1 (COX-1). These commonly used, non-
steroidal anti-inflammatory drugs (NSAID) include aspirin. Desensitization using carefully controlled administra-
tion of aspirin and long-term aspirin treatment have been shown to be effective. In our diverse cohort of AERD
patients, we identified patients who responded to aspirin treatment (responders), and those (more than one-
third) who failed this standard treatment (non-responders). Our preliminary data: AERD has a strong type 2
(T2) pro-inflammatory state likely driven by high systemic levels of prostaglandin D2 (PGD2). Systemic PGD2
levels in plasma significantly decrease after endoscopic sinus surgery, as do clinical signs of aspirin sensitivity
indicating that nasal polyp tissue is vital for promotion of T2 inflammation in AERD. In patients with undetecta-
ble levels of PGD2 in plasma (more than one-third of the study population), there are no detectable clinical re-
actions to aspirin after surgery. Non-responders to aspirin therapy in our AERD cohort had higher urinary
PGD2 metabolite levels, higher baseline total serum immunoglobulin (Ig) E levels, and detectable serum IgE
specific for Staphylococcus (S.) aureus enterotoxin A and/or B (SEA or SEB). We have also found that in non-
responders, total serum IgE significantly increased after aspirin treatment for 4 weeks. Previous research:
PGD2 activates T2-pro-inflammatory cells – T-helper 2 allergic (Th2A) cells through chemoattractant receptor-
homologous molecule expressed on Th2 cell (CRTH2) receptor, which binds PGD2. Unlike conventional Th2
cells, Th2A cells have high expression of hematopoietic prostaglandin D2 synthase (HPGDS), making PGD2
production by Th2A cells possible. Th2A cells are present in nasal polyps, where T2-inflammation is enhanced
by allergic response against bacterial pathogens, especially S. aureus. Initial administration of aspirin to AERD
patients leads to a multifold increase in systemic PGD2 levels. Continuous presence of both S. aureus antigen
and high levels of PGD2 likely contributes to activation of Th2A cells. We propose to focus on nasal polyp tis-
sue as the main driver of the T2 pro-inflammatory state. Central hypothesis: PGD2 and S. aureus synergisti-
cally activate Th2A cells in nasal polyps leading to aspirin treatment failure. Aim 1. Determine activation of
blood and nasal polyp Th2A cells in AERD patients according to clinical outcomes of aspirin treatment and in
response to stimulation by S. aureus. Aim 2. Determine whether stimulation of Th2A cells by S. aureus in-
creases CRTH2 receptor and HPGDS expression. Results will inform the field by examining the role that Th2A
cells play in aspirin treatment and how clinical outcomes could be modified by S. aureus-induced allergic re-
sponse. Studies may offer insight into T2-inflammation of AERD and its alleviation by aspirin; improve selection
of candidates for aspirin therapy; and lead to development of new therapies for patients who are refractory to
current treatment.
Status | Finished |
---|---|
Effective start/end date | 9/3/20 → 8/31/23 |
Funding
- National Institute of Allergy and Infectious Diseases: $209,375.00
- National Institute of Allergy and Infectious Diseases: $251,250.00
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