Immunomodulatory innate defense regulator (IDR)-1002 peptide in airway inflammation
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Date
2019-12-18
Authors
Piyadasa, Hadeesha
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Abstract
Allergic asthma is a chronic respiratory disease characterized by airway inflammation and hyper-responsiveness (AHR). Despite available treatments such as inhaled corticosteroids (ICS), ~20% patients do not respond to the treatments. Moreover, patients with uncontrolled asthma often have increased susceptibility to pulmonary infections. These challenges highlight the need to develop new therapeutic strategies.
Immunomodulatory molecules known as cationic host defense peptides (CHDP) can resolve both infections and inflammation. Synthetic peptides designed from CHDP are known as innate defense regulator (IDR) peptides. The focus of my research was to examine the beneficial potential of IDR peptides for airway inflammation, and to provide a fundamental understanding of how these peptides may control the pathobiology related to allergic asthma.
I systematically characterized the inflammatory and physiological changes induced by the allergen house dust mite (HDM) in a murine model, and examined the ability of an IDR peptide, IDR-1002, to mitigate the effects of HDM-challenge in mice. I demonstrated that administration of IDR-1002 reduces allergen-induced AHR, and eosinophil and neutrophil accumulation in the lungs of HDM-challenged mice. Concomitantly, IDR-1002 suppresses the abundance of HDM-induced interleukin (IL)-33, a known inflammatory cytokine that leads to tissue damage in the lungs and is known to contribute to ICS unresponsiveness. I demonstrated that suppression of IL-33 by IDR-1002 is essential for the anti-inflammatory activity of the peptide, but not its ability to reduce AHR in mice. In further studies, I generated a series of IDR-1002-derivatives with single amino acid substitutions, and showed that disruption of a central tryptophan (W8) in the IDR-1002 sequence selectively mitigates the anti-inflammatory function of the peptide, including the ability to suppress IL-33, without altering the peptide’s ability to reduce AHR. Thus, I have generated specific peptides that can be used to distinguish mechanisms related to airway inflammation compared to AHR. Overall, findings from my research provide the foundation for further development of IDR peptides as a new class of therapeutics for diseases characterized by airway inflammation and AHR, with potential to counter steroid-unresponsive disease.
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Keywords
Immunomodulatory peptides, Asthma, Airway inflammation, IL-33, Allergy, Airway hyper-responsiveness, IDR peptides