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Characterization of Immune Response in Corticosteroid-refractory Severe Asthma in Humans and Mice

Raundhal, Mahesh (2015) Characterization of Immune Response in Corticosteroid-refractory Severe Asthma in Humans and Mice. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Severe asthma (SA) remains a poorly controlled disease despite use of high doses of systemic corticosteroids (CS) although mild-moderate asthma (MMA) is responsive to low dose inhaled CS. This suggests that SA cannot be solely orchestrated by Th2 cells, which are dominant in milder disease. Analysis of broncholalveolar lavage cells isolated from MMA and SA patients revealed a significantly greater IFN-γ (Th1) immune response in the airways of severe asthmatics with lower Th2 and IL-17 responses. We modeled this complex immune response seen in human SA in mice including poor response to CS. Ifng-/- mice subjected to this SA model failed to mount airway hyperresponsiveness (AHR) without appreciable effect on airway inflammation. However, Il17ra-/- mice did not show any reduction in AHR although the mice displayed lower airway inflammation. Computer-assisted pathway analysis tools linked IFN-γ to secretory leukocyte protease inhibitor (SLPI), which is expressed by airway epithelial cells and an inverse correlation between IFN-γ and SLPI expression was detected in SA. Forced expression of SLPI in mice subjected to the SA model decreased AHR in the absence of CS, and it was further reduced when SLPI was combined with CS. Taken together, our study has identified a distinct immune response in SA highlighting a dysregulated IFN-γ-SLPI axis that impacts lung function.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Raundhal, Maheshmrr43@pitt.eduMRR43
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRay, Prabirrayp@pitt.eduRAYP
Committee CoChairRay, Anuradharaya@pitt.eduRAYA
Committee MemberWenzel ,
Committee MemberKolls, JayJay.Kolls@chp.eduJKK23
Committee MemberSarkar, Saumendrasaumen@pitt.eduSAUMEN
Date: 18 December 2015
Date Type: Publication
Defense Date: 24 August 2015
Approval Date: 18 December 2015
Submission Date: 8 December 2015
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 119
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: severe asthma, Interferon-gamma, Th17, corticosteroids, Th1
Date Deposited: 18 Dec 2015 13:32
Last Modified: 19 Dec 2016 14:42


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