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Treatment of Periodontal Disease Via Modulation of Innate Host Response

Shehabeldin, Mostafa (2021) Treatment of Periodontal Disease Via Modulation of Innate Host Response. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Periodontal disease (PD) is a chronic inflammatory disease characterized by progressive destruction of tooth supporting structures and microbial dysbiosis. The destructive inflammatory process underlying PD is mediated by components of both the innate and acquired immune systems including immune cells, cytokines, chemokines and lipid mediators. Macrophages and T-helper 17 (Th17) cells are key cellular mediators of the innate and acquired host responses in the periodontal environment, respectively. In many tissues including the periodontium, macrophages are the prototypic phagocytes of the innate immune response. These plastic cells can assume distinct phenotypic subsets to perform a wide array of functions ranging from host defense against invading pathogens to clearance of dead cells and promotion of tissue repair. Similarly, periodontal Th17 cells can exhibit both homeostatic and pathogenic subsets. Homeostatic Th17 cells are essential for immune surveillance and host defense by regulating neutrophils expansion and recruitment at oral barrier sites. Conversely, pathogenic Th17 cells arise in response to oral microbial challenge and drive inflammatory damage in PD via overproduction of their major cytokine IL-17A. In this study, we tested the therapeutic efficacy of modulating macrophages response or IL-17A activity in PD using two polymer based sustained delivery systems. To target macrophages, the chemokine CCL2 was encapsulated in PLGA microspheres and locally delivered at different stages of murine PD severity followed by analysis of bone levels, gene expression profile, osteoclastic activity, periodontal ligament organization and periodontal microbial load and composition. Using Sc-RNA sequencing technology, we also assessed murine periodontal macrophages gene expression profile and characterized their phenotypic subsets. We also tested the protective effect of local sustained delivery of IL-17A antibodies in murine periodontitis by assessing the changes in bone levels, osteoclastic activity and inflammatory markers. The overall aim of this study was to highlight the clinical translation potential of targeting cellular and non-cellular components of the innate and acquired immune response to treat PD.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Shehabeldin, Mostafamss124@pitt.edumss124
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSfeir, Charlescsfeir@pitt.educsfeir
Committee MemberNapierala, Dobrawadon11@pitt.edudon11
Committee MemberIntini, Giuseppegii5@pitt.edugii5
Committee MemberGaffen, Sarahsarah.gaffen@pitt.edusarah.gaffen
Date: 9 April 2021
Date Type: Submission
Defense Date: 9 April 2021
Approval Date: 3 June 2021
Submission Date: 22 April 2021
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 138
Institution: University of Pittsburgh
Schools and Programs: School of Dental Medicine > Dental Science
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Periodontal disease, bone loss, macrophages, host response
Date Deposited: 03 Jun 2021 19:02
Last Modified: 03 Jun 2022 05:00
URI: http://d-scholarship.pitt.edu/id/eprint/40637

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