Glowacki, Andrew
(2016)
Treating periodontal disease through the recruitment and expansion of endogenous regulatory T cells.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Periodontal disease, also known as gum disease, affects an estimated 64 million Americans and
is the leading cause of tooth loss. Current clinical therapies focus on the removal of invasive oral
bacteria that initiate the disease through scaling and root planing and administration of
antibiotics. However, it is now understood that tissue destruction in periodontal disease is carried
out by an exacerbated inflammatory immune response. Furthermore, recent literature suggests
that the severe forms of the disease may be characterized by a decrease in the presence of a
subset of cells responsible for directing immune regulation, Regulatory T cells (Tregs). To
address the underlying immune dysfunction, we have developed acellular approaches, utilizing
translatable bioerodible microspheres composed of poly(lactide-co-glycolide) capable releasing
factors that can recruit endogenous Tregs and induce local Tregs in the periodontium for the
treatment of periodontal disease. Specifically, we have developed microspheres that release the
Treg-associated C-C motif chemokine 22 (CCL22) and vasoactive intestinal peptide (VIP) for
the local recruitment of endogenous Tregs in vivo and prevention of alveolar bone resorption.
Furthermore, CCL22 microspheres led to a reduction in the expression of damaging
inflammatory mediators and conversely, led to an upregulation of anti-inflammatory molecules
that could potentially lead to tissue regeneration. Secondly, we demonstrate that CCL22
microspheres are capable of being administered using standard clinical techniques to effectively
treat ligature-induced periodontitis in beagle dogs. CCL22 microspheres reduce clinical scores
of inflammation including periodontal probing depths and bleeding on probing as well as
reduced tooth supporting alveolar bone resorption in dogs. Finally, we describe an alternative
strategy to bolster Treg population in situ, through the local expansion of Tregs by PLGA
microspheres releasing a combination of transforming growth factor beta (TGF-β), rapamycin
(Rapa) and interleukin 2 (IL-2). Administration of TGF-β, Rapa, IL-2 microspheres in a mouse model for periodontal disease significantly reduced the primary outcome of periodontal disease,
alveolar bone resorption. Taken together, controlled release formulations that harness the body’s
sophisticated immunoregulatory cells provide an easy-to-use, off-the-shelf therapeutic modality
for treating inflammatory periodontal disease and may become the next clinical standard
treatment.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
5 February 2016 |
| Date Type: |
Publication |
| Defense Date: |
29 October 2015 |
| Approval Date: |
5 February 2016 |
| Submission Date: |
2 December 2015 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
179 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Chemical Engineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Periodontal Disease, Controlled Drug Delivery, CCL22, Regulatory T Cells |
| Date Deposited: |
05 Feb 2017 06:00 |
| Last Modified: |
05 Feb 2021 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/26541 |
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