Balmert, Stephen C.
(2018)
Biomimetic Delivery of Regulatory T Cell Inducing Factors to Suppress Cutaneous Inflammation.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Allergic contact dermatitis (ACD) is a common T-cell-mediated inflammation resulting from repeated contact with allergens (e.g. nickel or poison ivy). Current treatments typically involve topical corticosteroids, which non-specifically and transiently suppress inflammation, but fail to address the underlying allergen-specific immune dysfunction. Here, we present two novel approaches that teach the immune system to tolerate contact allergens by inducing suppressive regulatory T cells (Tregs). Specifically, we leveraged biomimetic delivery systems to modulate the skin draining lymph node (DLN) microenvironment with microparticles (MPs) that release TReg-Inducing (TRI) factors, or the skin microenvironment with microneedle arrays (MNAs) that deliver vitamin D3 analog (MC903) to cultivate Treg-inducing tolerogenic dendritic cells (DCs).
We previously demonstrated that TGF-β1, rapamycin, and IL-2 (TRI) promote Treg differentiation in vitro; however, original TGF-β1 MPs exhibited an unexpected two-week delay in release, inconsistent with existing models of controlled release. Suspecting electrostatic interactions between cationic TGF-β1 and negatively charged PLGA MPs were responsible, we characterized the influence of charge on release from PLGA MPs. Release assays revealed inverse correlations between positive charge on encapsulated agents and release rates, and effects of polymer charge density. These results helped us to rationally reformulate TRI MPs using less charged PEG-PLGA to achieve faster release.
In acute murine models of ACD, new TRI MP formulations were injected near sites of allergen exposure to condition the skin DLN. By expanding allergen-specific Tregs and reducing pro-inflammatory effector T cells (Teff), TRI MPs inhibited hypersensitivity responses to subsequent allergen exposure in an allergen-specific manner, effectively preventing or reversing ongoing ACD. Much like TRI MP therapy, intradermal delivery of allergen and MC903 with MNAs also prevented sensitization and inhibited subsequent hypersensitivity responses in naïve and allergic mice by expanding Tregs and reducing Teff. Notably, treatment of human skin explants with MC903 MNA promoted tolerogenic cutaneous microenvironments and caused preferential migration of more tolerogenic DCs, previously shown to support Treg-induction. Collectively, these results suggest that simultaneous introduction of antigen and modulation of local skin or skin DLN with MC903 MNA or TRI MP can induce antigen-specific tolerance, with broad therapeutic applications for other inflammatory disorders, autoimmune diseases, or transplant rejection.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
24 January 2018 |
| Date Type: |
Publication |
| Defense Date: |
21 November 2017 |
| Approval Date: |
24 January 2018 |
| Submission Date: |
27 November 2017 |
| Access Restriction: |
3 year -- Restrict access to University of Pittsburgh for a period of 3 years. |
| Number of Pages: |
187 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
microparticle, microneedle array, PLGA, controlled release, allergic contact dermatitis, immunotherapy, immune tolerance, regulatory T cells, delayed type hypersensitivity, biomimetic, electrostatic, vitamin D3, IL-2, TGF-β1, rapamycin |
| Date Deposited: |
24 Jan 2018 20:52 |
| Last Modified: |
24 Jan 2021 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/33435 |
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