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TREG RECRUITMENT/INDUCTION FOR THE PREVENTION OF AN EXPERIMENTAL INFLAMMATORY MODEL OF DRY EYE DISEASE

Ratay, Michelle (2018) TREG RECRUITMENT/INDUCTION FOR THE PREVENTION OF AN EXPERIMENTAL INFLAMMATORY MODEL OF DRY EYE DISEASE. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Dry eye disease (DED) affects more than 10 million individuals in the United States. DED originates from disruption of the immunological homeostasis of the lacrimal functional unit (LFU). This disruption stems from persistent infiltration of pro-inflammatory effector CD4+ T lymphocytes (Teff) into the LFU, and reduced numbers and/or function of immunosuppressive regulatory T cells (Tregs). Current clinical treatments block pro-inflammatory signaling but do not address the underlying immunological imbalance in DED. Notably, in a healthy state, the body utilizes sophisticated regulatory mechanisms that include Tregs to promote immunological balance. Indeed, ex vivo expanded Tregs, adoptively transferred into mice with induced DED, effectively ameliorates disease symptoms. Using living Tregs to dynamically and responsively manipulate the local immunological milieu to treat DED would represent a departure from traditional drug-based treatments. Although Treg cell therapy is an extremely promising treatment for DED, ex vivo Treg expansion has significant limitations, such as regulatory hurdles, Treg plasticity, and high costs. For these reasons, we developed several acellular approaches that utilize biodegradable microspheres composed of poly(lactic-co-glycolic acid) to release different factors capable of recruiting endogenous Tregs and/or inducing local Tregs in the ocular tissue to restore immunological homeostasis. To this end, our data suggest that controlled release systems can generate and sustain a biological gradient of the Treg-preferential chemoattractant, CCL22, recruiting endogenous Tregs. In turn, these “Treg-recruiting formulations” reduce the symptoms of DED when placed locally in the lacrimal gland in a Concanavalin A-induced murine model of DED. Moreover, the local delivery of TGF-β, IL-2, and Rapamycin from similar controlled release systems induces local differentiation of naïve CD4+ T cells into FoxP3+ Treg, which in turn, prevents DED symptoms such as loss of tear production, maintenance of goblet cell density, and ocular surface damage. As an alternative approach to enhance Treg populations, we also investigated the administration of microspheres containing one factor, which may be more translational than three different factors, and demonstrated the prevention of signs of DED. Taken together, all of these microsphere formulations aim to mimic how the body resolves inflammation and may be a potential modern therapeutic engineered approach for DED.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Ratay, Michellemlg111@pitt.edumlg111
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairLittle, Stevensrlittle@pitt.edusrlittle
Committee MemberSanjeev, Shroffsshroff@pitt.edusshroff
Committee MemberYadong, Wangyw839@cornell.edu
Committee MemberJoel, SchumanJoel.Schuman@med.nyu.edu
Date: 17 April 2018
Date Type: Publication
Defense Date: 3 November 2017
Approval Date: 17 April 2018
Submission Date: 20 November 2017
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 199
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: Drug Delivery Ophthamology
Related URLs:
Date Deposited: 17 Apr 2019 05:00
Last Modified: 17 Apr 2019 05:00
URI: http://d-scholarship.pitt.edu/id/eprint/33487

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  • TREG RECRUITMENT/INDUCTION FOR THE PREVENTION OF AN EXPERIMENTAL INFLAMMATORY MODEL OF DRY EYE DISEASE. (deposited 17 Apr 2019 05:00) [Currently Displayed]

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