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Evaluation of TGF-beta, rapamycin, and IL-2 microparticle (TRI MP) treatment for disease prevention in models of type 1 diabetes and arthritis

Bassin, Ethan J. (2021) Evaluation of TGF-beta, rapamycin, and IL-2 microparticle (TRI MP) treatment for disease prevention in models of type 1 diabetes and arthritis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Autoimmune diseases are disorders in which the immune system attacks the body’s own tissues. These include type 1 diabetes (T1D) and rheumatoid arthritis (RA) in which the autoimmune targets are the pancreatic islets and the joints, respectively. T1D can be managed by insulin replacement therapy, but patients still have an elevated death risk and a reduced quality of life. Likewise, less than half of RA patients are able to achieve low disease activity with current therapeutic options.
Animal models of both diseases have found that the administration of antigen-specific regulatory T cells (Treg) suppresses auto-reactive effector T cells (Teff), which contribute to disease, and in turn prevents disease development or treats established autoimmunity. However, obstacles to the translation of antigen-specific Treg cell-therapy include obtaining sufficient cell numbers, and the cost and complexity of cell-therapy. Treatment with auto-antigen and/or immunomodulatory agent therapy has the potential to expand regulatory cell populations inside the body without the costs and challenges associated with cell-therapy. Our group has previously shown that subcutaneous administration of polymeric microparticles (MP), which release TGF-, rapamycin, and IL-2 (TRI MP), expands Tregs and limits Teff levels, resulting in disease prevention in several preclinical models.
Here we evaluated TRI MP in models of autoimmunity for the first time. Despite a small increase in antigen-specific Tregs by the injection site and the investigation of multiple alterations to both TRI MP and auto-antigen delivery, TRI MP did not have any added benefit to auto-antigen alone for disease prevention in the T1D model. In contrast, TRI MP significantly reduced the incidence and severity of arthritis in a preventative collagen-induced arthritis model of RA. While this was not associated with an increase in the percentage of Tregs, it was associated with reduced T cell proliferation and an increase in a FoxP3-CD25+ T cell population with elevated Treg-associated suppressive markers. Collectively this data suggests that TRI MP will have the greatest utility for models in which auto-antigen alone is not protective and that TRI MP dosing may need to be fine-tuned in each model to ensure increases in Tregs without systemic immunosuppression.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Bassin, Ethan J.ejb77@pitt.eduejb770000-0002-4883-4413
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPiganelli, Jon D.jdp51@pitt.edujdp51
Thesis AdvisorLittle, Steven R.srlittle@pitt.edusrlittle
Committee MemberBrown, Bryan N.brownb@upmc.edubryanbrown
Committee MemberDelgoffe, Greg M.gdelgoffe@pitt.edugdelgoffe
Committee MemberVignali, Dario A.dvignali@pitt.edudvignali
Date: 6 January 2021
Date Type: Publication
Defense Date: 3 December 2020
Approval Date: 6 January 2021
Submission Date: 18 December 2020
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 259
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: autoimmune disease, type 1 diabetes, collagen-induced arthritis, immunotherapy, tolerance, drug delivery, controlled release
Date Deposited: 06 Jan 2021 18:40
Last Modified: 06 Jan 2021 18:40
URI: http://d-scholarship.pitt.edu/id/eprint/40122

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