Crum, Raphael John
(2022)
Matrix-bound nanovesicles as an immunomodulatory therapy for rheumatoid arthritis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and progressive destruction of synovial joints that affects approximately 1% of the world’s population (approximately 7.5 million people). Synovial invasion of pro-inflammatory immune cells such as macrophages are involved in RA pathogenesis. The infiltrating immune cells release cytokines and autoantibodies that stimulate local macrophages and synovial fibroblasts to further secrete more pro-inflammatory cytokines and matrix-metalloproteases. This release of pro-inflammatory mediators results in cartilage and bone destruction. Further, the polarization of macrophages toward an M1, pro-inflammatory activation state strongly contributes to RA disease flareup, whereas an M2, anti-inflammatory activation state contributes to disease remission. Patients afflicted with RA present clinically with an increased ratio of M1:M2 macrophages in their joint synovium and synovial fluid (as high as 30-fold). While it is known that an M1:M2 disequilibrium contributes to RA disease progression, there are no contemporary therapeutics that specifically modulate macrophage activation state to promote disease remission through an M2, anti-inflammatory activation state.
An appropriately timed macrophage activation state transition, from an M1 to M2 activation state, can be induced by using acellular biologic scaffold materials composed of mammalian ECM. Within these biologic scaffolds are nanometer-sized, lipid membrane vesicles (50-200 nm in diameter) within the fibrillar network of ECM. These vesicles, the matrix-bound nanovesicles (MBV), are released upon degradation of ECM. Recent findings suggest that the effect of ECM bioscaffolds upon macrophage activation state is mediated largely by MBV embedded within ECM bioscaffolds. MBV are a distinct class of extracellular vesicles enriched in anti-inflammatory lipids, proteins, and miRNA. Evidence herein shows that MBV isolated from ECM markedly decrease arthritis in a rat model of pristane-induced RA through immunomodulation of systemic and local myeloid population. Therefore, the significance of the present research is that its results stand to contribute to a clear, unmet need for developing approaches to modulate, rather than to suppress, the pro-inflammatory immune response for patients with RA. Additionally, this research projects certain directions in the future development of MBV-based therapeutic materials for the treatment of RA and that of other autoimmune-driven pathologies.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
5 July 2022 |
| Defense Date: |
24 May 2022 |
| Approval Date: |
29 September 2023 |
| Submission Date: |
5 July 2022 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
266 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Rheumatoid Arthritis, Extracellular Matrix, Matrix-bound nanovesicles, Immunomodulation |
| Date Deposited: |
29 Sep 2023 14:42 |
| Last Modified: |
29 Sep 2023 14:42 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/43166 |
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