2026-09-18T20:00:44Zhttps://ecommons.cornell.edu/server/oai/requestoai:ecommons.cornell.edu:1813/1118142026-05-15T19:52:04Zcom_1813_35col_1813_47
Wheeler, Tibra Anita
der Meulen, Marjolein van
Singh, Ankur
Maher, Suzanne A.
2022-09-15T15:51:38Z
2022-09-15T15:51:38Z
2022-05
ProQuest Submission ID: 13083
ProQuest Publication ID: 29169027
https://hdl.handle.net/1813/111814
https://doi.org/10.7298/c956-9n28
15530004
147 pages
Osteoarthritis (OA) is a degenerative joint disease that affects millions of people worldwide. The molecular mechanisms of OA initiation and progression are poorly understood and currently, no disease-modifying treatments exist. Intra-articular injection of anti-inflammatory therapeutics is a common treatment option for OA but is limited by poor drug retention. While biomaterials-based strategies have been used to overcome the limitations of current OA treatments, there is a need for more targeted approaches. Understanding the immune response will enable the development of a rational immunotherapeutic approach targeting specific immune cells. However, the crosstalk of joint pathology with local lymph nodes in OA is poorly understood. We characterized the T cell immune response in local lymph nodes following the in vivo mechanical loading of joints. First, we analyzed the change in T cells in lymph nodes following load-induced OA using flow cytometry. T cells increased in the local lymph nodes and contributed to load-induced OA progression in the mouse knee. T helper and γδ T cells increased in the lymph nodes with prolonged cyclic tibial compression. Both pro- and anti-inflammatory cytokines increased with damaging joint loading. Next, we determined the role of T cell presence and migration in OA progression using TCRα-/- and Sphingosine-1-phosphate (S1P) receptor modulator-treated mice, respectively. Inhibiting T cell migration attenuated load-induced cartilage degradation and decreased localization of T cells in the synovium. Furthermore, the absence of T cells, but not γδ+ T cells (TCRα-/- mice), reduced cartilage degradation and osteophyte formation. Lastly, we engineered and assessed the in vivo efficacy of an injectable, protease-degradable PEG-4MAL hydrogel combined with a commonly-used corticosteroid, dexamethasone (DEX). PEG-4MAL hydrogels maintained their mechanical properties after cyclic compression and released therapeutics in an on-demand manner in vitro. Furthermore, the PEG-4MAL hydrogel functioned as a mechanical pillow to protect the knee joint from symptoms of load-induced OA in vivo. These results lay the foundation for the role of T cells in joint damage and suggest that the lymph node may modulate the immune response in OA. Our findings indicate T cell immunotherapies in combination with the PEG-MAL hydrogel system could be used to treat OA.
en
hydrogels
immunoengineering
osteoarthritis
T cells
T cell Immunomodulation in the Lymph Node for Inhibition of Load-Induced Osteoarthritis
dissertation or thesis
https://newcatalog.library.cornell.edu/catalog/15530004
application/pdf
Biomedical Engineering
Cornell University
Doctor of Philosophy
Ph. D., Biomedical Engineering
https://hdl.handle.net/1813/59810.2
Publication
Cornell Theses and Dissertations
Wheeler, Tibra Anita
5893a6ea-7af3-41d7-abc6-04bcd26ab5df
open.access
open.access
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<Abstract>Osteoarthritis (OA) is a degenerative joint disease that affects millions of people worldwide. The molecular mechanisms of OA initiation and progression are poorly understood and currently, no disease-modifying treatments exist. Intra-articular injection of anti-inflammatory therapeutics is a common treatment option for OA but is limited by poor drug retention. While biomaterials-based strategies have been used to overcome the limitations of current OA treatments, there is a need for more targeted approaches. Understanding the immune response will enable the development of a rational immunotherapeutic approach targeting specific immune cells. However, the crosstalk of joint pathology with local lymph nodes in OA is poorly understood. We characterized the T cell immune response in local lymph nodes following the in vivo mechanical loading of joints. First, we analyzed the change in T cells in lymph nodes following load-induced OA using flow cytometry. T cells increased in the local lymph nodes and contributed to load-induced OA progression in the mouse knee. T helper and γδ T cells increased in the lymph nodes with prolonged cyclic tibial compression. Both pro- and anti-inflammatory cytokines increased with damaging joint loading. Next, we determined the role of T cell presence and migration in OA progression using TCRα-/- and Sphingosine-1-phosphate (S1P) receptor modulator-treated mice, respectively. Inhibiting T cell migration attenuated load-induced cartilage degradation and decreased localization of T cells in the synovium. Furthermore, the absence of T cells, but not γδ+ T cells (TCRα-/- mice), reduced cartilage degradation and osteophyte formation. Lastly, we engineered and assessed the in vivo efficacy of an injectable, protease-degradable PEG-4MAL hydrogel combined with a commonly-used corticosteroid, dexamethasone (DEX). PEG-4MAL hydrogels maintained their mechanical properties after cyclic compression and released therapeutics in an on-demand manner in vitro. Furthermore, the PEG-4MAL hydrogel functioned as a mechanical pillow to protect the knee joint from symptoms of load-induced OA in vivo. These results lay the foundation for the role of T cells in joint damage and suggest that the lymph node may modulate the immune response in OA. Our findings indicate T cell immunotherapies in combination with the PEG-MAL hydrogel system could be used to treat OA.</Abstract>
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