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T cell Immunomodulation in the Lymph Node for Inhibition of Load-Induced Osteoarthritis

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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.

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147 pages

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2022-05

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hydrogels; immunoengineering; osteoarthritis; T cells

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der Meulen, Marjolein van

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Singh, Ankur
Maher, Suzanne A.

Degree Discipline

Biomedical Engineering

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Ph. D., Biomedical Engineering

Degree Level

Doctor of Philosophy

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Government Document

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dissertation or thesis

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