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Glycocalyx engineering approaches with polymers to impart immunomodulation for various therapies Luo, Haiming
Abstract
The endothelial glycocalyx is a dynamic structure on the cell surface comprised of various components, including glycoproteins, proteoglycans and glycolipids. This structure helps regulate the dynamic interaction between the cardiovascular system and the immune system, particularly in immune surveillance and regulation. Any injury or disruption to the endothelial glycocalyx can lead to undesirable immune responses. In organ transplantation, the glycocalyx structure is prone to damage as a result of ischemia reperfusion injury, leading to uncontrolled and unwanted immune rejection. Current strategies using immunosuppressants to inhibit immune responses target the entire immune system without specificity, leaving the rest of the body vulnerable to infections. Direct engineering of the glycocalyx using cell surface approaches offers a localized and safer alternative to mitigate glycocalyx damage and restore immunomodulatory function. This thesis introduces new approaches and tools for glycocalyx engineering, aimed at protecting its structure and regulating its immune functions. The transglutaminase-mediated cell surface engineering approach is presented as an easily adaptable technique for ligating polymers to various cell surfaces under different conditions. Using this approach, we designed bioactive polymers and assessed the therapeutic potential of polymer-mediated cell surface engineering in organ transplantation, specifically targeting ischemia reperfusion injury and immune-mediated rejection. We conducted in vitro and in vivo evaluations of glycocalyx-mimicking polymers. To mitigate oxidative damage in ischemia reperfusion injury, we tested linear polyglycerol sulfate polymers (LPGS-Q) through mouse artery transplantation. These polymers demonstrated the ability to scavenge superoxide radicals and reduce inflammation. Furthermore, to suppress immune responses, we applied sialic acid-containing linear polyglycerol glycopolymers (LPG-Q-Sia3Lac) in mouse kidney transplantation. These glycopolymers demonstrated immunosuppressive properties, possibly by engaging immune inhibitory sialic-acid-binding immunoglobulin-like lectins found on immune cell surfaces. Finally, the direct grafting of polysialic acid onto the glycocalyx through enzymatic polymerization is proposed as a promising cell surface engineering approach. Early in vitro studies involving endothelial cells and CAR T cells demonstrated immunomodulatory potential of this technique. These approaches serve to broaden the range of tools available for glycocalyx engineering to achieve immunomodulation locally. Consequently, new opportunities may emerge for the development of novel localized immunotherapies and the advancement of existing cell therapies.
Item Metadata
| Title |
Glycocalyx engineering approaches with polymers to impart immunomodulation for various therapies
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| Creator | |
| Supervisor | |
| Publisher |
University of British Columbia
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| Date Issued |
2023
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| Description |
The endothelial glycocalyx is a dynamic structure on the cell surface comprised of various components, including glycoproteins, proteoglycans and glycolipids. This structure helps regulate the dynamic interaction between the cardiovascular system and the immune system, particularly in immune surveillance and regulation. Any injury or disruption to the endothelial glycocalyx can lead to undesirable immune responses.
In organ transplantation, the glycocalyx structure is prone to damage as a result of ischemia reperfusion injury, leading to uncontrolled and unwanted immune rejection. Current strategies using immunosuppressants to inhibit immune responses target the entire immune system without specificity, leaving the rest of the body vulnerable to infections. Direct engineering of the glycocalyx using cell surface approaches offers a localized and safer alternative to mitigate glycocalyx damage and restore immunomodulatory function.
This thesis introduces new approaches and tools for glycocalyx engineering, aimed at protecting its structure and regulating its immune functions. The transglutaminase-mediated cell surface engineering approach is presented as an easily adaptable technique for ligating polymers to various cell surfaces under different conditions. Using this approach, we designed bioactive polymers and assessed the therapeutic potential of polymer-mediated cell surface engineering in organ transplantation, specifically targeting ischemia reperfusion injury and immune-mediated rejection. We conducted in vitro and in vivo evaluations of glycocalyx-mimicking polymers.
To mitigate oxidative damage in ischemia reperfusion injury, we tested linear polyglycerol sulfate polymers (LPGS-Q) through mouse artery transplantation. These polymers demonstrated the ability to scavenge superoxide radicals and reduce inflammation. Furthermore, to suppress immune responses, we applied sialic acid-containing linear polyglycerol glycopolymers (LPG-Q-Sia3Lac) in mouse kidney transplantation. These glycopolymers demonstrated immunosuppressive properties, possibly by engaging immune inhibitory sialic-acid-binding immunoglobulin-like lectins found on immune cell surfaces.
Finally, the direct grafting of polysialic acid onto the glycocalyx through enzymatic polymerization is proposed as a promising cell surface engineering approach. Early in vitro studies involving endothelial cells and CAR T cells demonstrated immunomodulatory potential of this technique. These approaches serve to broaden the range of tools available for glycocalyx engineering to achieve immunomodulation locally. Consequently, new opportunities may emerge for the development of novel localized immunotherapies and the advancement of existing cell therapies.
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| Genre | |
| Type | |
| Language |
eng
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| Date Available |
2024-09-30
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| Provider |
Vancouver : University of British Columbia Library
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| Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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| DOI |
10.14288/1.0436945
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| URI | |
| Degree | |
| Program | |
| Affiliation | |
| Degree Grantor |
University of British Columbia
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| Graduation Date |
2023-11
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| Campus | |
| Scholarly Level |
Graduate
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| Rights URI | |
| Aggregated Source Repository |
DSpace
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Attribution-NonCommercial-NoDerivatives 4.0 International