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Engineering a Novel Cell-Based Vaccine Using Immunoproteasome-Expressing Mesenchymal Stromal Cells.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Engineering a Novel Cell-Based Vaccine Using Immunoproteasome-Expressing Mesenchymal Stromal Cells./
作者:	Abusarah, Jamilah.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	208 p.
附註:	Source: Dissertations Abstracts International, Volume: 82-10, Section: B.
Contained By:	Dissertations Abstracts International82-10B.
標題:	Prostate. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28383952
ISBN:	9798708718013

Engineering a Novel Cell-Based Vaccine Using Immunoproteasome-Expressing Mesenchymal Stromal Cells.
Abusarah, Jamilah.

Engineering a Novel Cell-Based Vaccine Using Immunoproteasome-Expressing Mesenchymal Stromal Cells. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 208 p.

Source: Dissertations Abstracts International, Volume: 82-10, Section: B.

Thesis (Ph.D.)--McGill University (Canada), 2020.

This item must not be sold to any third party vendors.

Vaccination remains one of the most successful approaches in preventing and controlling several infectious diseases. This led to the recent concept of exploiting vaccination in the field of cancer immunotherapy to generate protective immune responses. Accordingly, engineering new vaccines capable of eliciting effective and suitable immune responses for different applications is an ongoing quest. Besides the commonly used dendritic cells (DCs), bone marrow-derived mesenchymal stromal cells (MSCs) have been also evaluated as cell-based vaccines due to the discovery of their antigen presentation properties upon interferon-gamma (IFNγ) priming. This approach is however limited as change in the dose and duration of IFNγ treatment can trigger opposing immunosuppressive properties in primed MSCs. To bypass this limitation, MSCs were gene-engineered to overexpress the immunoproteasome (IPr) subunits. These modified MSCs (MSC-IPr) not only exhibited stable antigen cross-presenting properties, but they were also capable of eliciting antigen-specific immune responses when used as prophylactic and therapeutic cancer vaccines and a significant protective effect as an anti-leishmania vaccine.Further genomic and proteomic analyses comparing wild-type (Ctrl) MSCs to MSC-IPr revealed distinct changes. More specifically, MSC-IPr exhibited unique secreatome and metabolic signatures including the activation of oxidative phosphorylation and increased production of reactive oxidative species (ROS) by the mitochondria. Treatment of MSC-IPr with various antioxidants and pharmacological inhibitors revealed an important role for ROS and lipid peroxidation in supporting antigen cross-presentation. For instance, the endosomal pH in MSC-IPr is more basic suggesting a beneficial role played by ROS in protecting captured antigen from non-specific degradation normally caused by the maturing intra-endosomal acidic environment. In sum, our results indicate that overexpression of the IPr subunits not only instills stable antigen presentation functions in MSCs, but also impacts on several cellular processes which are believed to be essential for their antigen cross-presentation properties. Closer analysis and elucidation of the role of metabolic activity in MSC-IPr will provide new tools to enhance, optimize and improve their antigen presentation properties and to thoroughly exploit them as propitious candidates for vaccine development.

ISBN: 9798708718013Subjects--Topical Terms:

794571
Prostate.
Subjects--Index Terms:

Cell-based vaccine

Engineering a Novel Cell-Based Vaccine Using Immunoproteasome-Expressing Mesenchymal Stromal Cells.
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500 $a Source: Dissertations Abstracts International, Volume: 82-10, Section: B.
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520 $a Vaccination remains one of the most successful approaches in preventing and controlling several infectious diseases. This led to the recent concept of exploiting vaccination in the field of cancer immunotherapy to generate protective immune responses. Accordingly, engineering new vaccines capable of eliciting effective and suitable immune responses for different applications is an ongoing quest. Besides the commonly used dendritic cells (DCs), bone marrow-derived mesenchymal stromal cells (MSCs) have been also evaluated as cell-based vaccines due to the discovery of their antigen presentation properties upon interferon-gamma (IFNγ) priming. This approach is however limited as change in the dose and duration of IFNγ treatment can trigger opposing immunosuppressive properties in primed MSCs. To bypass this limitation, MSCs were gene-engineered to overexpress the immunoproteasome (IPr) subunits. These modified MSCs (MSC-IPr) not only exhibited stable antigen cross-presenting properties, but they were also capable of eliciting antigen-specific immune responses when used as prophylactic and therapeutic cancer vaccines and a significant protective effect as an anti-leishmania vaccine.Further genomic and proteomic analyses comparing wild-type (Ctrl) MSCs to MSC-IPr revealed distinct changes. More specifically, MSC-IPr exhibited unique secreatome and metabolic signatures including the activation of oxidative phosphorylation and increased production of reactive oxidative species (ROS) by the mitochondria. Treatment of MSC-IPr with various antioxidants and pharmacological inhibitors revealed an important role for ROS and lipid peroxidation in supporting antigen cross-presentation. For instance, the endosomal pH in MSC-IPr is more basic suggesting a beneficial role played by ROS in protecting captured antigen from non-specific degradation normally caused by the maturing intra-endosomal acidic environment. In sum, our results indicate that overexpression of the IPr subunits not only instills stable antigen presentation functions in MSCs, but also impacts on several cellular processes which are believed to be essential for their antigen cross-presentation properties. Closer analysis and elucidation of the role of metabolic activity in MSC-IPr will provide new tools to enhance, optimize and improve their antigen presentation properties and to thoroughly exploit them as propitious candidates for vaccine development.
520 $a La vaccination reste l'une des meilleures solutions pour prevenir et controler les maladies infectieuses. Base sur ce succes, une variete de vaccins experimentales a ete developpe comme une forme d'immunotherapie contre le cancer dont le but est d'induire une reponse immunitaire protective.En plus des cellules dendritiques couramment utilisees dans le domaine de la vaccination, les cellules stromales mesenchymateuses derivees de la moelle osseuse (MSCs) sont encore evaluees comme outil pour la vaccination cellulaire en se basant sur la decouverte de leurs proprietes antigeniques lors de leur traitement a l'interferon-gamma (IFNγ). Mais ceci est limitee par la dose et de la duree du traitement avec l'IFNγ qui peut d'ailleurs declencher des proprietes immunosuppressives par les MSCs.Afin de surmonter ce probleme, des MSCs genetiquement modifies en exprimant les sous-unites de l'immunoproteasome (IPr) ont ete genere. Ces cellules modifiees (MSC-IPr) ne possedent pas seulement des proprietes antigeniques stables, mais sont aussi capables d'induire des reponses immunitaires specifiques lors de leurs utilisations comme vaccins prophylactiques et therapeutiques contre le cancer et la leishmania.Des analyses genomiques et proteomiques comparant les MSCs controles (Ctrl MSCs) et les MSC-IPr ont montre des changements distincts entre les deux types de cellules. Plus specifiquement, les cellules MSC-IPr possedent un secretome unique et des reactions metaboliques specifiques incluant l'activation de la phosphorylation oxydative et l'augmentation de la production des especes reactives de l'oxygene (ROS) par la mitochondrie. Le traitement de MSC-IPr avec une large variete d'antioxydants et d'inhibiteurs pharmacologiques a revele le role important des ROS dans le soutien de la presentation croisee d'antigenes. De plus, le pH endosomique des MSC-IPr est plus basiques suggerant que les ROS jouent un role positif dans la protection des antigenes captures des degradations non-specifiques causees normalement par l'environnement acidique dans l'endosome mature.En resume, nos resultats indiquent que la surexpression des sous-unites IPr n'a pas seulement creer des fonctions antigeniques stables dans les MSCs, mais a revele en plus leurs effets sur plusieurs processus cellulaires essentiels pour les proprietes de la presentation croisee d'antigenes. Des analyses plus detaillees pour mieux comprendre le role de l'activite metabolique dans les MSC-IPr pourraient donner des nouveaux outils afin d'ameliorer et optimiser les proprietes de presentation d'antigenes et de les exploiter dans le developpement de futurs autres vaccins.
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