Uticaj sastava mikrobiote creva na imunomodulatorna svojstva i imunoterapijski potencijal dendritskih ćelija i supresorskih ćelija mijeloidnog porekla
Influence of intestinal microbiota composition on immunomodulatory properties and immunotherapeutic potential of dendritic cells and myeloid derived suppressor cells
Аутори
Radojević, DušanОстала ауторства
Đokić, JelenaBožić Nedeljković, Biljana
Tomić, Sergej
Markelić, Milica
Jovčić, Branko
Докторска теза (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
Transfer mijeloidnih ćelija imunogenih ili supresivnih svojstava, ima velikipotencijal u lečenju malignih tumora ali i autoimunskih bolesti. Međutim, nije do krajaispitana veza funkcijskog potencijala mijeloidnih ćelija i sastava mikrobiote creva, kaojednog od ključnih regulatora imunskog sistema. U ovoj tezi je po prvi put ispitivana vezaizmeđu sastava mikrobiote creva i funkcijskog potencijala mijeloidnih ćelija, i to humanihdendritskih ćelija (DC) i supresorskih ćelija mijeloidnog porekla (MDSC) in vitro, kao ipotencijal MDSC pacova da suprimiraju autoimunski proces u modelu eksperimentalnogautoimunskog encefalomijelitisa (EAE). Rezultati su pokazali da DC dobijene od zdravihdonora koji su imali veći diverzitet mikrobiote creva i veću zastupljenost bakterija kojeproizvode masne kiseline kratkog lanca (SCFA) poseduju slabiji imunogeni potencijal uodnosu na DC poreklom iz donora koji su imali manji diverzitet mikrobiote i većuzastupljenost rodova Bifidobacterium i Collinsella. U model...u humanih MDSC je pokazanoda poliamini mikrobiote potenciraju imunosupresivna svojstva MDSC posredstvomintestinalnih epitelnih ćelija. Takođe, transfer MDSC aktiviranih prostaglandinom E2(MDSC-PGE2) u ţivotinje sa indukovanim EAE, ublaţava simptome EAE nakon migracijeu limfni sistem creva. Fenomen ublaţavanja simptoma EAE nakon transfera MDSC-PGE2je bio povezan sa smanjenom infiltracijom proinflamatornih i povećanom infiltracijomregulatornih ćelija u CNS i slezinu, očuvanjem integriteta intestinalne barijere, diverzitetamikrobiote creva i povećanjem zastupljenosti bakterija koje ispoljavaju imunoregulatorneosobine, poliamina i SCFA u fecesu. Ovi rezultati ukazuju na blisku povezanost mikro-biote creva i imunogenosti/supresivnosti mijeloidnih ćelija, što moţe biti iskorišćeno urazvoju novih efikasnijih terapija za maligne tumore i autoimunske bolesti.
The transfer of myeloid cells with immunogenic or suppressive properties holdsgreat potential for the treatment of malignant tumors or autoimmune diseases,respectively. However, the relationship between the functional potential of myeloid cellsand the composition of the gut microbiota, one of the most important regulators of theimmune system, has not yet been elucidated. In this thesis, we investigated for the firsttime the relationship between the gut microbiota composition and the functional potentialof myeloid cells, in human dendritic cell (DC) and myeloid derived suppressor cells(MDSC) differentiated in vitro, and the potential of rat MDSCs to suppress theautoimmune response in experimental autoimmune encephalomyelitis (EAE) model invivo. The results showed that DCs from healthy donors with higher gut microbiotadiversity and higher abundance of short-chain fatty acid (SCFA)-producing bacteria havelower immunogenic potential, in contrast to DCs from donors with lower gut microbiota...diversity and higher abundance of Bifidobacterium and Collinsella genera. In the humanMDSC model, polyamines produced by the microbiota were shown to enhance theimmunosuppressive properties of MDSCs by intestinal epithelial cells. Also, transfer ofanimal MDSCs activated with prostaglandin E2 (MDSC-PGE2) into animals with inducedEAE alleviates EAE symptoms after migration to the intestinal lymphatic system. Thephenomenon of alleviation of EAE symptoms after MDSC-PGE2 transfer was associatedwith decreased infiltration of pro-inflammatory and increased infiltration of regulatorycells in the CNS and spleen, maintenance of intestinal barrier integrity, diversity of theintestinal microbiota, and an increase in the abundance of immunoregulatory bacteria,polyamines, and SCFA in the feces. These results suggest a strong association between thegut microbiota and the immunogenicity/suppressiveness of myeloid cells that can beexploited in the development of new, more effective therapies for malignancies andautoimmune diseases.
Кључне речи:
dendritske ćelije / dendritic cells / antitumor therapy / myeloid derived suppressor cells / autoimmune diseases / experimental autoimmune encephalomyelitis / gut microbiota / polyamines / short-chain fatty acids / antitumorska terapija / supresorske ćelije mijeloidnog porekla / autoimunske bolesti / eksperimentalni autoimunski encefalomijelitis / mikrobiota creva / poliamini / masne kiseline kratkog lancaИзвор:
Универзитет у Београду, 2023Издавач:
- Универзитет у Београду, Биолошки факултет
URI
https://uvidok.rcub.bg.ac.rs/bitstream/handle/123456789/5241/Referat.pdfhttps://eteze.bg.ac.rs/application/showtheses?thesesId=9215
https://fedorabg.bg.ac.rs/fedora/get/o:30638/bdef:Content/download
https://plus.cobiss.net/cobiss/sr/sr/bib/121604617
https://nardus.mpn.gov.rs/handle/123456789/21542
https://imagine.imgge.bg.ac.rs/handle/123456789/2116
Колекције
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - THES AU - Radojević, Dušan PY - 2023 UR - https://uvidok.rcub.bg.ac.rs/bitstream/handle/123456789/5241/Referat.pdf UR - https://eteze.bg.ac.rs/application/showtheses?thesesId=9215 UR - https://fedorabg.bg.ac.rs/fedora/get/o:30638/bdef:Content/download UR - https://plus.cobiss.net/cobiss/sr/sr/bib/121604617 UR - https://nardus.mpn.gov.rs/handle/123456789/21542 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/2116 AB - Transfer mijeloidnih ćelija imunogenih ili supresivnih svojstava, ima velikipotencijal u lečenju malignih tumora ali i autoimunskih bolesti. Međutim, nije do krajaispitana veza funkcijskog potencijala mijeloidnih ćelija i sastava mikrobiote creva, kaojednog od ključnih regulatora imunskog sistema. U ovoj tezi je po prvi put ispitivana vezaizmeđu sastava mikrobiote creva i funkcijskog potencijala mijeloidnih ćelija, i to humanihdendritskih ćelija (DC) i supresorskih ćelija mijeloidnog porekla (MDSC) in vitro, kao ipotencijal MDSC pacova da suprimiraju autoimunski proces u modelu eksperimentalnogautoimunskog encefalomijelitisa (EAE). Rezultati su pokazali da DC dobijene od zdravihdonora koji su imali veći diverzitet mikrobiote creva i veću zastupljenost bakterija kojeproizvode masne kiseline kratkog lanca (SCFA) poseduju slabiji imunogeni potencijal uodnosu na DC poreklom iz donora koji su imali manji diverzitet mikrobiote i većuzastupljenost rodova Bifidobacterium i Collinsella. U modelu humanih MDSC je pokazanoda poliamini mikrobiote potenciraju imunosupresivna svojstva MDSC posredstvomintestinalnih epitelnih ćelija. Takođe, transfer MDSC aktiviranih prostaglandinom E2(MDSC-PGE2) u ţivotinje sa indukovanim EAE, ublaţava simptome EAE nakon migracijeu limfni sistem creva. Fenomen ublaţavanja simptoma EAE nakon transfera MDSC-PGE2je bio povezan sa smanjenom infiltracijom proinflamatornih i povećanom infiltracijomregulatornih ćelija u CNS i slezinu, očuvanjem integriteta intestinalne barijere, diverzitetamikrobiote creva i povećanjem zastupljenosti bakterija koje ispoljavaju imunoregulatorneosobine, poliamina i SCFA u fecesu. Ovi rezultati ukazuju na blisku povezanost mikro-biote creva i imunogenosti/supresivnosti mijeloidnih ćelija, što moţe biti iskorišćeno urazvoju novih efikasnijih terapija za maligne tumore i autoimunske bolesti. AB - The transfer of myeloid cells with immunogenic or suppressive properties holdsgreat potential for the treatment of malignant tumors or autoimmune diseases,respectively. However, the relationship between the functional potential of myeloid cellsand the composition of the gut microbiota, one of the most important regulators of theimmune system, has not yet been elucidated. In this thesis, we investigated for the firsttime the relationship between the gut microbiota composition and the functional potentialof myeloid cells, in human dendritic cell (DC) and myeloid derived suppressor cells(MDSC) differentiated in vitro, and the potential of rat MDSCs to suppress theautoimmune response in experimental autoimmune encephalomyelitis (EAE) model invivo. The results showed that DCs from healthy donors with higher gut microbiotadiversity and higher abundance of short-chain fatty acid (SCFA)-producing bacteria havelower immunogenic potential, in contrast to DCs from donors with lower gut microbiotadiversity and higher abundance of Bifidobacterium and Collinsella genera. In the humanMDSC model, polyamines produced by the microbiota were shown to enhance theimmunosuppressive properties of MDSCs by intestinal epithelial cells. Also, transfer ofanimal MDSCs activated with prostaglandin E2 (MDSC-PGE2) into animals with inducedEAE alleviates EAE symptoms after migration to the intestinal lymphatic system. Thephenomenon of alleviation of EAE symptoms after MDSC-PGE2 transfer was associatedwith decreased infiltration of pro-inflammatory and increased infiltration of regulatorycells in the CNS and spleen, maintenance of intestinal barrier integrity, diversity of theintestinal microbiota, and an increase in the abundance of immunoregulatory bacteria,polyamines, and SCFA in the feces. These results suggest a strong association between thegut microbiota and the immunogenicity/suppressiveness of myeloid cells that can beexploited in the development of new, more effective therapies for malignancies andautoimmune diseases. PB - Универзитет у Београду, Биолошки факултет T2 - Универзитет у Београду T1 - Uticaj sastava mikrobiote creva na imunomodulatorna svojstva i imunoterapijski potencijal dendritskih ćelija i supresorskih ćelija mijeloidnog porekla UR - https://hdl.handle.net/21.15107/rcub_imagine_2116 ER -
@phdthesis{ author = "Radojević, Dušan", year = "2023", abstract = "Transfer mijeloidnih ćelija imunogenih ili supresivnih svojstava, ima velikipotencijal u lečenju malignih tumora ali i autoimunskih bolesti. Međutim, nije do krajaispitana veza funkcijskog potencijala mijeloidnih ćelija i sastava mikrobiote creva, kaojednog od ključnih regulatora imunskog sistema. U ovoj tezi je po prvi put ispitivana vezaizmeđu sastava mikrobiote creva i funkcijskog potencijala mijeloidnih ćelija, i to humanihdendritskih ćelija (DC) i supresorskih ćelija mijeloidnog porekla (MDSC) in vitro, kao ipotencijal MDSC pacova da suprimiraju autoimunski proces u modelu eksperimentalnogautoimunskog encefalomijelitisa (EAE). Rezultati su pokazali da DC dobijene od zdravihdonora koji su imali veći diverzitet mikrobiote creva i veću zastupljenost bakterija kojeproizvode masne kiseline kratkog lanca (SCFA) poseduju slabiji imunogeni potencijal uodnosu na DC poreklom iz donora koji su imali manji diverzitet mikrobiote i većuzastupljenost rodova Bifidobacterium i Collinsella. U modelu humanih MDSC je pokazanoda poliamini mikrobiote potenciraju imunosupresivna svojstva MDSC posredstvomintestinalnih epitelnih ćelija. Takođe, transfer MDSC aktiviranih prostaglandinom E2(MDSC-PGE2) u ţivotinje sa indukovanim EAE, ublaţava simptome EAE nakon migracijeu limfni sistem creva. Fenomen ublaţavanja simptoma EAE nakon transfera MDSC-PGE2je bio povezan sa smanjenom infiltracijom proinflamatornih i povećanom infiltracijomregulatornih ćelija u CNS i slezinu, očuvanjem integriteta intestinalne barijere, diverzitetamikrobiote creva i povećanjem zastupljenosti bakterija koje ispoljavaju imunoregulatorneosobine, poliamina i SCFA u fecesu. Ovi rezultati ukazuju na blisku povezanost mikro-biote creva i imunogenosti/supresivnosti mijeloidnih ćelija, što moţe biti iskorišćeno urazvoju novih efikasnijih terapija za maligne tumore i autoimunske bolesti., The transfer of myeloid cells with immunogenic or suppressive properties holdsgreat potential for the treatment of malignant tumors or autoimmune diseases,respectively. However, the relationship between the functional potential of myeloid cellsand the composition of the gut microbiota, one of the most important regulators of theimmune system, has not yet been elucidated. In this thesis, we investigated for the firsttime the relationship between the gut microbiota composition and the functional potentialof myeloid cells, in human dendritic cell (DC) and myeloid derived suppressor cells(MDSC) differentiated in vitro, and the potential of rat MDSCs to suppress theautoimmune response in experimental autoimmune encephalomyelitis (EAE) model invivo. The results showed that DCs from healthy donors with higher gut microbiotadiversity and higher abundance of short-chain fatty acid (SCFA)-producing bacteria havelower immunogenic potential, in contrast to DCs from donors with lower gut microbiotadiversity and higher abundance of Bifidobacterium and Collinsella genera. In the humanMDSC model, polyamines produced by the microbiota were shown to enhance theimmunosuppressive properties of MDSCs by intestinal epithelial cells. Also, transfer ofanimal MDSCs activated with prostaglandin E2 (MDSC-PGE2) into animals with inducedEAE alleviates EAE symptoms after migration to the intestinal lymphatic system. Thephenomenon of alleviation of EAE symptoms after MDSC-PGE2 transfer was associatedwith decreased infiltration of pro-inflammatory and increased infiltration of regulatorycells in the CNS and spleen, maintenance of intestinal barrier integrity, diversity of theintestinal microbiota, and an increase in the abundance of immunoregulatory bacteria,polyamines, and SCFA in the feces. These results suggest a strong association between thegut microbiota and the immunogenicity/suppressiveness of myeloid cells that can beexploited in the development of new, more effective therapies for malignancies andautoimmune diseases.", publisher = "Универзитет у Београду, Биолошки факултет", journal = "Универзитет у Београду", title = "Uticaj sastava mikrobiote creva na imunomodulatorna svojstva i imunoterapijski potencijal dendritskih ćelija i supresorskih ćelija mijeloidnog porekla", url = "https://hdl.handle.net/21.15107/rcub_imagine_2116" }
Radojević, D.. (2023). Uticaj sastava mikrobiote creva na imunomodulatorna svojstva i imunoterapijski potencijal dendritskih ćelija i supresorskih ćelija mijeloidnog porekla. in Универзитет у Београду Универзитет у Београду, Биолошки факултет.. https://hdl.handle.net/21.15107/rcub_imagine_2116
Radojević D. Uticaj sastava mikrobiote creva na imunomodulatorna svojstva i imunoterapijski potencijal dendritskih ćelija i supresorskih ćelija mijeloidnog porekla. in Универзитет у Београду. 2023;. https://hdl.handle.net/21.15107/rcub_imagine_2116 .
Radojević, Dušan, "Uticaj sastava mikrobiote creva na imunomodulatorna svojstva i imunoterapijski potencijal dendritskih ćelija i supresorskih ćelija mijeloidnog porekla" in Универзитет у Београду (2023), https://hdl.handle.net/21.15107/rcub_imagine_2116 .