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
Докторанд
Radojević, DušanМентор
Đokić, JelenaЧланови комисије
Božić Nedeljković, BiljanaTomić, Sergej
Markelić, Milica
Jovčić, Branko
Метаподаци
Приказ свих података о дисертацијиСажетак
Transfer mijeloidnih ćelija imunogenih ili supresivnih svojstava, ima veliki
potencijal u lečenju malignih tumora ali i autoimunskih bolesti. Međutim, nije do kraja
ispitana veza funkcijskog potencijala mijeloidnih ćelija i sastava mikrobiote creva, kao
jednog od ključnih regulatora imunskog sistema. U ovoj tezi je po prvi put ispitivana veza
između sastava mikrobiote creva i funkcijskog potencijala mijeloidnih ćelija, i to humanih
dendritskih ćelija (DC) i supresorskih ćelija mijeloidnog porekla (MDSC) in vitro, kao i
potencijal MDSC pacova da suprimiraju autoimunski proces u modelu eksperimentalnog
autoimunskog encefalomijelitisa (EAE). Rezultati su pokazali da DC dobijene od zdravih
donora koji su imali veći diverzitet mikrobiote creva i veću zastupljenost bakterija koje
proizvode masne kiseline kratkog lanca (SCFA) poseduju slabiji imunogeni potencijal u
odnosu na DC poreklom iz donora koji su imali manji diverzitet mikrobiote i veću
zastupljenost rodova Bifidobacterium i Collinsel...la. U modelu humanih MDSC je pokazano
da poliamini mikrobiote potenciraju imunosupresivna svojstva MDSC posredstvom
intestinalnih epitelnih ćelija. Takođe, transfer MDSC aktiviranih prostaglandinom E2
(MDSC-PGE2) u ţivotinje sa indukovanim EAE, ublaţava simptome EAE nakon migracije
u limfni sistem creva. Fenomen ublaţavanja simptoma EAE nakon transfera MDSC-PGE2
je bio povezan sa smanjenom infiltracijom proinflamatornih i povećanom infiltracijom
regulatornih ćelija u CNS i slezinu, očuvanjem integriteta intestinalne barijere, diverziteta
mikrobiote creva i povećanjem zastupljenosti bakterija koje ispoljavaju imunoregulatorne
osobine, poliamina i SCFA u fecesu. Ovi rezultati ukazuju na blisku povezanost mikro-
biote creva i imunogenosti/supresivnosti mijeloidnih ćelija, što moţe biti iskorišćeno u
razvoju novih efikasnijih terapija za maligne tumore i autoimunske bolesti.
The transfer of myeloid cells with immunogenic or suppressive properties holds
great potential for the treatment of malignant tumors or autoimmune diseases,
respectively. However, the relationship between the functional potential of myeloid cells
and the composition of the gut microbiota, one of the most important regulators of the
immune system, has not yet been elucidated. In this thesis, we investigated for the first
time the relationship between the gut microbiota composition and the functional potential
of myeloid cells, in human dendritic cell (DC) and myeloid derived suppressor cells
(MDSC) differentiated in vitro, and the potential of rat MDSCs to suppress the
autoimmune response in experimental autoimmune encephalomyelitis (EAE) model in
vivo. The results showed that DCs from healthy donors with higher gut microbiota
diversity and higher abundance of short-chain fatty acid (SCFA)-producing bacteria have
lower immunogenic potential, in contrast to DCs from donors with lower gut... microbiota
diversity and higher abundance of Bifidobacterium and Collinsella genera. In the human
MDSC model, polyamines produced by the microbiota were shown to enhance the
immunosuppressive properties of MDSCs by intestinal epithelial cells. Also, transfer of
animal MDSCs activated with prostaglandin E2 (MDSC-PGE2) into animals with induced
EAE alleviates EAE symptoms after migration to the intestinal lymphatic system. The
phenomenon of alleviation of EAE symptoms after MDSC-PGE2 transfer was associated
with decreased infiltration of pro-inflammatory and increased infiltration of regulatory
cells in the CNS and spleen, maintenance of intestinal barrier integrity, diversity of the
intestinal microbiota, and an increase in the abundance of immunoregulatory bacteria,
polyamines, and SCFA in the feces. These results suggest a strong association between the
gut microbiota and the immunogenicity/suppressiveness of myeloid cells that can be
exploited in the development of new, more effective therapies for malignancies and
autoimmune diseases.