Uticaj sastava mikrobiote creva na imunomodulatorna svojstva i imunoterapijski potencijal dendritskih ćelija i supresorskih ćelija mijeloidnog porekla

Abstract

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 Collinsella. 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.