P094 Strain dependent difference in the progression of dextran sulphate sodium induced colitis is a consequence of the cross-talk between colon-infiltrating dendritic cells and T regulatory cells

Abstract

Dextran sulphate sodium (DSS) causes colon inflammation in C57BL6 mice (Th1 strain), while BALBc mice (Th2 strain) are relatively resistant to DSS-induced injury. The main aim of this study was to evaluate molecular mechanisms responsible for different progression of colitis in Th1 and Th2-dominant mouse strains. DSS (3%, molecular weight 40 kDa) was given to C57BL/6 and BALBc mice in place of normal drinking water for 5 days, followed by 5 days of recovery period. Disease Activity Index (weight loss, stool consistency, visible blood in faeces) and histology score (sum of “infiltration” and “damage of epithelium” sub-scores) were used to assess the severity of colitis. The phenotype of colon-infiltrated immune cells was determined by flow cytometry. BALBc mice developed less aggressive colitis then C57BL/6 mice. DSS-treated BALBc mice did not develop diarrhoea, gross rectal bleeding, and significant body weight loss. Level of pro-inflammatory cytokines (IL-12 and IL-1β) was significantly lower, while concentration of anti-inflammatory IL-10 was higher in sera of DSS-treated BALBc mice. The total number of IFN-γ and IL-17-producing T cells was lower in colons of DSS-treated BALBc mice. On contrary, there was significantly higher number of IL-4 and IL-10-producing T cells, as well as CD4+FoxP3+ T regulatory cells (Tregs) in colons of BALBc DSS-treated animals. Significantly lower number of IL-12 and IL-1β producing colon-infiltrating CD45+CD11c+ dendritic cells (DCs) and significantly higher number of IL-10 producing DCs was observed in DSS-treated BALBc mice. Lipopolysaccharide stimulated DCs, isolated from BALBc mice, produced lower amounts of IL-12 and expressed lower amounts of CD40, but express significantly higher amount of immunosuppressive Indoleamine 2,3-dioxygenase (IDO) when compared with similarly activated DCs isolated from C57BL/6 animals. Depletion of Tregs significantly aggravates clinical and histological symptoms of DSS-induced colitis in BALBc mice. Interestingly, transfer of DCs in Treg-depleted mice managed to recover Tregs number that resulted with the attenuation of colitis. This phenomenon was completely abrogated in the presence of IDO inhibitor, suggesting the importance of IDO for DC:Treg crosstalk in injured colons. Strain dependent difference in the progression of DSS-induced colitis is a consequence of the cross-talk between colon-infiltrating DCs and T regs.