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P037. Neutralization of CTLA-4 alleviates murine DSS-induced colitis through changing Th17-Treg profile

B. Xia, S. Huang, Zhongnan Hospital of Wuhan University School of Medicine, Department of Gastroenterology, Wuhan, China

Background

As a pivotal co-suppressive molecular in T cell activation, cytoxic T lymphocyte associated antigen-4 (CTLA-4) participates in peripheral tolerance and protection against autoimmunity. This study was aimed to investigate the influence of anti-mouse CTLA-4 monoclonal antibodies (anti-CTLA-4) on the immune response of murine model of ulcerative colitis.

Methods

Mice entering this study were separated randomly into three groups: the Mab group, the Control group and the Normal group. 3% Dextran sulfate sodium (DSS) solution was supplied for both group Mab and Control to induce acute colitis, and sterilized water was offered for group Normal. Group Mab were injected intraperitoneally with anti-CTLA-4 per day after the beginning of the study. As control, group Control was administrated with isotype of anti-CTLA-4 in the same way.

Results

Compared with group Control, mice in group Mab showed amelioration of colitis with lower disease activity index, MPO activity and histological scores of colonic tissue as well as less shortened length of colon (p < 0.05, respectively) (Figure 1); Th17 cells decreased (p = 0.029) and Treg cells increased in mesenteric lymph node (p = 0.006) (Figure 2). Protein expression of JAK-2, RORγt and IL-17A was reduced but level of STAT-3, phosphorylated STAT-3 and Foxp3 was up-regulated (p < 0.05, respectively).

Figure 1. After induction of colitis, disease activity index (DAI) was evaluated (b), H&E stained sections of colon was pictured (a), histological analysis was made (d) and MPO activity was detected (c). Colon length was examined (e and f).

Figure 2. The results of CD3+CD8−IL-17A+ and CD4+Foxp3+ cells in mesenteric lymph node examined by flow cytometry was shown (a), and the percentage of them was compared in colitis with or without anti-CTLA-4 treating (b).

Conclusion

Blocking CTLA-4 function with anti-CTLA-4 alleviated DSS-induced colitis in mice through changing the immune responses of Th17-Treg profile, which suggests anti-CTLA-4 as a potential therapeutic method for the therapy of ulcerative colitis.