Functional analysis of the immune modulator sCD83 in pathogenesis and therapy of inflammatory bowel diseases

点击翻译按钮获取中文摘要

Within this project we pursue the following 3 major aims: Aim 1: In our recent work, we could show that sCD83 is able to prophylactically prevent the development of acute inflammation in the murine DNBS colitis model. However, the DNBS-colitis model cannot recapitulate all features of human IBD. Thus, for the future clinical development of sCD83 it is absolutely vital to show its efficacy in different colitis models. Therefore we will analyze the therapeutic effects of sCD83 using the Oxazolone model. Aim 2: Regulatory T cells are crucial players in order to maintain immune homeostasis and to establish tolerance to commensal bacteria and food in the intestine. Thus, targeting / modulation of Tregs represent new and very promising strategies to modulate pathogenic immune responses in IBD patients. Previously we could show that on murine as well as on human Tregs CD83 expression is highly and rapidly upregulated after activation. However, the precise functional role of CD83 on Tregs is still completely unknown. In order to gain further insights, we generated conditional KO mice, whereby CD83 expression is specifically deleted on FoxP3 positive regulatory T cells. With the help of these animals we can now decipher the functional role of CD83 on Tregs in vitro as well as in vivo. For in vivo investigations we will use the adoptive transfer colitis model which is the best animal model to study the function of regulators T cells in colitis. Aim 3: It has been suggested that the innate lymphoid cells, that release high amounts of chemokines and cytokines upon activation, are important for regulatory and inflammatory immune responses in the mucosa of the GI tract. ILCs can be divided into three groups (1 ILC, 2 ILC and 3 ILC). Group 1 ILCs produce IFN-g and express T-bet (ILC1) or T-bet and Eomes (NK cells); group 2 ILCs include the signature transcription factors RORa and GATA3 and release IL-5 and IL-13; and all three group 3 ILCs are directed by RORgt: Lymphoid tissue-inducer (LTi) cells require the aryl hydrocarbon receptor (Ahr) and release IL-17 and IL-22, while NK cell receptor-positive ILC3s require Ahr and T-bet producing IL-12, IL-22 and IFN-g. IL-17, IL-22 and IFN-g producing NK cell receptor-negative ILC3s depend on RORgt and T-bet. While group 3 ILC cells protected from intestinal pathology, group 1 ILC subsets promote mucosal damage. The functional role of group 2 ILCs in the context of IBD is not fully understood. Here, we will investigate if sCD83 influences intestinal innate lymphoid cells (numbers and function) in the GI tract using the adoptive transfer colitis model in Rag1 negative mice.