Inflammatory bowel diseases (IBD) are chronic relapsing inflammatory conditions;the factors involved in their pathogenesis include the genetic background of patients, the effect of commensal or pathogenic bacteria in the gut, and abnormal activation of innate and adaptive immune responses. Dendritic cells (DCs) appear to play a role in modulating both the innate and adaptive immune response. DCs from the lamina propia of the intestines recognize and respond to bacterial components using pattern recognition receptors, such as Toll-like receptors (TLRs). TLRs sense a distinct repertoire of conserved microbial components, so that collectively, they can detect most microbes. TLRs are activated by specific components of microbes, such as: FMLP, LPS, PG-PS, lipoteicoic acid and certain host molecules. Once TLRs on DCs recognize bacterial components, DCs act as antigen presenting cells (APC), which are critical mediators of T cell activation. Previous studies have shown that T-cell resistance against apoptosis contributes to inappropriate T-cell accumulation and the perpetuation of chronic mucosal inflammation in inflammatory bowel diseases (IBDs). FasL and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) belong to a subgroup of the TNF superfamily which induces apoptosis by binding to their death domain containing receptors. Apoptosis-inducing ligands such as FasL and TRAIL have been found to play an important role in cell regulation. FasL is a type II transmembrane protein that belongs to the tumor necrosis factor family and is expressed in activated splenocytes and thymocytes, consistent with its involvement in T-cell-mediated responses. Recent data indicate that TRAIL may also induce apoptosis in various tissue cells and leukocytes. The central hypothesis of this proposal is that inducing the apoptosis of active CD4 T cells, mediated by the expression of FASL and TRAIL on DCs, will have a therapeutic effect against the characteristic inflammation that occurs during chronic IBD.
The specific aims of this proposal are to1) examine in vitro the interaction of T cells with DCs as an APC 2) to examine in vitro the effect of the apoptosis of active CD4 T-cells mediated by the expression of FASL and TRAIL on DCs 3) determine the effect of the apoptosis of active CD4 T-cells mediated by the expression of FASL and TRAIL in DCs during colitis. These studies will contribute to our understanding of the immune mechanisms that occur in colitis and to the possibility of using ex vivo-generated DCs as therapeutic tools for restoring intestinal immunity in the future.
| de Jesus, Edelmarie Rivera; Isidro, Raymond A; Cruz, Myrella L et al. (2016) Adoptive Transfer of Dendritic Cells Expressing Fas Ligand Modulates Intestinal Inflammation in a Model of Inflammatory Bowel Disease. J Clin Cell Immunol 7: |
