Multiple cell types are involved in the development and persistence of chronic inflammatory response. This also occurs in inflammatory bowel disease (IBD), where long-standing activation of immune and non-immune cells results in severe structural and functional abnormalities. Studies performed during the last funding period have defined the phenotypic and functional characteristics of two types of nonimmune intestinal cells, human intestinal microvascular endothelial cells (HIMEC) and intestinal fibroblasts (HIF), and assessed the interaction between these cells and mucosal T-cells. The results demonstrated that both HIMEC and HIF play an active role in immunity and inflammation through binding of T-cells and cytokine production. These observations strongly support the concept that immune-nonimmune cell interactions are critically involved in the pathogenesis and persistence of IBD. However, the interplay of cells in the mucosa needs to be better understood, particularly in regard to the mechanisms of recruitment of T-cells that stimulate local nonimmune cells. Cell-to-cell communication is controlled by a variety of chemotactic, adhesion and activation molecules that direct movement, contact and stimulation. This proposal will investigate the mechanisms regulating the recruitment of T-cells by HIMEC- and HIF-derived chemokines and the consequences of this effect. The expression of CD40L by activated T-cells and of its counter-receptor CD40 by nonimmune cells is an ideal system to study molecular mechanisms of cell interaction in an integrated fashion. Therefore, we will test the following central hypothesis: The CD40/CD40L system controls a self-perpetuating cycle of T-cell-nonimmune cell interactions that contribute to chronicity of IBD. This hypothesis will be tested by three specific aims: 1) Define the spectrum of T-cell chemokines produced by HIMEC and HIF; 2) Investigate T-cell chemotaxis in response to HIMEC- and HIF-derived chemokines; 3) Identify the receptor-ligand pairs and signaling pathways mediating T-cell-induced HIMEC and HIF chemokine production. Blockade of CD40 or CD40L may interrupt the chronic cycle of immune-nonimmune cell interactions occurring in IBD and result in clinical benefits, as suggested by animal models of autoimmunity and inflammation, including experimental IBD.
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