Constant exposure to antigens, food, commensal and pathogenic bacteria and viruses, in the mucosa necessitates a finely tuned balance between tolerance to inert antigens and controlled inflammation in response to pathogens. Disruption of this finely tuned homeostatic balance results in mucosal inflammation and disease such as Crohn's disease. This grant proposes to study the mucosal microenvironment, derived from a culture of a-cellular stroma in vitro, which allow extracellular matrix (stoma) associated molecules to be released into the supernatant, from normal mucosa and inflamed Crohn's mucosa. Stromal-associated factor regulation of T-cell proliferation and cytokine production will be studied to determine whether (1) (a) normal stromal factors down-regulate these T-cell functions and (b) the mechanisms by which this occurs;and (2) (a) stromal-factors derived from Crohn's mucosa permit T-cell responses, (b) the cytokines, and source of these cytokines responsible for permitting T-cell responses and (c) the mechanism by which these T-cell responses are promoted/resist normal down-regulation.
Crohn's disease is a T-cell-medicated auto- immune disease. By understanding mechanisms of T-cell regulation in normal mucosa as well as factors promoting T-cell responses in inflamed Crohn's disease mucosa, we will be poised to aid in the development of new biologic drug therapies.
|Huff, K R; Akhtar, L N; Fox, A L et al. (2011) Extracellular matrix-associated cytokines regulate CD4+ effector T-cell responses in the human intestinal mucosa. Mucosal Immunol 4:420-7|