Tumor Necrosis Factor-alpha (TNF-alpha) has been implicated as a mediator of inflammatory processes in IBD. A possible mechanism by which TNF-alpha generates this enhanced mucosal inflammation was suggested by studies in animals showing downregulation of mucosal Th1 cytokine production following anti-TNF-alpha treatment. The role of TNF-alpha as a mediator of immune function and mucosal inflammation in Crohn's disease has been demonstrated by dramatic clinical responses in a series of trials in which patients received a single infusion of anti-TNF-alpha monoclonal antibody. Follow-up evaluation of these patients demonstrated prolonged effects of the infusion with duration of response up to one year. This extended response is evident long after anti-TNF-alpha has cleared the body and suggests that the transient block of the direct, damaging effect of TNF-alpha is accompanied by a more sustained normalization of the characteristic exaggerated immune response. This concept is supported by parallel studies of patients responding to anti-TNF- alpha, in which mucosal Th1 cytokine responses in inflamed tissue were shown to be sequentially down-regulated to levels typical of uninvolved mucosa. These results demonstrate that TNF-alpha may mediate the enhanced mucosal Th1 cell production of IFN-gamma seen in Crohn's disease mucosa. It is likely that treatment with anti-TNF-alpha inhibits TNF-alphamediation of IFN-gamma production, resulting in a prolonged effect on mucosal inflammation in the majority of Crohn's patients. To begin to investigate the role of TNF-alpha in modulation of mucosal Th1 function, we have developed an in vitro system for Crohn's disease-like (Th1 phenotype) inflammation in lamina propria mononuclear cells, which we have used to demonstrate that prolonged exposure to TNF-alpha upregulates Th1 cytokine production. Preliminary data suggest that this upregulation requires the presence of non-T-cells and non-B-cells, and is IL- 12, IL-18, IL-4 and IL-10 independent. Multiple manipulations of peripheral blood cells to recreate this phenomenon have not been successful, suggesting that unique properties of the mucosal compartment may regulate the effects of TNF-alpha. To this end, co-culture of LPMC supernatants containing a heat soluble factor is capable of inducing PBMC to increase production of IFN-gamma in response to TNF-alpha. Our experimental system will further elucidate the mechanism(s) of TNF-alpha modulation of mucosal Th1 cell function. Furthermore, it will allow studies to define new targets for therapeutic approaches aimed at selectively downregulating the TNF-alpha mediated, enhancement of Th1 responses in Crohn's mucosa.
Showing the most recent 10 out of 37 publications
