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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056328-02
Application #
6178184
Study Section
Special Emphasis Panel (ZRG1-RAP (02))
Program Officer
Hamilton, Frank A
Project Start
1999-08-15
Project End
2004-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
2
Fiscal Year
2000
Total Cost
$266,473
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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