Evaluation of the Effect of Green Tea Polyphenols on IBD

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DESCRIPTION (provided by applicant): Interest in green tea as an agent for improving health and treating disease has increased in both the lay and scientific literature. Green tea consists of several components, with most research focusing on the polyphenol fraction. The green tea polyphenols (GrTP) include (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)- epicatechin-3-gatlate (ECG), and (-)-epigallocatechin-3-gallate (EGCG). Of these, EGCG accounts for greater than 40% of the total polyphenol content. Therapeutic and prophylactic benefits have been attributed to the potent anti-oxidant effects of the polyphenols, including reducing the risk of cancer. GrTP also have potent anti-inflammatory properties. GrTP have proven to be potent inhibitors of nuclear factor-kappa B (NF-kB), a key regutatory factor in the control of intestinal inflammation. Activation of NF-kB can be induced by a variety of stimulatory factors, such as the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-a) or interleukin-1 (IL-1), bacterial endotoxin, or oxidative stress. In unstimulated cells, NF-kB exists as a heterodimer comprised of p65 and p50 subunits, bound to a member of the inhibitor-kB (IkB) family of inhibitory proteins. NF-kB activators induce degradation of IkB by the 26s proteosome, by phosphorylation of two serines in the N-terminal regulatory domain of IkB by IkB kinase (IKK). The liberated NF-kB translocates to the nucleus, binds specific promoter sequences, and induces expression of proinflammatory cytokines. These cytokines are expressed at high levels in chronic inflammatory bowel disease (IBD). IL-1 and TNF-a also activate NF-kB in a positive regulatory loop. This may lead to amplification of the inflammatory response. NF-kB appears to play a significant role in inflammation, and is a likely target for anti-inflammatory therapies. Animal models of inflammation improved with GrTP administration. The scientific portion of this proposal intends to evaluate the use of GrTP in humans. Specific aim 1 will confirm that GrTP inhibit NF-kB activation in human peripheral blood monocytes. Specific aim 2 will evaluate the safety and tolerability of GrTP in volunteers with quiescent IBD, while defining the pharmacokinetics and pharmacodynamics of GrTP. Specific aim 3 will further evaluate the safety of GrTP in subjects with IBD, while providing preliminary data on the efficacy of this therapy in patients with active ulcerative colitis.