Location: Immunity and Disease Prevention Research2009 Annual Report
1a. Objectives (from AD-416)
Objective 1: Conduct a controlled, vitamin D supplementation trial in volunteers with vitamin D insufficiency (VDI) to determine if supplementation to achieve the proposed level of >75 nmol/L for maintenance of bone health is also appropriate for maintenance of immune function. • Sub-objective 1A. Determine if supplements decrease the production of proinflammatory and increase the production of anti-inflammatory cytokines and chemokines by innate immune cells stimulated ex vivo. • Sub-objective 1B. Determine if supplements decrease serum markers of inflammation and autoimmune activity, and increase serum levels of defensive molecules. • Sub-objective 1C. Determine if supplements decrease blood levels of proinflammatory T-helper type 1 (Th1) and Th17 cells and increase levels of anti-inflammatory T-regulatory (Treg) and Th2 cells. Objective 2: Determine the impact of plant polyphenols and polyphenol-rich foods on immune cell function using cell culture systems, mouse models, and human volunteers. Examine anti-inflammatory and anti-cancer activities of polyphenols in animal models, as well as inflammation and oxidative damage in studies with human volunteers, including overweight/obese individuals. • Sub-objective 2A. Analyze the effects of polyphenol-rich foods and individual plant polyphenols on immune cell function in vivo and ex vivo. • Sub-objective 2B. Examine anti-inflammatory activities of polyphenol-rich foods, individual plant polyphenols and vitamin A in mice and humans who are at risk for developing inflammatory disease, such as autoimmune mice and obese humans. • Sub-objective 2C. Evaluate the anti-cancer activity of polyphenol-rich foods and individual plant polyphenols. Objective 3: Examine the absorption of '-cryptoxanthin (CX) from supplements and foods, its contribution to vitamin A stores, and the impact of CX, other carotenoids and vitamin A on immune function. • Sub-objective 3A. Measure the absorption and metabolism of CX from Satsuma mandarin juice fed to healthy adult humans. • Sub-objective 3B. Estimate the impact of daily consumption of food sources of CX or '-carotene (BC) on plasma and breast milk concentrations of CX, BC and retinol in lactating women. • Sub-objective 3C. Determine the impact of CX on immune and bone marker status in the Mongolian gerbil. Objective 4: Determine if high-level vitamin A intake is associated with higher Th2 and Treg responses and lower Th1 and Th17 responses relative to adequate and deficient intake. • Sub-objective 4A. Using dietary and targeted gene disruption approaches in mice, determine if vitamin A enhances Th2 and Treg responses by acting directly on T cells. • Sub-objective 4B. Using subjects recruited in the vitamin D supplementation trial described under Objective 1, determine if vitamin A status is associated with higher blood levels of NK, NK-T, Th2 and Treg cells, and lower levels of Th1 and Th17 cells.
1b. Approach (from AD-416)
The impact of vitamins A and D, and plant polyphenols, on immune function will be examined using cell culture systems, mouse models, and human intervention trials. The anti-cancer activities of polyphenols will be examined in animal models. Absorption of beta-cryptoxanthin will be examined in gerbils and humans. Replacing 5306-51530-013-00D (1/09).
3. Progress Report
Subobjectives 1A-C: We have submitted an application to the human subjects review committee and are implementing new lab methods to be used for the pilot phase of this study. Subobjective 2A: The California Table Grape Commission awarded a grant for a human study to understand the anti-inflammatory role of grape powder in human volunteers at risk for developing cardiovascular disease. The agreement has been signed and transfer of funds to the USDA is in progress. Subobjective 2B: This human study to examine the anti-inflammatory effects of strawberries in obese individuals has been completed. Laboratory work and data analysis are in progress. Subobjective 2C: The signal transduction pathways for the phytochemical parthenolide (from the herb feverfew) has been analyzed in leukemia cells to determine the mechanism by which parthenolide induces cell death. Immunodeficient mice were used to study whether resveratrol or curcumin can kill leukemia. The leukemia was allowed to grow in immunodeficient NOD/SCID mice and resveratrol or curcumin was injected intraperitoneally every other day until the mice succumbed to the disease. Survival curves were compared between mice receiving the resveratrol, curcumin, the chemotherapeutic agent vincristine, or control solution. Lab work and data analysis are in progress. Subobjective 3A: Funds are not available for human study. A study on CX metabolism and vitamin A formation in gerbils was conducted and data is being analyzed that will lead to information that will decrease time and costs of the human study, possibly making it feasible. Subobjective 3B: Progress is described under number 7, International Cooperation. Subobjective 3C: Results from gerbil metabolism study are being analyzed and will be used to plan gerbil intervention study on immune response and bone metabolism. Subobjective 4A: This aim is not currently being pursued due to insufficient funds. Producing transgenic mice from the Rara targeting construct we have produced will require extramural funds, for which we have submitted an extramural grant proposal. Subobjective 4B: We have applied for extramural funds to pursue this aim using a revised approach involving comparison of continuous low-dose vitamin A supplements vs. high-dose supplements to increase liver stores that will not be feasible with subjects recruited under Subobjective 1.
1. Bioactive compound from the herb Feverfew active against leukemia cells in culture. Herbs, spices and other food components are thought to have health-promoting activities but many of the effects of these compounds have never been characterized at the biochemical level. Parthenolide, an active component in the medicinal herb feverfew, induces apoptotic cell death in high-risk leukemia cells, but has little toxicity against normal cells, which makes it a good candidate to prevent or treat cancer. ARS researchers in the Immunity and Disease Prevention Management Unit at the Western Human Nutrition Research Center in Davis, CA conducted experiments to characterize the effect of this compound on cancer cells. The study found that parthenolide is a potent activator of proteins involved in the stress signaling pathway in leukemia cells that leads to cell death. These results may indicate a preventive role for parthenolide against high-risk leukemia and warrant further investigations of the anti-leukemia activity of this phytochemical.