Objective:
The long-term goal of our research is to define the mechanisms by which micronutrients, particularly vitamin A and selected antioxidants, regulate immune function and inflammation. Vitamin A deficiency impairs immune function and increases the risk of disease, while moderate excesses in vitamin A intake may increase the risk of asthma. These risks cannot be adequately assessed without understanding the cellular and molecular mechanisms underlying the actions of vitamin A on immune function. Our specific objective is to define the effects of vitamin A on T-cell development of mice and to determine if men with marginal but 'adequate' vitamin A stores have impaired immune function. An additional goal is to determine how disruption of specific vitamin A receptors (RXR and RAR) affects T cell development. Since recent data indicate that unsaturated fatty acids may act via the RXR pathway the effect of dietary fat on RXR-mediated T cell development may also be investigated. Although many food-derived antioxidants have shown anti-cancer, anti-inflammatory, and anti-atherosclerotic activities, very few detailed studies of their beneficial or detrimental effects on the immune response have been performed. The specific goals here will be to understand how antioxidants found in foods may regulate lymphocyte activities and the immune response in general, and to define appropriate dietary intake levels of foods containing high concentrations of these antioxidants that would contribute to the production of a healthy immune system. Furthermore, the anti-inflammatory activity of these antioxidants will be analyzed to ascertain whether they may be useful in managing chronic inflammatory autoimmune disorders, such as autoimmune diabetes and multiple sclerosis.

Approach:
For the investigation of vitamin A in T-cell development, we will use cellular, molecular, and transgenic animal techniques to conduct these studies in vitro and in vivo using DO11.10 T-cell receptor transgenic mice and mice in which RXR has been disrupted in T cells. For the human studies, we will use stable isotope dilution methods to assess whole body vitamin A stores as well as a variety of immunologic methods to measure the number and function of T cells, B cells, monocytes, neutrophils, and NK cells in the peripheral blood of human volunteers. The human studies will be conducted at the International Centre for Diarrhoeal Disease Research, Bangladesh. To study the effects of antioxidants on immune function, several parameters of the immune response will be evaluated, including lymphocyte subset profiling, regulation of cytokine expression, whether apoptosis or growth arrest is induced, and changes in cytolytic function. Adverse and/or advantageous actions of these antioxidants on the immune system will be analyzed utilizing mice, by using immune cells isolated from the blood of healthy volunteers, and by evaluating immune responses in volunteers who have added defined levels of antioxidants to their diet. Anti-inflammatory activity of food-derived antioxidants in autoimmune diseases, such as type I diabetes and multiples sclerosis, will be initially conducted in non-obese diabetic (NOD) mouse and experimental allergic encephalitis mouse models, respectively, and may lead to future applications in humans with these diseases.