1a. Objectives (from AD-416)
1. Determine the effect and mechanisms of food components and their interaction with age on immune function and infectious diseases. a) Determine the mechanisms of Vitamin E-induced enhancement of T cell function in the aged with focus on early activation signaling and membrane related events. b) Determine the contribution of polymorphisms at cytokine genes to heterogeneity of vitamin E-induced effects on cytokine production and resistance to respiratory infections. 2. Determine the effect of reducing caloric intake on the immune response of humans. 3. Determine the effect and mechanisms of food components and their interaction with age on immune function and infectious diseases.
1b. Approach (from AD-416)
T cell function declines with age resulting in higher incidence of infections in the elderly. We showed that vitamin E (E) supplementation enhances T cell function in the aged. In Objective 1-A, we will test the hypothesis that T cell receptor (TCR)-induced signalosomes(combination of protein and lipids that are formed at the site of T cell and antigen presenting cells) exhibit age- and vitamin E (E)-related differences in their patterns of protein and lipid recruitment. We will identify qualitative and quantitative age- and E-related differences in the protein and lipid composition of signalosomes using an enhanced magnetic immunoisolation procedure and highly sensitive and quantitative proteomics and lipidomics methods. In objective 1-B, we will test the hypothesis that higher frequencies of specific cytokine polymorphisms contribute to incidence and severity of respiratory infection (RI) in the aged and that the effect of E on RI is dependent on cytokine genotype. This will be tested using data and DNA samples collected from a 1-year randomized, doubleblind, controlled (RTC) study of E supplementation in elderly. In Objective 2 we will test the hypothesis that a long- term calorie restriction (CR) intervention in humans will enhance T cell-mediated function and that the CR- mediated effect is due to intrinsic changes in T cells and/or a reduction in prostaglandin PGE2 production. This hypothesis will be tested utilizing subjects enrolled in the NIA- supported multi-center RTC, CALERIE Phase 2 and determining the effect of CR on T cell subsets proliferation, and intra- and extra-cellular cytokine, and PGE2 levels before, and following 1 and 2 years of 25% CR. These studies will help develop effective strategies to improve the immune response in the elderly.
3. Progress Report
Aging is associated with impaired function of T cells, key immune cells involved in fight against pathogens. The underlying mechanisms are not well known. We showed, using novel techniques to separate T cell membrane fractions known as lipid rafts, and mass-spectometry that changes in a glycosylceramides play a key role in age-asociated defects of the T cells. These results identify new targets for intervention strategies to alleviate age-related defects in T cells and resistance to infection in elderly. In the ongoing study to determine the effect of two years of calorie restriction (CR) on immune response in humans, we have completed sample collection for all three phases (baseline, y 1, & y 2) for 8, and two phases (baseline and 1) for 32 subjects. Data analyses from 24 subjects have been completed and submitted to our collaborators at Duke Univ. When completed, this work will generate the first data on long-term impact of CR on the human immune response. We previously showed that mice fed white button mushrooms (WBM) had better immune functions than control mice. Thus, we tested if WBM could afford a protection against influenza infection. We demonstrated that although WBM was able to enhance certain innate immune function, it did not provided the mice with protection against influenza infection, which may be due to the inability of WBM to enhanced specific anti-influenza immune response. Wolfberry (WB) has recently been shown to improve immune response. We determined whether WB can increase the host resistance to infection by enhancing immune response in an influenza infection animal model. We found that WB prevented infection-induced weight loss and reduced lung pathology due to influenza infection. We demonstrated that these effects of WB were due to increases in production of T cell growth factor IL-2 and proliferation of T cells as well as lowering of pro-inflammatory molecules that cause pathological symptom and weight loss following influenza infection. These results identify WB as a potential dietary intervention to improve resistance to influenza infection. Obesity in pregnancy is associated with an increase in infectious morbidity intra- amniotic, and wound infections. Increased infection rates may result from a difference in T cell sub population or function. Furthermore, these effects have been indicated to have life-long effects on the immune system of the fetus. We determine if obesity in pregnancy alters T cell composition or function. We found that obese women had fewer T cells of the kind involved in resistance to infection compared to lean controls . In addition, obese pregnant women had impaired T cell function as measured by their ability to proliferate in response to external stimuli such as those encountered during infection. These differences in the immune response of obese and lean pregnant women may explain the increase in infectious morbidity in obese pregnancy and have implications for fetal health and diseases in later life.