The molecular mechanism of age and vitamin E-induced change in immune response. Aging is associated with decline in T cell mediated function, which pre-disposes the elderly to higher incidence of infectious diseases and cancer. The age-related defect in T cells has been shown to be due to intrinsic declines in T cell function as well as increased production of prostaglandin (PG)E2 , a T cell suppressive factor, in macrophages. We demonstrated that the increased PGE2 production was due to ceramide mediated upregulation of cyclooxygenase 2 (COX-2) transcription, a key regulatory enzyme in PGE2 synthesis. Furthermore, we showed that ceramide upregulates COX-2 expression through increasing activity of nuclear transcription factor NF-κB (Claycombe et al., J. Biol. Chem. 2002, 277:30784-30791; Wu, et al., J. Biol. Chem. 2003, 278:10983-10992). Current studies investigate the mechanism of ceramide induced NF-κB upregulation in aged mice.
In addition, we have shown that in vivo vitamin E supplementation enhances T cell mediated function in the aged mice and elderly human (Meydani et al. Mech. Aging Devel., 34:191-201, 1986; Am. J. Clin. Nutr. 1990, 52:557-563; JAMA, 1997, 277:1381386). We further showed that vitamin E induces its effect by two distinct mechanisms: a) by decreasing PGE2 production, and thus reducing macrophage-mediated suppression, and b) by directly enhancing T cell function, independent of its effect on macrophage PGE2 production. E exerts its effect by improving the ability of naïve T cells from old mice to produce IL-2 and progress through cell division cycles (Adolfsson et al., J Immunol. 167: 3809-3817, 2001) The figure below illustrates possible mechanisms by which vitamin E affects T cell function.
 |
We further demonstrated that CD4+ T cells from old mice were less likely to form effective immune synapses than those from young mice as observed with lower redistribution of key signaling molecules Zap70, LAT, Vav, and PLCγ to the immune synapse and this age-related reduction in the formation of effective immune synapse is more dramatic in naïve than in memory populations. The age-associated impairement in effective immune synapse formation and distribution of above mentioned signaling molecules in CD4+ T cells can be reversed by vitamin E (Marko et al. J Immunol. 2007, 178:1443-1449). The figure below illustrates these pathways.
Our current studies are focused on determining molecular events which lead to age-related decline in effective immune synapse formation and its reversal by vitamin E. Furthermore, we are utilizing lipidomic and proteomic approaches to determine key membrane related changes associated with aging in T cells.
Our microarray analysis of gene expression profiles in T cells has provided additional information in delineating the underlying mechanism of age-related decrease in T cell function (Han et al. J Immunol. 2006, 177:6052-6061). We showed that T cells of old mice express significantly higher levels of suppressors of cytokine signaling 3 (SOCS3) and lower levels of growth factor independence-1 (Gfi-1) compared to those of young mice. These results suggest that relative to young T cells, less increase in activation-induced Gfi-1 expression in old T cells may result in higher levels of SOCS3 expression and suppressed T cell proliferation. We also showed that vitamin E supplementation in old mice increased expression of the genes for cell cycle related proteins including cyclin B, Cdc2 (Cdk1), and Cdc6, which suggests that altered cell cycle related proteins might underlie the effect of vitamin E in promoting cell division cycle and IL-2 production.
Nutrition, host-pathogen interaction, and resistance to infection. Host and pathogen interaction in the context of aging is also a subject of investigation in our laboratory. In a recent study (Gay, et al. PNAS, 2006, 103:13825-13830), we investigated the effect of host age on pathogenicity of Coxsackievirus B3 (CVB3). We found that old mice infected with a normally amyocarditic strain of CVB3, CVB3/0, had significantly higher mean heart viral titers compared with adult mice. Adult mice infected with CVB3/0 that was passed through an old host exhibited significantly higher heart viral titers, pathology, and weight loss than adult mice infected with either stock CVB3/0 or CVB3/0 passed through an adult host. Sequence analysis of virus, which was passed through an old mouse revealed 13 specific and reproducible nucleotide changes. These changes resulted in a sequence that matches the virulent CVB3/20 strain and are associated with promoting cardiovirulence. In contrast, we observed only one nucleotide change, low heart viral titers, and no heart and liver pathology in adult mice infected with a CVB3/0 virus that was passed through an adult host. These results demonstrate that the aged host promotes rapid selection of a pathogenic variant of CVB3 from an avirulent strain and introduces a new host-virus paradigm for studies of viral infection in the aged. The figure below illustrates these data.
Respiratory infections are among the leading causes of death in the elderly. Influenza virus, a common respiratory pathogen, accounts for over 10,000 deaths annually and over 40,000 deaths during epidemic years. Individuals 65 years and older accounted for 89% of all influenza associated deaths in 1992. These deaths were not typically due to influenza infection alone, but from complications that developed due to influenza infection. Previously, our laboratory showed that E supplementation reduces influenza viral infection in aged mice (Hayek, et al., J. Infect. Dis. 1997, 176: 273-276; Han, et al., Immunology, 2000, 100: 487-493). Recently, we have shown that 1 year of supplementation with 200 IU per day of vitamin E has a protective effect on upper respiratory tract infections in elderly nursing home residents (Meydani et al., JAMA, 2004, 292: 828-836). Our current studies are investigating the role of cytokine polymorphism and its interaction with vitamin E on cytokine production and resistance to respiratory infection.
Zinc plays an important role in immune function. In a recently published study, we investigated the association between serum zinc and pneumonia in nursing home elderly (Meydani, et al. Am J Clin Nutr, 2007, 86:1167-1173). Results showed that subjects with low serum zinc concentrations had a lower incidence of pneumonia, fewer new antibiotic prescriptions, a shorter duration of pneumonia, and fewer days of antibiotic use compared to those with normal serum zinc level. Normal baseline serum zinc concentrations were associated with a reduction in all-cause mortality. These results indicate that zinc supplementation to maintain normal serum zinc concentrations in the elderly may help reduce the incidence of pneumonia and associated morbidity. We are currently conducting a study to determine the effect of zinc supplementation on tissue levels of zinc and immune function in the nursing home elderly.
Aging, inflammation status, and nutritional modulation. Aging is associated with increase in type 2 diabetes (T2D) incidence; a low-grade inflammation in adipose tissue is implicated in development of insulin resistance; age-assoiated inflammation has been observed in certain tissues. In a recent study (Wu et al. J. Immunol, 2007, 179: 4829-4839), we investigated the effect of aging on inflammatory status of adipose tissue. Our results showed that visceral fat from old mice had significantly higher mRNA expression of pro-inflammatory cytokines IL-1β, IL-6, TNF-α, and COX-2 and lower expression of anti-inflammatory PPAR-γ than those of young. We further showed that adipocytes are not only major contributor to this inflammatory state by they also increase production of inflammatory cytokines in adipose tissue macrophages, thus further propagating inflammation. We further showed that sphingolipid ceramide, through activation of NF-κB was involved in this age-associated upregulation of inflammation in adipocytes.We are currently determining whether dietary blueberry supplementation could affect inflammatory state in high fat diet-induced obesity in a mouse model.
Modulation of immune response by functional foods. We have recently conducted animal studies and shown that dietary supplementation with white button mushroom enhanced natural killer activity, which is associated with higher levels of IFN-γ and TNF-α (Wu et al. J Nutr, 2007, 137:1472-1477). In another study we showed that in vitro supplementation promoted maturation of bone marrow derived dendritic cells and increased their antigen presenting function (Ren, et al. J Nutr, 2008, 138:544-550). We are currently using an influenza infection mouse model to determine whether the enhanced immune response by consumption of mushrooms could result in improved resistance to viral infection to prove its clinical relevance. Several ongoing animal studies are designed to determine the impact of other non-nutrient components of food on immune response and resistance to infection. These projects include “Impact of green tea EGCG on T cell function”, “Effect of a combination of multi-nutrients and whey-based protein on immune function”, and “Effect of tocotrienols on immune response”.
Collaborative Projects. The Nutritional Immunology Laboratory is involved in collaborative projects with several investigators within and outside Tufts University. Some of these are highlighted below.
• Effect of linoleic acid on immune response of humans, in collaboration with Dr. Alice Lichtenstien of JMUSDA-HNRCA as part of her project “Dietary fat, plasma lipids and other CHD risk factors”.
• Effect of calorie restriction on immune response of human, in collaboration with Dr. Suzanne Roberts of JMUSDA-HNRCA as part of her project “Dietary Energy Restrictions and Metabolic Aging in Humans”.
• Nutrition, Immunity & Health Status Of Elderly Ecuadorians in collaboration with Dr. Fernando Sempertegui of Corporacion Ecuatoriana De Biotecnologia, Quito, Ecuador.
• Effect of micronutrient supplementation on immunology, and epidemiology of TB in collaboration with Dr. Wafaie Fawzie of Harvard School of Public health as part of his project “Nutrition, Immunology and Epidemiology of TB”.
• Evaluation of cell-mediated immunity and antibody response to influenza vaccination: Role of vitamin E and zinc status, in collaboration with Drs. Laura Coleman and Edward Belongia of Marshfield Clinic, Marshfield, WI.
