Muscle tissue serves as a protein reservoir which is mobilized to meet the specific metabolic needs associated with various catabolic conditions in human subjects, such as trauma and critical illness. Glutathione is one of the most abundant short-chain peptides and a major source of non-protein thiol in the body, and tissue glutathione concentration is related to its oxidative capacity. Skeletal muscle is relatively unique with respect to a variety of metabolic properties, such as oxidative potential, patterns of amino acid utilization, and antioxidant enzyme activity. The glutathione concentration is not influenced by food intake, or by food deprivation. Moreover, there is no diurnal variation on muscle glutathione levels. Following elective surgery the muscle concentration of GSH (the reduced form) decreases by 40 % 24 h post-operatively, while the concentration of GSSG (the oxidized form) remains unaltered. During critical illness a similar decrease in the GSH concentration is seen, but in addition a change in the redox status indicative of an elevated GSSG level occurs. Furthermore, correlations between the concentrations of glutamine as well as glutamate and GSH exist in these patients. From available evidence accumulated it is clear that glutathione plays a pivotal role in the maintenance of the intracellular redox status, the antioxidant vitamin levels, and the antioxidant enzyme functions under various metabolic conditions. The effectiveness of glutathione protection in the individual tissue depends on the tissue concentration of glutathione as well as the capacity of the tissue to import GSH and to export GSSG. The mechanisms by which catabolism regulates tissue glutathione levels and the enzyme activities associated with the γ-glutamyl cycle are not completely understood and further studies need to be conducted.

Diet and immunity have been known to be linked to each other for centuries. In the last 30 years systematic studies have confirmed that nutrient deficiencies impair immune response and lead to frequent severe infections resulting in increased mortality, especially in children. Protein-energy malnutrition results in reduced number and functions of T-cells, phagocytic cells and secretory immunoglobulin A antibody response. In addition, levels of many complement components are reduced. Similar findings have been reported for moderate deficiencies of individual nutrients such as trace minerals and vitamins, particularly Zn, Fe, Se, vitamins A, B6, C and E. For example, Zn deficiency is associated with profound impairment of cell-mediated immunity such as lymphocyte stimulation response, decreased CD4+:CD8+ cells, and decreased chemotaxis of phagocytes. In addition, the level of thymulin, which is a Zn-dependent hormone, is markedly decreased. The use of nutrient supplements, singly or in combination, stimulates immune response and may result in fewer infections, particularly in the elderly, low-birth-weight infants and malnourished critically-ill patients in hospitals. The interactions between nutrition and the immune system are of clinical, practical and public health importance.

Immune function declines with age, leading to increased infection and cancer rates in aged individuals. In fact, recent progress in the study of immune ageing has introduced the idea that rather than a general decline in the functions of the immune system with age, immune ageing is mainly characterized by a progressive appearance of immune dysregulation throughout life. Changes appear earlier in life for cell-mediated immunity than for humoral immunity. Thus, agerelated modifications in cell-mediated immunity, i.e. changes in naive: memory T-cells, mature: immature T-cells, T-helper 1: T-helper 2 cells are more important in the elderly than changes in humoral immunity, i.e. CD5: CD5+ cells or length of antibody responses. Such evolution of the immune system has been linked to declining thymus function and to accumulative antigenic influence over the lifespan. In contrast, innate immunity (macrophage functions) is preserved or even increased during the ageing process. This finding shows that the ‘primitive’ immune system is less affected by the ageing process than the sophisticated specific immune system. The present review focuses on innate and cell-mediated immune changes with ageing. It provides evidence that primary changes (intrinsic modifications in the immune system) and secondary changes (resulting from environmental influences during the lifespan) exert different influences on the immune system. Primary changes, occurring in healthy individuals, seem less important nowadays than they were considered to be previously. For example, interleukin 2 secretion in some very healthy aged individuals is comparable with that in younger adults. Primary immune changes may not explain the increased incidence and severity of infections observed in the elderly population. Secondary immunological changes are far more frequent and are certainly responsible for most of the immune modifications observed in the elderly population. Environmental factors leading to secondary immune dysfunctions include not only antigenic influence, which is a reflection of diseases experienced over the lifespan, but also many other factors such as drug intake, physical activity and diet; factors for which important changes occur in the elderly population. Nutritional factors play a major role in the immune responses of aged individuals and the present review shows that nutritional influences on immune responses are of great consequence in aged individuals, even in the very healthy elderly.

The incidence of infectious diseases, particularly respiratory diseases, increases with age. Age-associated decline in immune function contributes to the increased susceptibility of the aged to infections. Vitamin E supplementation has been shown to improve some aspects of immune function in aged animals and human subjects. The protective effect of vitamin E against viral or bacterial infections in experimentally-challenged young animals has been reported. We investigated the effects of supplementation with vitamin E and other antioxidants on resistance to influenza infection in young and old animals. While vitamin E-supplemented young mice showed only a modest reduction in lung viral titre, vitamin E-supplemented old mice exhibited a highly significant (P< 0.05) reduction in viral lung titre. In subsequent studies, we focused on the mechanism of vitamin E-induced reduction of influenza viral titre. The results of these studies as well as those reported by other investigators on the relationship between vitamin E and infectious diseases will be reviewed.

The association between viral disease and nutrition has long been thought to be due to effects on the host immune system. This theory suggests that when a host is malnourished, the immune system is compromised, and thus increased susceptibility to viral infection will occur. However, the virus itself may also be affected by the nutritional status of the host. We have demonstrated that a normally-benign strain of coxsackievirus B3 (CVB3/0) becomes virulent in either Se-deficient or vitamin E-deficient mice. Although the deficient animals are immunosuppressed, the virus itself is also altered. Six nucleotide changes were found in the virus that replicated in the deficient mice, and once these mutations occurred, even mice with normal nutrition became susceptible to disease. Thus, the nutritional status of the host was able to transform an avirulent virus into a virulent one due to genomic changes in the virus. We believe that a common mechanism of oxidative stress is the underlying cause of the genetic changes. Both vitamin E and Se act as antioxidants, and benign virus inoculated into GSH peroxidase (EC 1.11.1.9)-knockout mice will also convert to virulence due to genomic changes. Our work points to the importance of host nutrition during a viral disease, not only from the perspective of the host, but from the perspective of the viral pathogen as well.

Many epidemiological studies have shown an association between diets rich in carotenoids and a reduced incidence of many forms of cancer, and it has been suggested that the antioxidant properties of these compounds are a causative factor. Attention has focused on the potential role of one specific carotenoid, β-carotene, in preventing cancer, and numerous publications have described in vitro experiments and animal studies which suggest that not only can this carotenoid protect against the development of cancer, but also several other chronic diseases. Since the immune system plays a major role in cancer prevention, it has been suggested that β-carotene may enhance immune cell function. Several human trials, using dietary β-carotene supplementation with a wide range of intakes, have been undertaken to address this hypothesis. The general conclusion of these studies is that this compound can enhance cell-mediated immune responses, particularly in the elderly. The present article will review some of these human studies and, hopefully, complement the reviews of other authors associated with the present symposium, some of whom will also describe work in this area. Potential mechanisms for the effects of carotenoids on immune function will also be reviewed. Finally, possible reasons for the failure of three major prospective studies to demonstrate a beneficial effect of β-carotene supplementation on lung cancer risk will be discussed.

Studies in animal models and cell lines show that vitamin A and related retinoids play a major role in immunity, including expression of mucins and keratins, lymphopoiesis, apoptosis, cytokine expression, production of antibody, and the function of neutrophils, natural killer cells, monocytes or macrophages, T lymphocytes and B lymphocytes. Recent clinical trials suggest that vitamin A supplementation reduces morbidity and mortality in different infectious diseases, such as measles, diarrhoeal disease, measles-related pneumonia, human immunodeficiency virus infection and malaria. Immune responses vary considerably during different infections, and the available data suggest that the modulation of immune function by vitamin A may also vary widely, depending on the type of infection and immune responses involved.

Pregnancy is associated with a skewing towards T-helper (Th)2-like cell populations. During the first years of life, the neonatal immune responses towards allergens deviate towards a balanced Th1 and Th2-like immunity. The difference between atopic and nonatopic individuals may be how readily the immune deviation takes place. The high prevalence of allergies in industrialized countries is in contrast with the low prevalence of allergies in Eastern Europe, with a life style similar to that prevailing in Western Europe 40 years ago. The discussion on the impact of environmental changes on the incidence of asthma and other allergies has been limited mostly to the possible effects of a deteriorating air quality, poorly ventilated houses and an increased exposure to certain allergens, notably house dust mites. None of these factors can more than marginally explain the observed regional differences in the prevalence of allergic diseases. The concept of ‘life style’ should therefore be expanded considerably. The mother is a significant ‘environmental factor’ in early infancy. Human milk contains components that enhance the maturation of the immune system of the newborn infant. However, there are considerable individual variations in the composition of human milk. Recent studies indicate an imbalance in the gut flora of allergic, compared with non allergic infants, and in Swedish children compared with Estonian children. As the microbial flora drives the maturation of the immune system, changes in its composition may play a role for the higher prevalence of allergy. The future search for significant environmental factors should be directed towards other areas that have not yet been explored. The intestinal microflora is one of these factors that deserve a closer analysis.

Strenuous exercise is followed by lymphopenia, neutrophilia, impaired natural immunity, decreased lymphocyte proliferative responses to mitogens, a low level of secretory immunoglobulin A in saliva, but high circulating levels of pro- and anti-inflammatory cytokines. These exercise-induced immune changes may provide the physiological basis of altered resistance to infections. The mechanisms underlying exercise-induced immune changes are multifactorial and include neuroendocrinological and metabolic mechanisms. Nutritional supplementation with glutamine abolishes the exercise-induced decline in plasma glutamine, but does not influence post-exercise immune impairment. However, carbohydrate loading diminishes most exercise effects of cytokines, lymphocyte and neutrophils. The diminished neutrophilia and elastase (EC 3.4.21.37) responses to eccentric exercise in elderly subjects were enhanced to levels comparable with those of young subjects by fish oil or vitamin E supplements. However, although vitamin C supplementation may diminish the risk of contracting an infection after strenuous exercise, it is not obvious that this effect is linked to an effect of vitamin C on exercise-induced immune changes. In conclusion, it is premature to make recommendations regarding nutritional supplementation to avoid post-exercise impairment of the immune system.

The triad of human immunodeficiency virus (HIV) infection, nutritional status and immune function are intimately related, each factor having effects on the others. The dominant effect in this three-way relationship is the effect of HIV infection on nutritional status, an effect which, until the advent of potent anti-retroviral drugs, has been manifest primarily as wasting. Recently, more complex metabolic abnormalities have become apparent, particularly fat redistribution syndromes, hyperlipidaemia and hypercholesterolaemia. For the converse effect, the effect of nutritional state on HIV disease progression, there is good evidence that clinical outcome is poorer in individuals with compromised nutrition. However, the beneficial effects of nutritional support have been more difficult to demonstrate. For macronutrients, effective macronutrient supply improves survival in severely-malnourished individuals and may have beneficial effects in less-severely-affected individuals. Micronutrient deficiencies appear to be involved in modifying clinical HIV disease and may also be associated with enhanced mother-to-child transmission of virus, particularly in developing countries. Intervention trials in this setting are currently under way. In conclusion, the interaction of HIV infection and nutrition is of great importance not just because of the major impact that HIV infection has on nutritional state, but also because strategies to improve nutritional status, both quantitatively and qualitatively, may have a beneficial effect on the clinical and immunological course of the disease.

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