I am very pleased to introduce our guest expert, Dr. Simin Nikkin Meydani, Chief of the Nutritional Immunology Lab at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. Simin's primary interest is how nutrition can modulate the immune system, especially in the elderly. However, over the years, she has expanded her interests to other population groups.

Simin, let me begin our discussion by reminding Cyberounders that the concept that inadequacies or excesses of nutrition can affect the immune system is not a new one. Perhaps, you could give us some historical background about nutrition and the immune system.

Meydani

The concept of the existence of a relationship between nutrition and immunity goes back many years.(1) Scientists first noted that during famine periods there was high morbidity and mortality from infectious diseases. Fifty to 60 years ago, scientists started to put all of these observations together and postulated a relationship between the nutrient status of the host, the function of the immune system and, therefore, resistance to infectious diseases.

Early work, done in humans, on the essentiality of nutrients, supported the relationship. Scientists were able to show that deficiency of several micro- and macronutrients produced impairment of the immune function and that has been further demonstrated by work done in animals. Subsequently, the association of this impairment in the immune function with infectious diseases has been shown in both animal and human models. There exists a lot of animal evidence indicating that, when you impair the immune function through nutrient deficiency, you reduce an animal's resistance to infectious diseases. We have shown, for example, that low protein status results in more tuberculosis and that vitamin E levels affect resistance to E. coli infection and viral infections.

Vitamin A Deficiency

From developing countries, where a good degree of both macro- and micronutrient deficiency still exists, we have human data that shows that protein-calorie malnutrition is associated with an increased incidence of infectious diseases. Additionally, individual nutrient deficiencies, for example vitamin A or zinc deficiency, are associated with increased incidence of respiratory diseases and diarrheal diseases.(2)

Mason

I would also like to add that the World Health Organization has taken a very proactive role in this regard, particularly pertaining to the issue of subtle vitamin A deficiency in the third world. It has become clear, over the last decade, that subtle vitamin A deficiency (of insufficient magnitude to cause eye damage) is still sufficiently severe to impair the immune system. Children of the third world have a much higher risk of measles and other common infections, a risk that has been dramatically reduced merely by supplementing with vitamin A.

Meydani

Even in the U.S., an economically developed nation, vitamin A supplementation is being considered for low socio-economic groups of children because we know mild vitamin A deficiency also exists in that setting.

Mason

Simin, let's now move on to a more contemporary topic. If I'm not mistaken, your interest is not primarily directed towards replenishing people with either macro- or micronutrient deficiencies but, instead, looking at a very different aspect of this field.

Supraphysiologic Doses of Nutrients: Do They Help Fight Disease?

Meydani

Right. While micro- and macronutrient deficiencies are a big problem in developing countries, it's not really a preeminent problem in developed countries, although, as we've discussed, certain segments of the population in the developed world do have marginal deficiencies of specific nutrients. More pertinent to these countries is the prevalence of chronic diseases and the reemergence of certain infectious diseases.

If you look at epidemiological data from the 1960s to 1990, you will notice that there has been an increase in the incidence of particular infectious diseases in the developed world. Obviously, some of the rise is attributable to the AIDS epidemic but we have also seen an increased incidence of respiratory infection, which occurs, in part, because there are more elderly people.

Researchers like myself are interested in whether supraphysiologic doses of nutrients can affect the immune response, particularly among the elderly. As we age, a dysregulation of the immune function occurs. The resultant decrease in the cell-mediated immune response may be a major factor in the higher incidence of infectious diseases, especially respiratory infections, in the elderly. Is it possible, we wonder, to improve immune function with nutrient supplementation and, thereby, increase resistance to these emerging infectious diseases?

Mason

Let me also point out that optimizing function of the immune system is not only important in regard to warding off infectious diseases but also has a significant role in the prevention of cancer.

Simin, just to underscore the wide spectrum of individuals in the population we are talking about, let me remind our audience that not only is the immune system reproducibly impaired as we age but populations, such as acutely hospitalized patients, people with chronic inflammatory disorders, people with immunodeficiency conditions (e.g., HIV infections) and all patients taking immunosuppressive drugs chronically following organ transplantation or for other conditions, are individuals who might benefit from optimization of their immune function.

Meydani

You might also want to add to that list the fact that environmental stress can cause impairment of immune function. We now know, for example, that medical students who are close to their exams go through a lot of stress and have an associated impairment of immune function. We also know that environmental pollutants can adversely affect immune function. For example, the metabolism of some pollutants affects the level of certain nutrients.

Mason

Supplementation of which micronutrients have demonstrated the most potential benefit for the immune system?

Meydani

Among the macronutrients (proteins, carbohydrates and lipids), there is not much evidence for a relationship between carbohydrates and immune response. In contrast, we know that a deficiency of protein can impair immune function; there is evidence for that in both human and animal models.

Essential Amino Acids and the Immune Response

A deficiency of any essential amino acid would, obviously, adversely affect the immune response because the body cannot synthesize proteins well if essential amino acids are limiting in quantity. On the other hand, it remains unclear whether a deficiency or surplus of any non-essential amino acids can alter the immune response.

Much discussion in the surgical literature has focused on arginine supplementation and its apparent enhancement of the immune response. It is a controversial topic. In our own animal model experiments, we have not been able to show any benefit from increasing the level of arginine in the diet of the rat, although studies from other investigators have indicated a beneficial effect of additional arginine.

Supplementation with nucleotides may also enhance immune function but, again, I don't think the evidence is strong -- further work needs to be done.

Do Lipids Affect Resistance?

With respect to lipids, both the level of fat and the type of fat in the diet may have significant impact on the immune system. In animal models, a high intake of fat can impair the immune system. In terms of type of fat, the evidence is less clear. There is a popular belief, at least among scientists, that polyunsaturated fatty acids have an adverse effect on immune function. However, one needs to be very precise when discussing this topic because there are different types of polyunsaturated fatty acids. When we reviewed this literature a few years ago, we didn't find any evidence that n-6-polyunsaturated fatty acids, if given at moderate levels, have an adverse effect on immune function.

Recently, interest has focused on the long chain polyunsaturated fatty acids derived from fish oil (n-3-fatty acids or omega-3 fatty acids). There are also shorter chain omega fatty acids derived from plants (you can find them in soybean oil and black current seed oil).

These fatty acids, especially those derived from fish oil, have been shown to have an anti-inflammatory effect by reducing production of proinflammatory cytokines (IL-1, TNF and IL-6)(3),(4) and proinflammatory prostoglandins and leukotrines (prostoglandin E2 and leukotrine B4). Consequently, there have been clinical trials conducted to look at their effect on rheumatoid arthritis and colitis. The clinical evidence to date is not strong but holds some promise.

In the arthritis trials, some of the subjective measures of the disease were significantly improved by administering fish oil but some of the more objective markers of disease were not as impressively affected by giving the N-3 fatty acids. The evidence for effect in colitis was also not compelling. There was some effect but not to the point where you could replace anti-inflammatory drugs with fish oil. More trials are ongoing and we may, in the future, have a better understanding of what role these oils may play in treatment of these conditions.

Among older people, one interesting observation was that, while omega-3-fatty acids reduced the production of pro-inflammatory cytokines, they had an adverse effect on T-cell mediated function -- production of cytokine IL-2, the ability of the T-cells to proliferate and the delayed hypersensitivity skin response were all reduced.(4) In further work, we were able to show that this side effect of fish oil occurred because the fish oil increased the need for antioxidant nutrients, for example, vitamin E. If you provided, we found, an adequate level of antioxidants, then you would not see this adverse effect on T-cell mediated function.

Mason

I think it's fair to say, Simin, that the use of selective fatty acids has been shown to modulate the immune system in some regards but the potency of the effects, when used against inflammatory conditions, is relatively modest. Perhaps, we should think of these agents as adjunctive therapy and not as primary therapy. Along the same lines, maybe we should perceive the use of fatty acid modulation of the immune system in a preventive mode, rather than in a treatment mode.

It's also worth remarking that modulating the immune system is, frequently, a double-edged sword -- by reducing the inflammatory response, one can also impair the effectiveness of the immune system to combat against infections and other external forces that it was designed to deal with.

Micronutrient Supplementation

Let's now turn to the issue of micronutrients. Simin, I know you've been primarily interested in the utility of vitamin E in regard to enhancing of the immune system. What can you tell us about the other micronutrients that you and other researchers have examined and their ability to modulate the immune system?

Meydani

There has been interest in several micronutrients in regard to immune function. Historically, the most famous example is vitamin C and the common cold. The jury is still out on vitamin C. In my mind, there is not really concrete evidence that supplementation with megadoses of vitamin C is effective in reducing colds and infections. Perhaps it's because definitive studies haven't yet been done.

I think the best evidence we have on micronutrient supplementation is vitamin E. Let's remember to separate the issue of deficiency from supplementation. A deficiency of almost any micronutrient impairs the immune response and leads to an increase in the incidence of infection, so, in cases where there is a suspicion of a micronutrient deficiency, we need to correct the deficiency and this will certainly improve the immune response. Of more immediate interest to me is that supplementation with selected micronutrients, even in individuals who are apparently replete, does appear to enhance the immune response. The effect has been observed most clearly in the elderly. We have worked with vitamin E and have shown that, in healthy elderly, supplementation with vitamin E will significantly improve the immune response.(5) We have tested several doses of vitamin E and concluded that the optimal dose for improvement of immune response in elders is 200 IU per day. Little benefit is obtained by going to a higher level. This has been supported by a more recent study conducted in the Netherlands, where they also found improvement in immune response in the elderly with vitamin E supplementation.

Bogden(6) and Chandra(7) have done similar studies using a mixture of vitamins and minerals at recommended levels (or higher than recommended for vitamin E) and have shown that you can improve the immune response in the older population. Chandra's study not only was able to improve immune response but also observed a decrease in the number of sick days and the need for antibiotics in the elderly population.

Zinc has also been studied in regard to immune response. Supplementation with zinc has been effective in improving immune response in elders who had low zinc status. However, among elders with adequate zinc status, supplementation with zinc did not improve their immune response and, in fact, probably had an adverse effect on it.(6)

Clinical Outcomes

Mason

Simin, let me direct our conversation towards a question that I think our audience is going to be very interested in, and that is how one translates the improvement in the immune system into improvement in clinical outcomes? Aside from the Chandra study, which did show a decrease in the number of infectious sick days and a decreased need for antibiotics, have there been other studies that demonstrate that, in association with this improvement in the immune system, there is actually improved clinical outcome? And, in the absence of those studies, perhaps because they haven't been done yet, what compelling animal evidence can you tell us about that would suggest that this really is a promising field in terms of clinical implications?

Meydani

Except for Chandra's study, there are not much clinical human data that exist to support the association. In the setting of deficiency of nutrients in the developing world, there is obviously a higher incidence of infection but, as far as supplementation above basal needs, there is no direct clinical evidence.

In the case of vitamin E, the only evidence we have is indirect evidence from animal studies and some preliminary studies in humans. For example, we were able to show in a human study that there was a downward trend in the number of self-reported infections in subjects who were supplemented with vitamin E. There is also epidemiological evidence from France which demonstrated that elders who have higher plasma levels of vitamin E had a lower incidence of infectious diseases in the preceding three years. There are many animal studies that indicate that supplementation above required levels with vitamin E increases resistance to both bacterial and viral diseases. From our own work, particularly in older animals, we have shown that supplementation with vitamin E significantly decreases lung viral titre in animals who have been exposed to influenza infection.

So the evidence we have is mostly indirect from animal models and epidemiological observations. We are now doing human studies in order to obtain better evidence. We are looking at the effect of vitamin E supplementation on incidence of infectious disease in older populations and we should have those results in a few years.

There is one very interesting study, done in animals, which I think has a lot of implications for humans. Dr. Melinda Beck and Orville Levander showed that selenium or vitamin E deficiency of the host causes mutation in coxsakie virus 3B.(8) The mutation results in conversion of a non-virulent type of virus to a virulent type that causes cardiomyopathy. This suggests that nutritional status of the host can be very important in the emergence of particularly virulent forms of conventional pathogens.

Mason

I would like to thank Dr. Meydani for the fascinating insights she has provided us with today and underscore the last statement she made, namely, that this is a field that is in rapid evolution. Be assured, over the next several years, we are going to hear a lot more about clinical situations where nutrition can effectively modulate the immune system for the benefit of the patient.