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Vol. 04 Issue 3, Early Fall 1999

Environmental Factors and a Balanced Immune System: A Key to Cell-Mediated Immunity, Cancer Resistance and Allergy
The Ribbon 

Rodney R. Dietert, Professor of Immunotoxicology
Department of Veterinary Microbiology and Immunology and
the Institute for Comparative and Environmental Toxicology, Cornell University

The Importance of Effective Immune Surveillance

The tragedy of AIDS has raised awareness of the key role of proper immune function in cancer avoidance/tumor resistance. With HIV infection, the development of AIDS and reduced 'host surveillance capacity' (the ability of our immune systems to screen for anything inappropriate), there has been the dramatic increase in the incidence of an otherwise relatively rare tumor, Kaposi's sarcoma. Such an association underscores the existence of two fundamental processes, either of which can lead to an increased likelihood of cancer: 1) an increase in the rate at which cancer cells emerge within the individual or 2) a decrease in the capacity of the immune system to identify and eliminate cancer cells that occur in each of us. Clearly, changes on either end of this delicate immune surveillance-cancer balance could result in the emergence of cancer. Some chemicals exist that will operate through one or the other of these processes, but chemicals like the fungal toxin, aflatoxin, can increase cancer cell formation while simultaneously decreasing the capacity of the immune system to fight cancer. For this reason, it has become important to identify not only environmental toxins which might represent mutagen/carcinogens, but also chemicals which are immunotoxic and could depress host resistance to cancer.

The Race Between Immune Response and Cancer Cell Proliferation

In some cases, individuals may succumb to cancer by the immune system failing to recognize the tumor as inappropriate (a genetic blind spot for the tumor) and never mobilizing against it. However, it appears that in a majority of instances, tumor resistance becomes a "race" between the capacity of the tumor cells to replicate and spread versus the rate at which tumor-fighting immune cells can be produced. Elegant experiments in animals have shown that by giving the immune system a two week head start in the "race" against cancer, tumor burdens large enough to kill 1,000 animals can be successfully destroyed in a single animal. Therefore, the first issue regarding effective immune surveillance is to ensure that environmental factors do not impair the capacity of the immune system to compete well in the proliferation race with tumor cells or affect recognition of a tumor.

The Changing Landscape of Immunotoxicology

Historically, the search for immunotoxins during the 1980s and early '90s focused on chemicals which caused wholesale destruction of the immune system. Fortunately, such chemicals are relatively rare and can usually be readily identified. However, more recent efforts have centered on environmental factors which may produce subtle, yet equally problematic changes to the immune system. These chemicals can cause functional immune imbalances which do not produce total immunosuppression, but rather cause shifts in host responses such that our defense against certain diseases are, nevertheless, compromised. Since major losses of immune cells or complete destruction of immune organs usually does not occur in these instances, the identification of such immunotoxins is relatively challenging.

The Basis of Immune Balance

The issue of immune balance was first recognized in 1986 when researchers like Dr. Tim Mosman and colleagues provided evidence explaining why the immune system is able to tailor responses to fit the particular disease challenge at hand (Mosman et al., 1986). For a long time immunologists marveled at the fact that most immune responses mobilize the particular sectors of the immune system best suited to fight the disease (i.e. certain types of antibodies are produced when needed and cancer fighting killer lymphocytes are preferentially generated when appropriate). But little was known about the possible controls over such directed responses. These researchers showed that specific types of T lymphocytes (called type 1 or type 2 helper cells) directed immune responses toward fighting cancer and viral infections or toward fighting certain bacterial and parasitic infectious challenges. In part, this explains why we mobilize precise types of responses which are needed to overcome specific disease challenges. Clearly, a healthy balance of type 1 and type 2 response capacity is necessary if we are to overcome the full spectrum of disease challenges over the course of a lifetime. The flip side of the issue is that an imbalance in type 1 versus type 2 T helper function could produce a major gap in disease resistance including resistance to cancer. Additionally, some forms of imbalance could increase the likelihood of immune-mediated diseases such as autoimmunity, allergy and asthma.

The basis of type 1 versus type 2 T helper function is linked to the production of immune hormones known as cytokines, lymphokines or interleukins. For example, type 1-associated responses are characterized by the production of interleukins-2 and -12 and interferon-gamma. These cytokines are important in the long-term defense against cancer mediated by cytotoxic T lymphocytes. Cytotoxic T lymphocytes are able to attack and lyse cancer cells with considerable specificity and precision. Therefore, they are clearly important in overall resistance to cancer. Additionally, interleukin-2 aids other immune cells such as Natural Killer cells in their fight against tumor cells while interferon-gamma can help to arm macrophages for the production of anti-tumor factors such as nitric oxide. Natural Killer cells and macrophages participate in our front-line defense against emerging cancers and can attack tumor cells within a matter of hours. Therefore, they aid in fighting the very earliest stages in tumor formation and complement the action of cytotoxic T lymphocytes which require days or even weeks to be produced. In contrast, type 2-associated responses involve the suppression of interferon-gamma production and an elevated production of interleukins -4, -5 and -10. In particular, interleukins -4 and -10 can promote IgE-mediated allergic responses (IgE stands for immunoglobulin E, an anitbody that causes histamine release from mast cells) as well as some forms of asthma. These types of responses do little to fight cancer and to the extent that they might represent the predominant response of an unbalanced immune system, the unsuited immune response could allow tumors to progress unabated. In reality, few responses are purely type 1 or type 2, but clearly, the balance of these functional capacities in an individual could influence the quality of the tumor fighting potential as well as the risk of allergic disease and/or asthma.

Chemicals Altering Immune Balance

With those fundamental immunology principles in mind, recent research in immunotoxicology has emphasized a search for environmental factors which might produce T helper (Th) lymphocyte functional imbalances. Among chemicals thought to reduce protection afforded by cell-mediated immunity (type 1) with an increased risk of autoimmunity and allergic disease (type 2) are the heavy metals. In particular, exposure to lead (Pb) and mercury (Hg) appear to represent significant health risks. In the case of mercury, it appears to cause a shift in the host response in favor of Th2 (T helper type 2) responses with concomitant increases in the incidence of certain autoimmune disease. (Prigent, et al., 1995).

While lead has been a focus of childhood behavioral and learning problems, the effect of low-to-moderate levels of lead on the immune system is emerging as an equally serious concern. This topic was recently covered in a review by Dr. MaryJane Selgrade and colleagues (Selgrade et al., 1997). Lead has been shown, in rodents, to cause a shift in Th1/Th2 function. Dr. David Lawrence and other researchers at SUNY-Albany demonstrated that lead can alter the differentiation of T helper cells producing a reduction in those Th1 cells responsible for fighting viral infections and cancer (Heo et al., 1996, 1998). Our own laboratory at Cornell extended these observations to show that exposure to levels of lead which do not affect adult pregnant rats nevertheless cause persistent changes in the immune system of their developing daughters (Miller et al., 1998; Chen et al., 1999). This suggests, as is already suspected for lead-induced-neuro-behavioral toxicity, that embryos and immature offspring may be particularly susceptible to lead-induced immunotoxicity.

Other Potential T-helper-disrupting Chemicals

While Pb and the other heavy metals have been implicated in Th disfunction, it is likely that they are not the only environmental factors of concern when it comes to Th problems. Some of the factors currently under examination for T helper imbalance-producing immunotoxicity are UV radiation and various air pollutants (e.g. ozone, sulfur dioxide, diesel exhaust particles). However, in the case of inhaled gases such as ozone and diesel exhaust particles, it is not clear whether the potential enhancement of respiratory allergy results from a purely local effect in the airways or from more systemic changes. It is clear that exposure to ozone, diesel particles or the hydrocarbons from diesel exhaust is likely to result in greater histamine release and/or increased local inflammation in allergic subjects (Molifino et al., 1991; Muranaka et al., 1986; Takenaka et al., 1995). Additionally, some evidence suggests that exposure to diesel exhaust particles can produce enhanced Th2 activity beyond the area of local allergen exposure (e.g. extending to include at a minimum, upper body areas) (Fujimaki et al., 1994). Therefore, it is likely that the list of environmental factors known to produce Th imbalances will increase within the next few years.

Differential Risk

The fact that embryos are susceptible to immune changes at lead dosages which are safe for adults points to another issue in immunotoxicology and in toxicology in general. That is the fact that differential risk exists within the human population. In the case of Pb, there is a clear age-related risk difference. Developmental windows of hyper-vulnerability are likely to exist for certain toxicant exposures. Additionally, the genetic background of an individual can influence whether or not a low-level toxicant exposure has problematic health implications. Therefore, a longer term goal of the immune-cancer risk research is to identify those segments of the population at greatest health risk from real-life exposures. This extends beyond overt immunotoxicity studies to the topic of aging and cancer resistance. For example, historically it has been immunological dogma that Th1 function declines with aging in a reciprocal manner to the age-related increase in cancer incidence within the human population. However, from a preventative medicine perspective, it is probable that the lifetime course of chemical exposures (including dietary intake) can influence whether this age-related loss of protection against cancer actually occurs. Therefore, as more attention is paid to environmental influences on Th function, there are opportunities for improved resistance to cancer across the entire age spectrum.

Summary

Several types of environmental chemicals (beyond just the heavy metals) have the capacity to alter T helper cell balance. The disruption of appropriate Th balance is an environmental health change which appears to explain, at least in part, the recent rise in childhood asthma. Clearly, problematic environmental exposures which would increase the risk of asthma while reducing immune protection against cancer would be of significant public health concern. With the new directions undertaken in immunotoxicology, it is hoped that Th-disrupting chemicals can be identified, potentially problematic exposures avoided and the health risk to humans and wildlife, thereby, reduced.

Acknowledgments: The author expresses appreciation to Terry-Bunn Gomez, Forrest Sanders, Judy Seltzer and Elizabeth Kao for their assistance in the preparation of this article. The research of the author's laboratory supporting, in part, this report is funded by NIEHS (National Institute of Environmental Health Sciences) grant # ES05950 with funds provided by the EPA in support of the Cornell Superfund Basic Research and Education Program grant.

References

Chen, S., K.A. Golemboski, F. S. Sanders and R R. Dietert. Persistent effect of in utero meso-2,3-dimercaptosuccinic acid (DMSA) on immune function and lead-induced immunotoxicity. Toxicology 132: 67-79. 1999.

Fujimaki, H., O. Nohara, T. Ichinose, N. Watanabe, and S. Saito. IL-4 production in mediastinal lymph nodes in mice intratracheally instilled with diesel exhaust particles. Toxicology 92: 261-268. 1994.

Heo, Y., P.J. Parsons and D.A. Lawrence. Lead differentially modifies cytokine production in vitro and in vivo. Toxicol. Appl. Pharmacol. 138: 149-157. 1996.

Heo, Y., W.T. Lee and D.A. Lawrence. Differential effect of lead and cAMP on development and activities of Th1-and Th2-lymphocytes. Toxicol. Sci. 43: 172-185. 1998.

Miller, T.E., K.A. Golemboski, R. Ha, T. Bunn, F.S. Sanders and R.R. Dietert. Developmental exposure to lead causes persistent immunotoxicity in Fischer 344 rats. Toxicol. Sci. 42: 129-135. 1998.

Molifino, N.A., S.C. Wright, I. Katz, S. Tarlo, F. Silverman, P.A. McClean, J.P. Szalai, M. Raizenne, A.S. Slutsky andN. Zamel. Effect of low concentrations of ozone on inhaled allergen responses in asthmatic subjects. Lancet 388: 199-203. 1991.

Mosman, T.R., H. Cherwinski, M.W. Bond, M.A. Giedlin and R.L. Coffman. Two types of murine helper T cell clones. I Definition according to profiles of lymphokines activities and secreted proteins. J. Immunol. 136: 2348-2357. 1986.

Muranaka, M., S. Suzuki, K. Kizumi, S. Takafuji, T. Miyamoto, R. Ikemori and H. Tokiwa. Adjuvant activity of diesel exhaust particulates for the production of IgE antibody in mice. J. Allergy Clin. Immunol. 77: 616-623. 1986.

Prigent, P., A. Saoudi, C. Pannetier, P. Graber, J.Y. Bonnefoy, P. Druet and F. Hirsch. Mecuric chloride, a chemical responsible for T helper cell (Th2)-mediated autoimmunity in Brown Norway rats, directly triggers t cell to produce interleukin-4. J. Clin. Invest. 96: 1484-1489. 1995.

Selgrade, M., D.A. Lawrence, S.E. Ullrich, M.I. Gilmour, M.R. Schuyler and I. Kimber. Modulation of T-helper cell populations: potential mechanisms of respiratory hypersensitivity and immune suppression. Toxicol. Appl. Parmacol. 145: 218-229. 1997.

Takenaka, H. K. Zhang, D. Diaz-Sanchez, A. Tsien and A. Saxon. Enhanced human IgE production result from exposure to the aromatic hydrocarbons from diesel exhaust: direct effect on B cell IgE production. J. Allergy Clin. Immunol. 95: 103-115. 1995.


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Rodney R. Dietert, Professor of Immunotoxicology Department of Veterinary Microbiology and Immunology
and the Institute for Comparative and Environmental Toxicology, Cornell University

Last Update 06.23.00