Tumour antigens have long been identified on murine neoplastic cells, but their presence was evidenced on human neoplastic cells only very recently, hence the debate on whether the concept of the immunosurveillance of cancer as proposed by Paul Ehrlich in the early years of this century was valid. This concept served as a rationale for extensive research efforts to design cancer immunotherapy in the ss, but these efforts proved largely unsuccessful.
The recent discovery of human tumour antigens fuelled the renewed interest in the design of anticancer vaccines. However, it is no longer accepted that specific immune responses can be involved in the induction of cancer by physical or chemical agents. NK cells are considered to play a major role in the protection against cancer.
Interestingly, the majority of polycyclic aromatic hydrocarbons are carcinogenic and the majority of those which are carcinogenic, induce a decrease in NK cell activity. Another important issue is the interaction between immunosuppression and oncogenic viruses. In fact, a number of immunosuppression-related malignancies are induced by viruses, such as the Epstein-Barr virus and human papilloma viruses.
Activation of the Epstein-Barr virus was evidenced in patients with lymphoproliferative disorders associated with azathioprine or cyclosporine treatments Birkeland et al. One attractive, and widely accepted, hypothesis is that dormant Epstein-Barr virus infection is facilitated by impaired T cell function in relation to immunosuppressive therapy. Interestingly, total recovery was noted in a few patients with B lymphoma associated with immunosuppressive therapy when the immunosuppressive regimen could be stopped or decreased. Similarly, immunoallergic reactions have been suggested to be more frequent in immunocompromised patients.
Severe hypersentivity reactions to medicinal products, such as sulphonamides, have been repeatedly described in patients with AIDS. Although an alteration in enzyme activities has been suggested or evidenced in some instances, it is unclear whether this mechanism can account for all the reported hypersensitivity reactions Koopmans et al. At the present time, no experimental or clinical data indicate that chemically-induced immunosuppression is associated with more frequent immuno-allergic reactions.
It has been long recognised that potent immunosuppressive agents, such as cyclophosphamide or cyclosporine, can enhance immune responses, in particular delayedtype hypersensitivity, in given conditions of drug administration in relation to antigen injection. Similarly, chemicals, such as cadmium, lead or selenium, were shown to enhance the immune response at very low levels of exposure, although higher levels of exposure were associated with immunosuppression Zelikoff and Thomas, The dose-response curve is therefore quite unusual and the possibility remains that immunostimulation and immunosuppression can occur with the same chemical depending on the conditions of exposure.
Introduction to Immunotoxicity
The possible health consequences of these findings remain to be established. This may, however, be misleading. Strictly speaking, immunosuppression is a profound abrogation suppression of the immune response, whereas immunodepression refers to a decrease in the immune response. In the latter situation, the immune response is only partly impaired. From the perspective of immunotoxicity risk assessment, this distinction can be useful as the majority of treatments with medicinal products and exposures to environmental chemicals when found to exert direct immunotoxic effects, only depress the immune response and do not suppress it totally.
Therefore, when one such mechanism is impaired in relation to immunotoxic exposure, one or several mechanism s can exert their compensatory influence, so that the resulting consequence is the lack of overt change. Although antimicrobial resistance was consistently shown to be markedly impaired in patients treated with potent immunosuppressive agents, it is more difficult to identify whether and to what extent antimicrobial resistance is impaired following exposure to chemicals which depress, but do not totally abrogate, the immune response, that is to say immunodepressive chemicals.
Available human data, although limited, nevertheless suggest that chemically-induced immunodepression can be associated with more frequent infections.
Supportive evidence comes from patients with autoimmune diseases, such as rheumatoid patients treated with low-dose immunosuppressive treatments. Opportunistic infections have been described, even though uncommonly in rheumatoid patients Segal and Sneller, Similarly, human beings inadvertently exposed to brominated or chlorinated biphenyls, which are known to impair the immune response, were shown to develop more frequent respiratory infections Kuratsune et al.
However, lymphomas have been reported in a few rheumatoid patients treated with low-dose cyclophosphamide or methotrexate Kamel et al. Although a limited body of evidence is available to support the hypothesis that mild-tomoderate impairment of the immune response immunodepression is a condition associated with more frequent infections and lymphomas, the issue whether susceptible individuals are at a greater risk of developing these complications should be raised.
One example is the recent epidemic which killed thousands of seals from the North Sea Harwood, Seals were infected by a mutant virus of the distemper virus family, but surprisingly the animals were far more susceptible to the virus than expected. The North Sea is heavily polluted by metals and hydrocarbons which are potently immunodepressive in laboratory animals. When comparing seals fed contaminated herring from the North Sea to seals fed herring from the far less polluted Atlantic Ocean, statistically significant differences were noted in several key immune parameters.
In any case, the issue of whether chemical immunodepression can exacerbate a latent immune deficiency can be expanded to groups of the population that are likely to be more susceptible, such as infants, elderly people, and patients with AIDS. Although no firm answer is available, the coming years should bring helpful information and allow a more accurate risk assessment of immunotoxicants.
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In this context, the expected development of human epidemiological immunotoxicology is likely to be critical. Oxford: Oxford Press. B, 59— Immunol Allergy Clin. B, 91— New Scientist, 18 February, 38— KASS, E. AIDS, 9, — A human disaster caused by PCBs and related compounds. Fukuoka: Kyushu University Press.
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LI, P. Drug React. Acute Poisoning Rev. PENN, I.
New York: Plenum Medical. In: Experimental Immunotoxicology Smialowicz, R. Health, 48, — Other terms, such as immunorestoration or immune-enhancement, have also been commonly used, but these linguistic differences are more likely to reflect limitations in our current understanding of the potential for pharmacological immunomanipulation or immunostimulation than a scientifically established situation. Even though early medicinal products proposed for use as immunostimulants, such as levamisole, Corynebacterium parvum and thymic hormones, did not prove to exert marked therapeutic activity Smalley and Oldham, , adverse effects in some patients treated with these medicinal products were described more than ten years ago Descotes, a; Davies, , and the clinical experience gained with the use of the most recent recombinant cytokines to treat human patients, largely confirmed these early reports.
Because the focus of immunotoxicologists has so often been on immunosuppression, very few medicinal products, and occupational or environmental chemicals have been recognised to exert unexpected or adverse immunostimulating properties. To some extent, the anti-H2 histamine receptor antagonist cimetidine Ershler et al. Similar adverse reactions are typically noted following the administration of vaccines, particularly recall injections in small children. Slower administration, lower dose and treatment with oral pentoxyphylline or indomethacin were shown to reduce the incidence and severity of this syndrome.
The mechanism of flu-like reactions is not fully understood Vial and Descotes, a. Exacerbation of underlying diseases Shortly after their introduction into the clinical setting, immunostimulating agents were found to exacerbate or facilitate a variety of underlying diseases in treated patients, namely dormant diseases, autoimmune diseases and immuno-allergic reactions.
Early and speculative reports were later largely confirmed following the introduction of therapeutic recombinant cytokines to treat patients with a variety of pathological conditions. Dormant diseases When the early immunostimulating agents were introduced into the clinical setting, they were often empirically administered to patients with varied and supposedly or conclusively documented immunopathological conditions. Similar, although less frequent, adverse reactions were reported with other immunostimulating agents, such as thymic hormones, BCG, or microbial extracts Descotes, a.
As discussed later, initiation of treatment with immunostimulating agents can also be associated with exacerbation of immune-allergic reactions induced by unrelated allergens. Autoimmune diseases The introduction of therapeutic recombinant cytokines into the clinical setting showed that immunostimulation can be associated with more frequent autoimmune diseases Miossec, ; Vial and Descotes, a. Thyroid disorders are by far the most common findings. Interferon treatments were associated with thyroid diseases, including hypothyroidism, hyperthyroidism and biphasic thyroiditis, in 5 to 12 per cent of patients and the majority of these patients had serum antithyroid auto-antibodies, i.
Thyroid disease is still more common in patients treated with IL-2 up to 35 per cent.
Most of these patients present with hypothyroidism and antithyroid auto-antibodies. Overall, the fact that autoimmune diseases are more frequent in patients treated with recombinant cytokines provides further evidence, if need be, for the pivotal role of cytokines in the pathogenesis of many immuno pathological conditions.
Because of their pleiotropic effects and redundancy, it is unlikely that one single cytokine can be the key determinant in the occurrence of immune disorders or immune-mediated clinical symptoms, but it may act as a booster Vial and Descotes, a. Importantly, the clinical and biological signs of autoimmune diseases associated with immunostimulating agents are similar to those of the corresponding spontaneous diseases, in sharp contrast to most drug-induced autoimmune reactions, as discussed later in this volume see Chapter 6.
Autoimmune reactions have been reported following various chemical exposures, but the mechanism involved is unknown and no evidence is currently available to suggest that immunostimulation might be the causative mechanism. In addition, the actual incidence of autoimmune diseases associated with occupational or environmental chemical exposures is not known.
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Some authors claimed that chemical exposures are common causative factors, but so far no conclusive epidemiological data have confirmed these claims. Tilorone, an interferon inducer developed in the early s, was shown to increase IgE production in the rat, whereas total serum IgE levels and skin eruptions were found to be more frequent in rheumatoid patients treated with levamisole than in non-treated rheumatoid controls Descotes, a. Data from the post-marketing surveillance of immunostimulating agents are scarce, but exacerbation of asthma, eczema and rhinitis has been reported shortly after the introduction of these medicinal products in some patients.
Interestingly, immune-allergic reactions have been described in patients treated with recombinant cytokines Vial and Descotes, , , b. These reactions include tubulo-interstitial nephritis, angioneurotic oedema, and linear IgA bullous dermatosis. Finally, cancer patients treated with IL-2 were shown to develop significantly more hypersensitivity reactions to radiological contrast media than matched cancer patients without a history of IL-2 treatment, but these findings failed to be confirmed by other investigators Vial and Descotes, a.
Inhibition of hepatic drug metabolism It has long been recognised that infectious diseases, particularly viral infections Koren and Greenwald, ; Kraemer et al. IL-1 is likely to play a pivotal role.
Frontiers in Toxicology | Immunotoxicology
Pathological conditions associated with hyperproduction of IL-1 have long been known to result in an inhibition of cytochrome Pdependent pathways. Such pathological conditions include viral infections in humans and adjuvant-induced arthritis in rats. IL-2 was also shown to potentiate the effects of phenobarbital. More recent experimental work suggested that IL-6 is actually the key factor. The molecular mechanism of cytochrome P downregulation by immunostimulating agents is relatively well understood.
In contrast to other known inhibitors of cytochrome P, such as cimetidine and erythromycin, which bind to and inhibit several cytochrome P isoenzymes, neither IL-1 or IL-6 have been shown to bind to cytochrome P Interestingly, immunostimulating agents which can effectively increase interferon production downregulate cytochrome Pdependent pathways of hepatic drug metabolism.
Interferons are known to inhibit protein synthesis and downregulation of cytochrome P has been repeatedly suggested to involve alterations in apoprotein synthesis or breakdown, and not a general decrease in the synthesis of hepatic microsomal proteins. However, immunostimulating agents acting through non-interferon-mediated effects have also been shown to downregulate several cytochrome P isoforms. A decrease in several cytochome P mRNAs has been evidenced and the possibility raised that a common, but still putative, intermediate, which is unlikely to be IL-6, is involved.
Immunostimulation and immunosuppression Immunosuppressive drugs, such as cyclophosphamide or cyclosporine, have been shown to enhance antigen-specific immune responses depending on the dose and time of administration in relation to antigen injection. In contrast, medicinal products with immunostimulating properties can sometimes prove to be immunosuppressive Vial and Descotes, In sharp contrast to early expectations, immunostimulating drugs have so far been largely unsuccessful in curing of most malignancies.
Early findings suggested that tumour facilitation could even occur. In addition, an increased incidence of clinically significant infectious complications affecting the urinary tract or the catheter site, has been repeatedly reported in patients treated with IL-2 infusion. Interestingly, impaired humoral and cell-mediated immune responses have been found in patients treated with high dose IL Hepatology, 17, — Drug Regul Affairs, 3, 45— Drug Metab.
In vivo augmentation of nonspecific and specific immune responses.