Association of tumor necrosis factor-alpha and interleukin-1 gene polymorphisms with silicosis.

Silicosis, an interstitial lung disease prevalent among miners, sand blasters, and quarry workers, is manifested as a chronic inflammatory response leading to severe pulmonary fibrotic changes. Proinflammatory cytokines, such as TNFalpha and IL-1, produced in the lung by type II epithelial cells and alveolar macrophages, have been strongly implicated in the formation of these lesions. Recently, a number of single nucleotide polymorphisms (SNPs), which quantitatively affect mRNA synthesis, have been identified in the TNFalpha promoter and IL-1 gene cluster and their frequency is associated with certain chronic inflammatory diseases. To assess the role of these SNPs in silicosis, we examined their frequency in 325 ex-miners with moderate and severe silicosis and 164 miners with no lung disease. The odds ratio of disease for carriers of the minor variant, TNFalpha (-238), was markedly higher for severe silicosis (4.0) and significantly lower for moderate silicosis (0.52). Regardless of disease severity, the odds ratios of disease for carriers of the IL-1RA (+2018) or TNFalpha (-308) variants were elevated. There were no significant consistent differences in the distribution of the IL-1alpha (+4845) or IL-1beta (+3953) variants with respect to disease status. In addition, several significant gene-gene and gene-gene-environment interactions were observed. Different associations between moderate cases and controls versus severe cases and controls were also observed in a number of these multigene comparisons. These studies suggest that gene-environment interactions involving cytokine polymorphisms play a significant role in silicosis by modifying the extent of and susceptibility to disease.

Effect of influenza virus infection on ovalbumin-specific IgE responses to inhaled antigen in the rat.

Upper respiratory tract viral infections have been reported in clinical studies to serve as risk factors for allergic sensitization. In order to study the relationship linking influenza virus illnesses to development of allergy, murine models of allergen sensitization were previously employed. These models showed that lethal influenza viruses were able to trigger allergen-specific immunoglobulin E (IgE) production and to inhibit tolerance to repeated exposure to aerosolized allergen in the mouse. The disadvantage of these murine models consists in the utilization of virulant and lethal strains of influenza virus. A nonlethal rat-adapted influenza virus (RAIV) host resistance model has been developed in our laboratory. It was used to evaluate the effect of influenza virus infection on IgE responses to inhaled ovalbumin (OA) in the rat. The high IgE-responder Brown-Norway (BN) rat was chosen for further study after comparing the IgE response to OA in Fischer 344 (F344) and BN rats. On d 1, BN rats were sensitized by administration of 1 mg OA subcutaneously alone or together with aluminum hydroxide (200 mg) and Bordetella pertussis (15 x 10(9) killed bacilli per rat in 1 ml), or only received saline. Rats were either infected with RAIV or sham-infected on d 0 (24 h prior to sensitization) or on d 15, 17, or 57. Rats were exposed for 3 min to aerosolized OA (OA 3% in phosphate-buffered saline) every week, starting on d 18. Serum OA-specific IgE was evaluated by reverse enzyme-linked immunosorbent assay (ELISA) 3 d after each OA challenge. BN rats elicited a detectable OA-specific IgE response that decreased after repeated aerosol exposures. Influenza virus infection transiently increased the OA-specific IgE response when rats were immunized with OA alone and were infected 1 d prior to the first challenge and also when rats received only saline on d 1, were exposed each week to aerosolized OA, and were infected prior to the seventh challenge. These results, with data previously reported in mice, emphasize the importance of upper respiratory tract viral infection in increasing IgE responses to allergens and may be of importance in human disease.

Histopathological changes in the upper respiratory tract of F344 rats following infection with a rat-adapted influenza virus.

The present study determined the morphogenesis of upper respiratory tract disease in rats following infection with a rat-adapted influenza virus. Sixty-eight 60-day-old, male F344 rats were infected by intranasal inoculation and necropsied at days 1, 2, 4, 7, 14, and 28 post-inoculation (PI). Responses to infection were studied by routine light microscopy for histopathologic changes and immunocytochemistry for localization of viral antigen. Severe infection-induced changes involved the respiratory epithelium and underlying lamina propria, and the nasal-associated lymphoid tissue, with minimal involvement of the transitional epithelium. The lesions were most severe on the septum and the medial aspect of the nasoturbinates. Viral antigen, located in the respiratory epithelium of affected regions at days 1 and 2 PI, was associated with neutrophilic infiltration and epithelial necrosis and erosion. At day 4 PI, an infiltrate of lymphocytes, macrophages, and fewer neutrophils was present, often accompanied by epithelial regeneration. Changes in the nasal-associated lymphoid tissue were evaluated using morphometric analysis and consisted of hyperplasia (days 4 to 7 PI) followed by progressive involution (days 14 to 28 PI). Mild lesions associated with foci of viral antigen were also observed in the nasal olfactory epithelium on days 1, 2, and 4 PI. The changes observed in the present study indicate the potential value of rat-adapted influenza virus infection as a model of human influenza.

Characterization of upper respiratory disease in rats following neonatal inoculation with a rat-adapted influenza virus.

Neonatal F344 rats were infected with a rat-adapted influenza virus (RAIV) to use as a potential model to study the combined effects of air pollutant exposure with early life respiratory viral infections. Initially, 6-day-old pups were intranasally inoculated with RAIV or medium alone, and nasal and lower respiratory tract (LRT) tissues were assessed histologically at 1, 3, 6, and 13 days postinoculation (DPI). Immunologic assessments included thymic lymphocyte quantification and anti-RAIV immunoglobulin production. Pups then received two inoculations (at 6 and 30 days of age), with histologic and immunologic assessment 6 and 13 days after the second inoculation and bronchoprovocation testing 5-8 weeks later. Following the single RAIV inoculation, IgM and IgG1 measurements increased at 6, 11, and 15 DPI, with IgG1 being greater at 11 and 15 DPI. Nasal lesions were evident as early as 1 DPI and primarily involved the anterior dorsal medial meatus and adjacent dorsal atrio- and nasoturbinates. Alterations included epithelial cell exfoliation and necrosis, mild erosions, suppurative and nonsuppurative inflammation, intraepithelial neutrophil accumulations, and intraluminal exudate. By 3 DPI, olfactory epithelial damage was multifocal or locally diffuse, with degeneration of sensory cells and variable inflammation. By 13 DPI, lesions were essentially repaired. Minimal changes were apparent in the LRT despite evidence of viral replication in the lungs 24 hours after inoculation (> 3 log10 plaque-forming units/lung). Pups reinoculated with RAIV at 30 days of age did not develop significant histologic lesions, nor did they exhibit increased airway responsiveness when assessed as young adults. In spite of their immature immune status at the time of initial infection, 13 days after the second RAIV inoculation, IgG1 increased substantially. Thus, neonatal RAIV infection resulted in acute nasal epithelial injury and inflammation, alterations that may allow subsequent evaluation of viral disease-air pollutant interactions.

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on influenza virus host resistance in mice.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes numerous immunotoxic effects including thymic involution and an immunosuppression of nonspecific as well as specific cell- and humoral-mediated immunity. TCDD administration to laboratory animals also results in a decreased resistance to numerous bacteria, viruses, and parasites. Effects on virus host resistance appear to be among the most sensitive effects of TCDD immunotoxicity. However, previous studies have not achieved a no effect level. The present studies utilized an influenza virus host resistance model in mice to quantify the sensitivity of this model to TCDD and to determine the NOAEL (no observed adverse effect level) of TCDD for influenza virus. Results indicated that a single dose of TCDD at 0.10, 0.05, or 0.01 microgram/kg resulted in an increased mortality to Hong Kong influenza virus when mice were challenged 7 days after TCDD administration. Increased mortality was not correlated with increased virus titers in the lungs. TCDD at 0.005 or 0.001 micrograms/kg had no effect on influenza-induced mortality. TCDD alone did not affect thymus weight at any dose administered in this study. TCDD also did not alter the virus-enhanced increase in lung weight:body weight ratio nor the virus-induced decrease in thymus weight. Thus, low levels of TCDD exposure lead to enhanced mortality to influenza virus; however, the mechanism of this effect remains to be elucidated. Nonetheless, enhanced mortality to influenza virus in mice following a single dose of 10 ng TCDD/kg represents the most sensitive adverse effect yet reported for TCDD.

Immunotoxicology of regional lymphoid tissue: the respiratory and gastrointestinal tracts and skin.

The area of immunotoxicology has grown significantly over the past decade. Most of the research on methods development and validation and mechanisms of action have focused on the systemic immune system (i.e, spleen, thymus). However, since the regional/mucosal immune system plays an important role in host resistance and is also potentially exposed to significant levels of chemicals, it should also be considered a potential target. The objective of this symposium was to increase the awareness and importance of examining the effects of xenobiotics on the regional/mucosal immune response. The speakers presented an overview of the rapidly growing field of regional immunology with emphasis on the respiratory tract, gut, and skin. The complex intercellular distribution and limited number of immune cells within the various regional lymphoid tissue have resulted in the use of a variety of methods to study the immune response of these tissues. These methods and results of studies which examined the effects and mechanisms of action of chemicals and uv light on the regional immune response were discussed.

Immunotoxicological investigation using pharmaceutical drugs. In vitro evaluation of immune effects using rodent or human immune cells.

In order to evaluate the relevance of in vitro methods for immunotoxicity assessment, the effects of pharmaceutical drugs on lymphoproliferative and cytotoxic functions of mouse splenocytes and human peripheral blood mononuclear cells (hPBMC) were studied. A comparison of sensitivity of immune cells from different origins to an in vitro exposure to different xenobiotics was performed using non-immunosuppressive (cimetidine and furosemide) and immunosuppressive (azathioprine (AZA), cyclosporine A (CSA), and dexamethasone (DEX)) drugs. For CSA, sensitivity of both rat and mouse splenocytes following in vitro exposure was compared to the one of hPBMC. Immune function tests included lymphoproliferative response to mitogenic lectins (concanavalin A (Con A) and phytohemagglutinin (PHA-P)) or to allogeneic cells (mixed leukocyte response (MLR)) and cytotoxicity assays (cytotoxic-T lymphocyte (CTL) and natural killer (NK) cell-mediated cytolysis). Additionally, to evaluate how well in vitro assays represent the in vivo situation, a comparison of the effect of cyclosporine A on the same immune function tests following in vivo or in vitro exposure was performed. The data obtained show numerous similarities in the effects observed following in vitro exposure of rodent or human cells to the drugs and a very similar sensitivity of rat and mouse cells to CSA in vitro. Discrepancies between human and rodent cells such as lymphoproliferative response to PHA-P following exposure to DEX or sensitivity of CTL-mediated cytolysis to CSA do exist. In vitro assays were very representative of the in vivo situation, both in the rat and in the mouse, following CSA exposure, except for NK cell activity in the rat. These data show the usefulness of in vitro systems for immunotoxicity assessment. They allow direct comparison of rodent and human systems, and could be representative, for drugs altering specifically the immune system like CSA does, of the in vivo situation.

Influenza virus host resistance models in mice and rats: utilization for immune function assessment and immunotoxicology.

Each year influenza viruses are responsible for epidemic respiratory diseases with excess morbidity and mortality. The severity of influenza diseases ranges from mild upper respiratory tract infections to severe lower respiratory tract infections involving pneumonia, bronchiolitis and coincidental bacterial super-infections. The immune response to influenza viruses can be schematically divided into a cascade of non-specific and specific functions. These functions are involved at different well defined time points after infection. We describe in this manuscript three influenza models utilized in our laboratory: (i) a highly virulent influenza virus (influenza A/Hong Kong/8/68 (H3N2) virus) adapted to B6C3F1 mice, (ii) a mouse-adapted influenza A/Port Chalmers/1/73 (H3N2) virus, and (iii) a rat-adapted influenza virus (RAIV) model (influenza A/Port Chalmers/1/73 (H3N2)). This rat-adapted influenza model has been mainly utilized as a model to assess local immunotoxic effects of inhaled environmental pollutants such as phosgene. These host resistance models are also useful for assessing the effect of systemically-induced immunosuppression or immunomodulation by drugs or chemicals on the local pulmonary immune response to influenza virus. The comparison of these different models allowed two major conclusions: (a) viral replication and mortality are two different endpoints and are not necessarily linked (no mortality was observed with Port Chalmers virus in the mouse although the virus replicates to high titers in the lung with a kinetic pattern comparable to the one obtained with Hong Kong virus), (b) mortality, viral replication, and immune function assessment are different endpoints that can be used, depending on the question addressed.

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on pulmonary influenza virus titer and natural killer (NK) activity in rats.

Suppression of immune function and enhanced susceptibility to infection in mice is one of the more sensitive indicators of TCDD toxicity. Recent efforts to demonstrate similar effects in the rat have shown that there are considerable differences between the two species. The purpose of this study was to determine the effect of TCDD exposure on (a) an influenza virus host resistance model in rats and (b) natural killer cell activity in the lung and spleen. Fischer 344 rats were treated with 10 micrograms TCDD/kg body weight via gavage and infected intranasally with rat-adapted influenza virus (RAIV) 7 days later. Virus-augmented NK activity assessed at 48 hr postinfection in the lung was significantly suppressed in rats treated with 3, 10, or 30 micrograms TCDD/kg body weight. Spontaneous NK activity in either lung or spleen was not affected by TCDD exposure. Significantly higher virus titers were observed on Days 2, 3, and 4 postinfection in the lungs of rats treated with TCDD (10 micrograms/kg). TCDD had no effect on the amount of virus recovered from nasal lavage. Acute exposure to TCDD did not significantly affect lung and body weights in rats infected with RAIV except in the highest dose (30 micrograms/kg) treated rats. Rats exposed to repeated doses of TCDD showed a significant increase of lung weights and L/B ratios when rats were infected with RAIV after TCDD exposure. Virus-augmented pulmonary NK activity in these rats was significantly suppressed; however, the suppression was not more profound than that in rats exposed to a single dose of TCDD.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced and prolonged pulmonary influenza virus infection following phosgene inhalation.

Animal infectivity models have been important in the demonstration of enhanced susceptibility to viral and bacterial infection as a result of low-level toxicant exposure. This study demonstrated an enhanced and prolonged viral infection using an influenza virus infectivity model in the rat following exposure to the toxicant gas phosgene. Fischer-344 rats exposed to either air or a sublethal concentration of phosgene demonstrated peak pulmonary influenza virus titers 1 d after infection. Virus titers in rats exposed to air declined rapidly falling below detectable levels by 4 d after infection. However, a significantly enhanced and prolonged pulmonary influenza virus infection was observed on d 3 and 4 after infection in rats exposed to phosgene. Virus was cleared below detectable limits on d 5 after infection in animals exposed to phosgene. Thus, inhalation of sublethal concentrations of phosgene resulted in an increased severity of pulmonary influenza virus infection. This study provides a demonstration of the effective use of a rat viral infectivity model to detect the immunotoxicity of inhaled pollutants. This model will allow future studies to focus on the immunological mechanism(s) responsible for the enhanced and prolonged pulmonary influenza virus infection.

Effects of PCB (Aroclor 1254) on non-specific immune parameters in rhesus (Macaca mulatta) monkeys.

The effects of low level, chronic polychlorinated biphenyl--Aroclor 1254--(PCB) exposure were investigated on non-specific immune parameters in female rhesus (Macaca mulatta) monkeys. Five groups of monkeys were orally administered with PCB at concentrations of 0, 5, 20, 40 or 80 micrograms/kg bw/day. Immunotoxicity testing was initiated after 55 months of exposure. The serum hemolytic complement activity in all PCB treated groups was significantly higher (P less than 0.05) than that in the control group. A statistically significant dose-related increase in natural killer cell activity was evident at the 75:1 effector to target cell ratio. Similarly, a statistically significant dose-related increase was noted for thymosin alpha-1 levels but not for thymosin beta-4 levels. Statistically significant increased interferon levels were noted in the 20 and 80 micrograms/kg groups compared with the control group while the levels in the 40 micrograms/kg group were decreased significantly compared with the control group. The production of tumor necrosis factor by monocytes in the PCB treated groups was not different to that in the control group. The results indicated that long term exposure to PCB modulate several non-specific immune parameters.

Examination of immune parameters and host resistance mechanisms in B6C3F1 mice following adult exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Adult female B6C3F1 mice were given a single ip dose of 0, 01, 1.0, or 10.0 micrograms/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and examined for immune function and host resistance 7-10 d later. Exposure to TCDD resulted in a significant dose-related decrease in induction of both IgM and IgG antibody-forming cells. This suppression was noted for both T-dependent and T-independent antigens. TCDD at a dosage of 10 micrograms/kg was shown to suppress production of antibody to viral hemagglutinin. In contrast, TCDD exposure had no significant effect on natural killer cell function, production of interferon, or various parameters of macrophage function. Assessment of host resistance revealed a significant increase in susceptibility to fatal infection with influenza virus, but no significant alteration in susceptibility to infection with the bacterium Listeria monocytogenes.

Natural killer activity in Fischer-344 rat lungs as a method to assess pulmonary immunocompetence: immunosuppression by phosgene inhalation.

Phosgene, also known as carbonyl chloride, carbon oxychloride, and chloroformyl chloride, is a toxic air pollutant and a potential occupational health hazard. Studies were initiated (a) to evaluate the measurement of pulmonary natural killer (NK) activity as a method to assess pulmonary immunocompetence, and (b) to determine whether exposure to phosgene resulted in local pulmonary or systemic immune dysfunction. Fischer-344 male rats were exposed either to filtered air or to 1.0 ppm phosgene gas for four hours. The effect of phosgene on lung NK activity was quantified at different times after acute phosgene exposure. Pulmonary NK activity was measured by mincing lung tissue into small pieces prior to incubation with collagenase. Whole-lung homogenate was assayed for NK activity utilizing a 4 hour 51-Cr-release assay with YAC-1 cells as target cells. Acute phosgene exposure resulted in a suppressed pulmonary NK activity on days 1, 2, and 4 after exposure; however, normal levels of biological activity were observed 7 days after exposure. The suppressed NK activity was not restored after removal of adherent cells from the lung homogenate, thus indicating that the effect of phosgene on NK activity was not due to immunosuppression via mobilization of suppressor alveolar macrophages. Pulmonary immunotoxicity was also observed after exposure at 0.5 ppm, while no adverse effects were observed at 0.1 ppm phosgene. Systemic immunotoxic effects were observed for NK activity in the spleen, but not in the peripheral blood. It is thus important in pulmonary immunotoxicology to evaluate systemic immune functions, since secondary effects--distant to the original interaction--may occur with potentially serious consequences. Cells exhibiting natural killer activity comprise a part of the nonspecific innate immunity that is important in defense against both neoplastic and viral diseases. Any perturbation of this important nonspecific immunological mechanism may result in a compromised host more susceptible to infectious and neoplastic disease.

Immunosuppression of pulmonary natural killer activity by exposure to ozone.

Ozone is an oxidant gas and an ubiquitous oxidant air pollutant with the potential to adversely affect pulmonary immune function with a consequent increase in disease susceptibility. Pulmonary natural killer (NK) activity was measured in order to assess the pulmonary immunotoxicity of continuous ozone exposure. Continuous ozone exposures at 1.0 ppm were performed for 23.5 hours per day for either 1, 5, 7, or 10 consecutive days. Pulmonary immune function was assessed by measuring natural killer (NK) activity from whole-lung homogenates of male Fischer-344 rats. Results of this study indicated that continuous ozone exposure for 1, 5, or 7 days resulted in a significant decrease in pulmonary NK activity. This suppressed pulmonary NK activity returned to control levels after continuous exposure to ozone for 10 days. The suppressed pulmonary NK response was thus attenuated and returned to normal values in the continued presence of ozone gas. This attenuation process is dynamic, complex, and doubtless involves several cell types and/or products of these cells. Pulmonary NK activity was also suppressed at 0.5 ppm ozone, but not at 0.1 ppm ozone, following 23.5 hours of exposure. NK activity is important for defense against viral, bacterial, and neoplastic disease. The depressed NK activity resulting from continuous ozone exposure could therefore result in a compromised ability to defend against pulmonary diseases.

Enhancement of natural killer cell activity and interferon production by manganese in young mice.

The effect that MnCl2 has on murine splenic natural killer (NK) cell activity was investigated in infant (10 days old), pre-weanling (18 days old) and weanling (24 days old) C57BL/6J mice. A single intraperitoneal injection of 10, 20 or 40 micrograms MnCl2/g body weight caused a significant enhancement in NK activity, as determined by the in vitro 51Cr release assay. Comparable enhancement of NK activity was observed for age-matched mice injected intraperitoneally with polyinosinic polycytidylic acid (Poly I:C). Both MnCl2 and Poly I:C caused elevations in serum interferon levels. Time-course studies revealed that interferon levels returned to normal within 48 hours following injection with either MnCl2 or Poly I:C; however enhanced NK activity persisted for up to 48 hours in Poly I:C-injected mice and 72 hours in MnCl2-injected mice. The administration of rabbit anti-asialo GMl to MnCl2-injected mice completely abrogated the enhanced NK activity. In addition, the injection of rabbit anti-mouse interferon alpha, beta but not gamma completely abrogated the enhanced NK activity. In addition, the injection of rabbit anti-mouse interferon alpha, beta but not gamma completely abrogated the enhancement of NK activity by MnCl2 and to a lesser extent the enhancement of NK activity by Poly I:C. These results indicate that despite low levels of NK activity in pre-weanling mice, MnCl2 is capable of enhancing this activity by 8-9 fold. Furthermore, Mn-enhanced NK activity in these young mice appears to be mediated by the production of interferon alpha, beta.

Effects of 7,12-dimethylbenz[a]anthracene, benzo[a]pyrene and cyclosporin A on murine cytomegalovirus infection: studies of resistance mechanisms.

Susceptibility to murine cytomegalovirus (MCMV) was enhanced by treating B6C3F1 and CD-1 mice subcutaneously with 100 mg 7,12-dimethyl-benz[a]anthracene (DMBA)/kg fractionated over a 2 week period prior to sub-lethal infection. Virus-augmented natural killer cell (NKC) activity was depressed in B6C3F1 mice treated with 100 mg DMBA/kg, while serum interferon (IFN) levels were unaffected. Treatment with 50 mg DMBA/kg had no effect on susceptibility to virus or virus-augmented NKC activity. Susceptibility to MCMV was not affected by treating mice with 400 mg benzo[a]pyrene (B[a]P)/kg using the same exposure regimen. Virus-augmented NKC activity was suppressed in B[a]P-treated mice, but the magnitude of the suppression (18%) was much less than that for DMBA-treated mice (39%). Susceptibility to MCMV, virus-augmented NKC and IFN induction were not affected in mice treated intraperitoneally with 50 mg cyclosporin A (CSA)/kg/day for 5 days and infected on the 5th day of treatment. In contrast, enhanced susceptibility to MCMV and depressed NKC activity were observed in mice treated by the same exposure regimen on days 1-5 post infection. Susceptibility was not affected by CSA given on days 5-9 post infection. The data are useful not only because they show that DMBA and appropriately-timed CSA treatments suppress virus augmented NKC and enhance susceptibility to MCMV, but also because they help to define the relative importance of certain immune responses in defending against the infection, thus improving the usefulness of MCMV as a host resistance model for immunotoxicity testing. The data suggest that chemicals which depress NKC are likely to enhance susceptibility to MCMV, and conversely that effects on NKC should be suspected when chemical exposure enhances susceptibility to MCMV.

Rat leukocyte interferons: production of an acid-labile interferon after induction with Newcastle disease virus.

Rat leukocytes produce three interferon species after infection with Newcastle disease virus. Two of the three interferon species (22-24,000 and 30,000 daltons) were acid and heat stable, protected rat and mouse cells from virus-mediated cytopathic effect (CPE), and were neutralized by antisera to mouse L-cell (alpha/beta) interferon. The third, 30,000-dalton interferon species was heat and acid labile; protected rat, mouse, human, and bovine cells from virus-mediated CPE; and was neutralized by antisera to mouse L-cell interferon and human leukocyte interferon. Thus, the rat leukocyte interferon system is similar to the human system in the kinetics of interferon production, the production of multiple interferons, heterologous antiviral activity, molecular weight, and in the production of an acid-labile species. The rat leukocyte interferon system therefore represents an important model for examining the normal production and action of acid-labile interferons and their possible role in the regulation of leukocyte function and cellular differentiation.

Selective immunosuppression in mice of natural killer cell activity by ochratoxin A.

Ochratoxin A, a naturally occurring mycotoxin, has recently been shown to cause renal and hepatic carcinomas in mice. In the present studies, the effects of ochratoxin A on immune mechanisms associated with tumor resistance were examined in mice using dose levels similar to those that cause neoplasia. Ochratoxin A was shown to specifically inhibit natural killer (NK) cell activity and increase the growth of transplantable tumor cells without altering T-cell- or macrophage-mediated antitumor activity. In contrast, ochratoxin B, a much less toxic ochratoxin, did not influence immune function. Polyinosinic:polycytidylic induced interferon was markedly reduced in mice following exposure to ochratoxin A although total serum protein levels were slightly increased. Injection of polyinosinic:polycytidylic enhanced NK activity in the presence of ochratoxin A, although the level of enhancement was slightly lower than that produced by the agent in the absence of ochratoxin A. Thus, ochratoxin appears to suppress NK cell activity by inhibiting production of basal interferon. Additionally, these findings suggest a possible role for altered NK cell function in the development of mycotoxin-induced carcinogenesis.