Lung function changes in mice sensitized to ammonium hexachloroplatinate.

Occupational exposure to halogenated platinum salts can trigger the development of asthma. The risk to the general population that may result from the use of platinum in catalytic converters and its emerging use as a diesel fuel additive is unclear. To investigate pulmonary responses to platinum, we developed a mouse model of platinum hypersensitivity. Mice were sensitized through application of ammonium hexachloroplatinate (AHCP) to the shaved back on days 0, 5 and 19, and to each ear on days 10, 11 and 12. On days 24 and 29, mice were challenged by oropharyngeal aspiration with AHCP in saline. Before and immediately after challenge, pulmonary responses were assessed using whole body plethysmography (WBP). A dose-dependent increase in immediate responses was observed in AHCP-sensitized and challenged mice. On days 26 and 31, changes in ventilatory responses to methacholine (Mch) aerosol were assessed by WBP; dose-dependent increases in Mch responsiveness occurred in sensitized mice. Lymph node cell counts indicate a proliferative response in lymph nodes draining the sites of application. Bronchoalveolar lavage fluid harvested from sensitized mice contained an average of 5% eosinophils compared to less than 0.5% in non-sensitized mice (p < 0.05); significant increases in total serum immunoglobulin E were observed for all sensitized mice. Although a second airway challenge on day 29 affected some results, only one airway challenge was needed to observe changes in lung function.

Evaluation of the ToxRTool's ability to rate the reliability of toxicological data for human health hazard assessments.

Regulatory agencies often utilize results from peer reviewed publications for hazard assessments. A problem in doing so is the lack of well-accepted tools to objectively, efficiently and systematically assess the quality of published toxicological studies. Herein, we evaluated the publicly available software-based ToxRTool (Toxicological data Reliability assessment Tool) for use in human health hazard assessments. The ToxRTool was developed by the European Commission's Joint Research Center in 2009. It builds on Klimisch categories, a rating system established in 1997, by providing additional criteria and guidance for assessing the reliability of toxicological studies. It also transparently documents the study-selection process. Eight scientists used the ToxRTool to rate the same 20 journal articles on thyroid toxicants. Results were then compared using the Finn coefficient and "AC1" to determine inter-rater consistency. Ratings were most consistent for high-quality journal articles, but less consistent as study quality decreased. Primary reasons for inconsistencies were that some criteria were subjective and some were not clearly described. It was concluded, however, that the ToxRTool has potential and, with refinement, could provide a more objective approach for screening published toxicology studies for use in health risk evaluations, although the ToxRTool ratings are primarily based on study reporting quality.

TNF-alpha enhanced allergic sensitization to house dust mite in brown Norway rats.

We have recently demonstrated that pulmonary exposure to residual oil fly ash (ROFA) resulted in enhanced sensitization to house dust mite (HDM) and augmented the development of allergic lung disease after allergen challenge. This effect was associated with increased tumor necrosis factor alpha (TNF-alpha), a macrophage- and epithelial cell-derived cytokine that promotes granulocyte migration to the lung. The present study examined whether exogenous administration of TNF-alpha enhances sensitization to HDM. One day prior to pulmonary sensitization with 10 microg HDM (5 microg each on days 1 and 3), female Brown Norway rats were instilled via the trachea with either 2.0 microg recombinant rat TNF-alpha, 2.0 microg bovine serum albumin (BSA), or 1,000 microg ROFA, and were challenged with 10 microg HDM 14 days later. Antigen-induced immediate bronchoconstriction responses, antigen-specific immunoglobulin E (IgE) titers, lymphocyte proliferation, (cytokines (TNF-alpha and interleukin [IL]-13), and eosinophils were elevated in rats treated with ROFA or TNF-alpha compared with BSA-treated controls after HDM challenge. Intratracheal administration of anti-TNF-alpha monoclonal antibody during ROFA exposure did not reduce ROFA-enhanced lymphocyte proliferation or IgE titers, but had a trend for reduced pulmonary inflammation. This study demonstrates that TNF-alpha has similar adjuvant activity as ROFA, but other factors may fulfill this function when TNF-alpha activity is blocked.

Air pollutant-enhanced respiratory disease in experimental animals.

Studies in animals have shown that a wide range of airborne particulates including cigarette smoke, acid aerosols, metals, organic compounds, and combustion products can interfere with the normal defense processes of the lung to enhance susceptibility to respiratory infection or exacerbate allergic diseases. Such detrimental effects are less easy to quantify in humans because of the difficulties in obtaining comprehensive exposure history and health status in large populations and because of the inherent dangers of inducing disease in clinical studies. In this article we describe examples of how air pollutants affect lung disease in experimental animal systems. This information can be used to predict the health risk of simple and complex exposures and to lend insight into the mechanisms of air pollution toxicity.

Dose response for UV-induced immune suppression in people of color: differences based on erythemal reactivity rather than skin pigmentation.

Ultraviolet radiation (UVR) is known to suppress immune responses in human subjects. The purpose of this study was to develop dose responses across a broad range of skin pigmentation in order to facilitate risk assessment. UVR was administered using FS 20 bulbs. Skin pigmentation and UVR sensitivity were evaluated using Fitzpatrick classifications, minimal erythemal dose (MED), slope of the erythemal dose response curve (sED), baseline pigmentation and tanning response. To assess immune responses dinitrochlorobenzene (DNCB) was applied to irradiated buttock skin 72 h after irradiation. Two weeks later DNCB was applied to the inside upper arm. Skin thickness was measured before and after challenge. Dose response was modeled (to obtain a regression line) for the entire group of 185 subjects. With the exception of sED none of the above-mentioned pigmentation indicators contributed significantly to variability around the regression line. Thus, differences in sensitivity for multiple skin types based on Fitzpatrick classification or MED were not observed. However, differences in immune sensitivity to UVR were detected between subjects with steep erythemal dose response curves and those with moderate or flat responses. For subjects with steep erythemal responses the dose calculated to suppress the immune response by 50% was 114 mJ/cm2. This group included individuals with Fitzpatrick skin types I-V, MED for these subjects ranged from 30 to 80 mJ/cm2. The 50% suppression dose for subjects with weak or no erythemal response could not be computed (the dose response was flat). This resistant group included subjects with skin types IV-VI and MED for these subjects ranged from 41 to > 105 mJ/cm2. This study provides a human dose response for UVR suppression of contact sensitivity that will be useful in risk assessment. It is the first study to provide this information using the FS sun lamp and is the first study to include people of color. The sED appears to be a new variable for identifying sensitive subjects at risk of UVR-induced immune suppression.

Animal models to assess the effects of air pollutants on allergic lung disease.

Animal models provide toxicologists with useful tools for assessing risks associated with respiratory allergy. Both the mouse and BN rat models described exhibit many of the features of human allergic asthma. It is clear that environmental contaminants can exacerbate the expression of these features. Work is under way to explore underlying mechanisms and to develop methods for applying these data to human health risk assessment.

Enhanced allergic sensitization by residual oil fly ash particles is mediated by soluble metal constituents.

Epidemiological studies have demonstrated an association between elevated levels of particulate matter (PM) air pollutants and exacerbation of asthma symptoms. We have shown in a Brown Norway (BN) rat model of house dust mite (HDM) allergy that preexposure to residual oil fly ash (ROFA) particles enhanced the sensitization phase such that the secondary immune response and associated lung injury were increased after allergen challenge. To determine whether the metals present in ROFA mediated this effect, BN rats were intratracheally instilled with either ROFA (1000 microg) or acidified saline + NiSO(4) (105.12 microg), VSO(4) (98.2 microg), FeSO(4) (58.49 microg), or a mixture (Mix) of each metal. HDM-specific IgE was higher in the serum of the ROFA, Ni, V, and Mix groups than in the HDM group after challenge, and antigen-induced bronchoconstriction responses were increased in the Ni group. Lymphocyte proliferation to antigen was increased in the ROFA, Ni, and V groups compared to controls. Total protein and eosinophil peroxidase levels were elevated in the Fe group, and eosinophil numbers in the bronchoalveolar lavage fluid (BALF) were increased in the ROFA and Fe groups compared to HDM control. IL-5 and IL-13 mRNA expression was also increased in the lung tissue of all metal and ROFA-treated groups, while BALF IL-10 was elevated in the Fe and Mix groups, and IL-6 and TNF-alpha were elevated in the metal and ROFA-treated groups compared to controls. These results suggest that ROFA's metallic constituents mediate enhancement of sensitization to HDM and that pulmonary inflammation may play a role in this adjuvant effect.

Allergen-triggered airway hyperresponsiveness and lung pathology in mice sensitized with the biopesticide Metarhizium anisopliae.

Metarhizium anisopliae is an entomopathogenic fungus recently licensed for indoor control of cockroaches, a major source of allergens. While M. anisopliae has been shown to be non-infectious and non-toxic to mammals there has been only limited research on potential allergenicity. Using a mouse model, we previously demonstrated allergic immune and inflammatory responses to this agent. The present study was designed to determine whether these responses were associated with changes in pulmonary responses, lung pathology, and the cytokine profile in bronchoalveolar lavage fluid (BALF). Soluble factors from fungal components were combined in equal protein amounts to form M. anisopliae crude antigen (MACA). BALB/C mice were intratracheally (i.t.) challenged with 10 microg MACA 14 days post intraperitoneal sensitization with 25 microg fungal antigen in aluminum hydroxide adjuvant. Physiological and cellular changes were examined. The mice were tested for airway hyperresponsiveness before (No Chal) and after (1, 3, and 8 days post challenge (DPIT)) MACA IT challenge. Subsequently, serum, BALF and the lungs were harvested. All treatment groups concurrently demonstrated significant non-specific pulmonary inflammation (neutrophil influx) and increased pulmonary sensitivity to methacholine (Mch) at 1 DPIT MACA challenge. Where as both adjuvant treated and naïve mice airway responses had returned to near normal levels by 3 DPIT, mice which were previously sensitized with MACA were still hyperresponsive to Mch challenge at 3 and 8 DPIT. This hyperresponsiveness correlates with eosinophil and lymphocyte influx, which is maximal at 3 DPIT and still elevated at 8 DPIT. Interleukin (IL) 5 was elevated for all treatment groups at 1 DPIT but only the MACA sensitized mice maintained elevated levels for both 3 and 8 DPIT. Furthermore, MACA sensitized mice had a more extensive inflammatory histopathology at all examined time points with peribronchial and perivascular infiltrates, like those associated with allergic responsiveness, peaking at 3 DPIT. These pulmonary pathologic changes appeared to be consistent with elevated levels of serum and BALF total IgE, BALF IL-4, eosinophils, and lymphocytes following MACA IT challenge in MACA sensitized mice. There were no significant differences among the three treatment groups with regard to BALF interferon (IFN) gamma. The cytokines profiled indicate a Th2-type response, which is reflected in the cellular influx and total IgE induction. These data further indicate that immune inflammatory responses, observed in mice following MACA sensitization and challenge, are associated with physiologic changes and histopathology characteristic of allergic disease.

The effect of a vitamin A acetate diet on ultraviolet radiation-induced immune suppression as measured by contact hypersensitivity in mice.

The adverse health effects caused by increased exposure to ultraviolet radiation (UVR) due to deterioration of stratospheric ozone are of major concern. These health effects include sunburn, skin cancer, cataracts and immune suppression. Immune suppression has been associated with the release of cytokines, a defect in antigen presentation, induction of suppressor T cells and suppression of contact hypersensitivity (CH). CH is typically assessed by the mouse ear swelling test (MEST). Previous studies have demonstrated enhanced CH responses with vitamin A acetate (VAA) dietary supplementation assessed by MEST and the local lymph node assay (LLNA). To determine the effect that VAA has on UVR-induced immune suppression, we examined both the induction and elicitation phases of CH using murine models. The MEST was used to evaluate the interaction of UVR and VAA on CH elicitation. However, a positive MEST response requires that the induction phase as well as the elicitation phase of CH be functional. The LLNA was used to evaluate the interaction of UVR and VAA only on CH induction. We tested the hypothesis that mice maintained on a VAA-enriched diet are more resistant to UVR-induced immune suppression (CH) than those maintained on a control diet. Mice were maintained on a VAA-enriched or the control diet for 3 weeks and then exposed to UVR 3 days prior to sensitization with 2,4-dinitrofluorobenzene (DNFB). VAA enhanced the MEST response in both UVR-exposed and non-UVR-exposed mice. The VAA-enriched diet did not significantly alter the LLNA response in either UVR- or non-UVR-exposed mice. However, there was significant suppression in CH by UVR as measured by the LLNA. These results indicate that (1) the VAA-enriched diet does not restore the number of proliferating cells in the CH induction phase of UVR-induced immunosuppression; (2) the immunosuppressive effects of UVR affect the induction phase of CH; and (3) the LLNA should be examined as an alternative to the MEST for measurement of UVR-induced immunosuppression. The data indicate that the VAA-enriched diet enhanced the elicitation response (MEST) but not the earlier induction phase (LLNA). Further studies are necessary to define mechanisms of action, but modulation of cytokines and effects of specific lymphocyte subsets, as well as systemic effects and local modulation at the site of elicitation are possible. Additionally, future studies to evaluate the effect of the VAA-enriched diet when multiple doses of both UVR and DNFB are used would be of interest for both the LLNA and MEST end-points.

Attenuated allergic responses to house dust mite antigen in feed-restricted rats.

Caloric restriction has been shown to alter a broad range of immunological end points in both experimental animals and humans. The objective of this study was to investigate the effect of short-term moderate feed restriction (25% reduction) on allergic immune responses in Brown Norway rats. After 3 weeks of acclimation to their feed regimens, rats were sensitized and 2 weeks later challenged with house dust mite (HDM) antigen via intratracheal instillation. Feed restriction resulted in lower levels of antigen-specific IgE in serum and reduced antigen specific lymphoproliferative activity in pulmonary lymph nodes. Feed restriction also attenuated pulmonary inflammation, as evidenced by lower levels of lactate dehydrogenase and total protein, decreased infiltration of neutrophils and eosinophils, and reduced secretion of pro-inflammatory cytokine tumor necrosis factor (TNF)-[alpha] in bronchoalveolar lavage fluid. In addition, feed restriction decreased TNF-[alpha] secretion in serum and decreased mRNA expression of TNF-[alpha] and interleukin-6 in pulmonary lymph nodes. We conclude that feed restriction strongly dampened the allergic immune responses to HDM in rats and that this attenuation was associated with decreased expression and secretion of pro-inflammatory cytokines.

Linking environmental agents and autoimmune disease: an agenda for future research.

Autoimmune diseases are influenced by multiple factors including genetics, age, gender, reproductive status, hormones, and potential environmental contaminants. A workshop, "Linking Environmental Agents and Autoimmune Diseases," was convened at the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, 1-3 September 1998, to review current knowledge about links between environmental exposures and autoimmune disease, to identify and prioritize research needs, and to develop an integrated, multidisciplinary research agenda. Participants spent the last half-day of the workshop in small group discussions for the purpose of developing consensus on research needs. Research needs identified were a) develop research tools needed to explore links between environmental agents and autoimmune disease; b) establish a disease registry or surveillance system; c) develop and validate strategies for screening chemicals for the potential to induce or exacerbate autoimmune disease; d) develop an emergency response strategy to gain information from accidental exposures; and e) conduct hypothesis-driven research in occupationally exposed groups and/or in experimental animals. There was consensus that meetings like this workshop and projects that facilitate interactions between specialties should be encouraged. A multidisciplinary approach is needed to address this problem.

Residual oil fly ash exposure enhances allergic sensitization to house dust mite.

Epidemiological studies have shown an association between elevated levels of particulate matter air pollution and increased morbidity and hospital visits in asthmatics. Residual oil fly ash (ROFA) is a primary combustion particle containing sulfate and metals such as vanadium, nickel, and iron. In this study the effect of ROFA on sensitization to house dust mite (HDM) was examined in a Brown Norway rat model of pulmonary allergy. Rats were instilled via the trachea with 200 or 1000 micrograms ROFA 3 days prior to local sensitization with 10 micrograms HDM and were challenged with 10 micrograms HDM 14 days later. Immunological endpoints were examined at 2, 7, and 14 days after sensitization and at 2 and 7 days after challenge (16 and 21 days post-sensitization, respectively). Antigen-specific immunoglobulin E and associated immediate bronchoconstriction responses to antigen challenge were increased in the ROFA-treated groups compared with the HDM control group. Lymphocyte proliferation to antigen was enhanced at Days 7 and 21 in the bronchial lymphocytes of ROFA-treated groups. Bronchoalveolar lavage fluid (BALF) eosinophil numbers and lactate dehydrogenase were significantly increased in the 1000 micrograms ROFA group at Days 2 and 16, BALF total proteins were elevated at Days 2 and 7 in both ROFA-treated groups, and BALF interleukin (IL)-10 was elevated in the 1000 micrograms ROFA group at Day 2. These results suggest that ROFA has an adjuvant effect on sensitization to HDM.

Use of immunotoxicity data in health risk assessments: uncertainties and research to improve the process.

A number of environmental contaminants can suppress immune responses and enhance susceptibility to infectious and/or neoplastic disease. Most of the evidence for immunotoxicity of such contaminants has been obtained from laboratory animal studies and risk assessors must make decisions about risk to the human population based on these studies. Uncertainties associated with this process include determining what level of immune suppression is adverse, extrapolating across species from rodent to human, and across levels of biologic organization from effects on immune function at the cellular level to effects on incidence of disease at the population level, accounting for intra-species variability, and assessing the relationship between effects following acute, subchronic, and chronic exposure. This paper reviews immunotoxicity data that may be applied to the development of risk assessment methods and models designed to reduce some of these uncertainties.

Immune responses in farm workers after exposure to Bacillus thuringiensis pesticides.

Although health risks to pesticides containing Bacillus thuringiensis (Bt) have been minimal, the potential allergenicity of these organisms has not been evaluated. Therefore, a health survey was conducted in farm workers before and after exposure to Bt pesticides. Farm workers who picked vegetables that required Bt pesticide spraying were evaluated before the initial spraying operation (n = 48) and 1 and 4 months after (n = 32 and 20, respectively). Two groups of low- (n = 44) and medium- (n = 34) exposure workers not directly exposed to Bt spraying were also assessed. The investigation included questionnaires, nasal/mouth lavages, ventilatory function assessment, and skin tests to indigenous aeroallergens and to a variety of Bt spore and vegetative preparations. To authenticate exposure to the organism present in the commercial preparation, isolates from lavage specimens were tested for Bt genes by DNA-DNA hybridization. Humoral immunoglobulin G (IgG) and immunoglobulin E (IgE) antibody responses to spore and vegetative Bt extracts were assayed. There was no evidence of occupationally related respiratory symptoms. Positive skin-prick tests to several spore extracts were seen chiefly in exposed workers. In particular, there was a significant (p < 0.05) increase in the number of positive skin tests to spore extracts 1 and 4 months after exposure to Bt spray. The number of positive skin test responses was also significantly higher in high (p < 0.05) than in low- or medium-exposure workers. The majority of nasal lavage cultures from exposed workers was positive for the commercial Bt organism, as demonstrated by specific molecular genetic probes. Specific IgE antibodies were present in more high-exposure workers (p < 0.05) than in the low and medium groups. Specific IgG antibodies occurred more in the high (p < 0.05) than in the low-exposure group. Specific IgG and IgE antibodies to vegetative organisms were present in all groups of workers. Exposure to Bt sprays may lead to allergic skin sensitization and induction of IgE and IgG antibodies, or both.

Allergic responses to the biopesticide Metarhizium anisopliae in Balb/c mice.

Metarhizium anisopliae is used as a microbial pesticide to control cockroaches and other insects. M. anisopliae has demonstrated neither infectivity nor toxicity in mammals. However, allergenicity has not been assessed. M. anisopliae is a prototype for other organisms released into the environment for pesticide or other beneficial applications. Hence this study is part of an effort to develop methods for screening such organisms for allergenic potential. Soluble factors from fungal components were combined in equal protein amounts to form a crude fungal antigen (MACA). Balb/c mice were intratracheally (IT) challenged with 25 micrograms fungal antigen 13 days post intraperitoneal sensitization with the fungal antigen in alhydrogel adjuvant. Additionally, mice were sensitized with adjuvant alone or chitin media in adjuvant as experimental controls. Serum and bronchoalveolar lavage fluid (BALF) were harvested prior to challenge and at 1 and 7 days post IT challenge (DPIT). These mice exhibited immune and pulmonary inflammatory responses to MACA characteristic of allergy. Total serum IgE for antigen-sensitized animals increased 7.6- and 14.7-fold over that for chitin media and adjuvant controls, respectively, at 7 DPIT. Less striking increases were seen at 24 DPIT and prior to challenge. BALF IL-4 was dramatically elevated only in MACA-sensitized and challenged mice and only at 1 DPIT. Additionally, there was a dose-dependent increase in BALF eosinophils from MACA-sensitized mice at both 1 and 7 DPIT. While lymphocyte counts were increased for all treatment groups at 1 DPIT, by 7 DPIT lymphocyte counts for MACA-sensitized mice only were significantly elevated compared to controls. Pulmonary inflammation, edema, and cell damage were apparent at 1 DPIT (25 micrograms MACA), as indicated by a neutrophilic influx and elevated levels of total protein and LDH, in both sensitized and control groups. These effects were significantly decreased, but not eliminated by reduction of the challenge dose to either 10 or 5 micrograms MACA. While BALF IL-4 was also reduced at the lower challenge doses, eosinophilia and total IgE were unchanged. The data suggest that the crude fungal extract MACA contains one or more potent allergens and that total IgE may be useful in the identification of the allergen(s).

Altered alveolar macrophage function in calorie-restricted rats.

Alveolar macrophage functions associated with clearance of bacteria from the lung were assessed in male Fischer 344 rats maintained on a 25% calorie-restricted diet. Calorie-restricted and ad libitum-fed (control) rats were exposed to concentrations of ozone known to compromise phagocytic function of alveolar macrophages. Ozone suppressed alveolar macrophage phagocytosis of latex beads in vitro in ad libitum-fed rats, but not in calorie-restricted rats. In fact, caloric restriction enhanced phagocytic function in both control and ozone-exposed animals. Ad libitum-fed rats exposed to ozone and challenged with Streptococcus zooepidemicus experienced a prolonged infection and influx of polymorphonuclear leukocytes (PMN), whereas calorie-restricted rats exposed to ozone cleared the bacteria in 24 h without an inflammatory response. Bacterial endotoxin-stimulated in vitro production of nitric oxide and tumor necrosis factor (TNF)-alpha as well as expression of TNF-alpha and interleukin-6 messenger RNAs were all lower in alveolar macrophages isolated from calorie-restricted rats. Together, the data suggest that caloric restriction enhances resistance to gram-positive bacteria, while lowering the production of proinflammatory mediators elicited by endotoxin, a component of gram-negative bacteria. Although increased bacterial resistance is considered beneficial, reduction in the lung's ability to induce inflammatory mediators can have both positive and pathophysiologic consequences.

Enhanced allergic responses to house dust mite by oral exposure to carbaryl in rats.

Epidemiological studies have demonstrated an association between use of carbamate insecticides, including carbaryl, and increased incidence of allergic asthma in farmers. In this study the effect of oral carbaryl exposure on the development of allergic responses to house dust mite (HDM) was examined in female Brown Norway rats. Rats were gavaged for 2 weeks with 0, 2, 10, or 50 mg/kg/day of carbaryl. They were sensitized with a subcutaneous injection of HDM in aluminum hydroxide adjuvant 3 days after the beginning of carbaryl exposure and challenged with antigen via the trachea 1 day after the final carbaryl ingestion. Two days after challenge, antigen-specific cell proliferation in pulmonary lymph nodes was significantly higher in the 50 mg/kg group than in controls, while antigen-specific splenocyte proliferation was decreased in groups dosed with 2, 10, and 50 mg/kg carbaryl. Total protein and lymphocyte number in bronchoalveolar lavage (BAL) fluid were also increased in the 50 mg/kg group. By 7 days after challenge, immune-mediated pulmonary inflammation (eosinophils), antigen-specific immunoglobulin (Ig) E level in serum, and antigen-specific IgE and IgA levels in BAL fluid were significantly elevated in the 50 mg/kg group. No apparent change was observed for lactate dehydrogenase and eosinophil peroxidase in BAL fluid, while the number of BAL macrophages were decreased in groups dosed with 10 and 50 mg/kg carbaryl. The results suggest that carbaryl may cause systemic immune suppression, while enhancing pulmonary allergic responses to house dust mite antigen.

Transfer of allergic airway responses with serum and lymphocytes from rats sensitized to dust mite.

House dust mite (HDM) antigen is one of the most common allergens associated with extrinsic asthma. In a model of allergic lung disease, Brown Norway (BN) rats sensitized to HDM with alum and Bordetella pertussis adjuvants produce high levels of IgE antibody and experience bronchoconstriction, increased airway hyperresponsiveness (AHR) to acetylcholine (ACh), and pulmonary inflammation after antigen challenge. The purpose of this study was to determine whether these asthmatic symptoms could be transferred from sensitized animals to naive recipients via humoral or cellular factors. Syngeneic recipient rats were injected (intraperitoneally with 4 x 10(7) cells (precultured overnight with either HDM or bovine serum albumin [BSA]) from lymph nodes of sensitized or control rats, respectively. Other groups received a tail-vein injection of serum from either HDM-sensitized or control rats. Antigen challenge in rats injected with sensitized cells caused increases in pulmonary inflammation and in AHR, but no changes in immediate bronchoconstriction as compared with control recipients. Antigen challenge in serum recipients resulted in immediate bronchoconstriction but had no effect on AHR or on pulmonary inflammation. These data show that immune-mediated lung inflammation and AHR are promoted by antigen-specific lymphocytes, whereas immediate allergic responses are caused by serum factors.

Modulation of T-helper cell populations: potential mechanisms of respiratory hypersensitivity and immune suppression.

Information presented at this symposium indicates that modulation of Th cell responses is one means by which xenobiotics may cause immunotoxicity. A shift from Th1 to Th2 responses can enhance both infectious and allergic disease. Hence, in some cases, a common mechanism may be responsible for effects that are generally considered to be very different. Because cytokines produced in the inflammatory process play a role in modulation of Th cell responses, there is a mechanism by which agents that appear to have only local effects at the portal of entry may, in fact, affect immune responses systemically. An understanding of conditions which trigger certain cytokine responses may be useful not only in understanding inflammation but also in predicting certain kinds of immunosuppressive and allergic responses. Future studies in this area are likely to provide insights into many areas of immunotoxicology.