Effect of Diesel Exhaust Particle Extracts on Induction of Oral Tolerance in Mice

Shin Yoshino*,{dagger},1, Hideyuki Hayashi{ddagger}, Shinji Taneda§, Hirohisa Takano, Masaru Sagai|| and Yoki Mori§

* Department of Pharmacology, Kobe Pharmaceutical University, Kobe 658-8558, Japan; {dagger} Department of Microbiology, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan; {ddagger} Department of Clinical Toxicology and Metabolism and § Department of Immunology and Microbiology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Tobetsu, Hokkaido 061-02, Japan; Pathophysiology Research Team, National Institute for Environmental Studies, Tsukuba, Ibaraki 305, Japan; and || Department of Nursing and Human Sciences, Faculty of Health Sciences, Aomori University of Health and Welfare, Aomori 030-8505, Japan

Received September 6, 2001; accepted December 4, 2001


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We examined the effect of diesel exhaust particle (DEP) extracts on oral tolerance in mice. For this examination, a single DEP sample was consecutively extracted with hexane (HEX-DEP), benzene (BEN-DEP), dichloromethane (DIC-DEP), methanol (MET-DEP), and 1 M ammonia (AMM-DEP). Residues unextracted (UNE-DEP) with the last extraction solvent 1 M ammonia were also used to test their ability to induce oral tolerance. To immunize mice, hen egg lysozyme (HEL) emulsified with an equal volume of CFA was injected sc (day 0). Oral tolerance was induced by feeding 10 mg HEL on days –5, –4, –3, –2, and –1. DEP, each DEP extract, and UNE-DEP were intranasally administered immediately after each feeding of HEL. The results showed that oral administration of HEL markedly suppressed production of anti-HEL IgG antibodies as well as proliferative responses of spleen cells to HEL. The suppression of anti-HEL IgG antibody production and the cell proliferation by the oral antigen was significantly blocked by DEP, DIC-, AMM-, and UNE-DEP. Neither HEX-, BEN-, nor MET-DEP modulated the orally induced suppression of these immune responses. When the levels of anti-HEL IgG2a antibodies and IFN-{gamma} (Th1 responses) and anti-HEL IgG1 antibodies and IL-4 (Th2 responses) were determined, DEP and DIC-DEP diminished the suppression of both Th1 and Th2 responses observed following oral administration of HEL. In contrast, UNE- and AMM-DEP prevented the reduction of Th1 but not Th2, and Th2 but not Th1 oral tolerance, respectively. Thus, UNE-DEP appears to contain compounds that block induction of Th1 but not Th2 oral tolerance, whereas AMM-DEP have compounds that abrogate induction of Th2 but not Th1 oral tolerance. DIC-DEP, as well as DEP, appear to contain components that block induction of both Th1 and Th2 oral tolerance. As oral tolerance is thought to play a critical role in preventing Th1 as well as Th2 food allergy, the blockade of oral tolerance by these DEP extracts suggests that DEP may contain compounds different in hydrophobicity associated with the cause of such adverse immunologic responses to food proteins.

Key Words: diesel exhaust particle extracts; oral tolerance; Th1; Th2; cytokine.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Diesel exhaust particles (DEP) generated by diesel engine-powered cars consist of carbon cores that absorb a number of compounds including polyaromatic hydrocarbons, nitroaromatic hydrocarbons, heterocyclics, quinones, aldehydes, and aliphatic hydrocarbons (Draper, 1986Go; Schuetzle, 1983Go). The carbon cores also absorb a trace of heavy metals such as iron, copper, chromium, and nickel (Vouk and Piver, 1983Go). DEP have been implicated in the incidence of allergic respiratory diseases, including asthma and rhinitis, in which Th2 immune responses appear to be involved (Diaz-Sanchez, 1997Go; Sagai et al., 1996Go). A number of studies also showed that DEP facilitated production of IgE antibodies (Diaz-Sanchez et al., 1994Go; Tsien et al., 1997Go) and secretion of Th2 cytokines such as IL-4, -5, -6, -8, -10, and -13 (Diaz-Sanchez et al., 1997Go; Takano et al., 1997Go). We recently demonstrated that DEP augmented not only Th2, but also Th1 immune responses, including secretion of IFN-{gamma} and production of antigen-specific IgG2a antibodies (Yoshino and Sagai, 1999aGo).

Oral administration of antigen induces immunological unresponsiveness to the antigen termed oral tolerance (Weiner et al., 1994Go), which is thought to contribute to the prevention of food hypersensitivity (Mowat, 1994Go). There is also the evidence in some patients that food allergies may be associated with asthma and atopic dermatitis in which Th2 cytokines appear to play a role (Sabbah et al., 1997Go). Although the exact mechanism of induction of oral tolerance is unknown, possibilities include deletion (Chen et al., 1995Go) and anergy (Whitacre et al., 1991Go) of antigen-specific lymphocytes and suppression of inhibitory cytokines including TGF-ß and IL-4 secreted from regulatory T cells (Chen et al., 1994Go). Takefuji et al. (1987) showed that 125I-ovalbumin given to mice intranasally reached not only the lung via the airway but also the gut via the esophagus. We also observed marked deposits of DEP in intestinal tissues after exposure to airborne particulates (unpublished data), suggesting that DEP may modulate oral tolerance. In fact, our previous studies demonstrated that DEP blocked oral tolerance in mice, suggesting that the airborne particulates may be associated with the cause of adverse immunologic responses (Yoshino et al., 1998Go). However, in these studies, compounds from DEP that modulated oral tolerance were not identified.

In this study, as a part of the identification of DEP compounds responsible for blocking oral tolerance, DEP were consecutively extracted with hexane (HEX-DEP), benzene (BEN-DEP), dichloromethane (DIC-DEP), methanol (MET-DEP), and 1 M ammonia (AMM-DEP) to separate compounds different in hydrophobicity. Residues unextracted with the last extraction solvent AMM (UNE-DEP) was also used. Here we show that DEP, DIC-, AMM-, and UNE-DEP, but not other DEP extracts, blocked induction of oral tolerance. Furthermore, DIC-DEP as well as DEP themselves abrogated induction of both Th1 and Th2 oral tolerance, whereas UNE-DEP blocked Th1 but not Th2, and AMM-DEP blockedTh2 but not Th1 oral tolerance.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Animals.
Male DBA/1J mice, 8–9 weeks of age, were used in all experiments. The mice were bred in the animal breeding unit of Saga Medical School, Saga, Japan. They were maintained in a temperature- and light-controlled environment with free access to standard rodent chow and water. Five mice per group were used in each experiment.

Immunization.
Mice were immunized sc at the base of the tail with 100 µg HEL (Sigma Chemical Co., St. Louis, MO) dissolved in 50 µl 0.9% NaCl and emulsified with an equal volume of CFA (Difco Laboratories, Detroit, MI).

Induction of oral tolerance.
Oral tolerance was induced by the methods described previously (Inada et al., 1997Go). Briefly, mice were fed 10 mg HEL dissolved in 0.25 ml 0.9% NaCl through a syringe fitted with an 18-G ballpoint needle on days –5, –4, –3, –2, and –1 before immunization with HEL. As a control, 0.25 ml 0.9% NaCl was orally given daily on the above days.

Extraction of compounds from diesel exhaust particles (DEP).
DEP were generated by a diesel engine with four cylinders and collected on a glass filter in a constant-volume sampler system as described previously in detail (Sagai et al., 1993Go). Chemical compounds from a single DEP sample were separated by the consecutive extraction with hexane (HEX-DEP), benzene (BEN-DEP), dichloromethane (DIC-DEP), methanol (MET-DEP), and 1 M ammonia (AMM-DEP), in that order. The most hydrophobic compounds were extracted with hexane and the least hydrophobic chemicals were separated with ammonia. Residues unextracted (UNE-DEP) with the last extraction solvent (1 M ammonia) were also used in experiments. The extraction solvents were evaporated and the residues weighed. The weight ratios of HEX-, BEN-, DIC-, MET-, AMM-, and UNE-DEP extracted to DEP were 34.2, 12.5, 5.6, 17.8, 11.7, and 18.2%, respectively. The residues were dissolved in ethanol, then suspended in PBS (5 mg/ml). The final concentration of ethanol in the suspensions was 0.5%. Fifty µl of each suspension was intranasally administered immediately after each feeding of HEL. Fifty µl of PBS containing 0.5% ethanol alone was given as a control.

Measurement of HEL-specific antibodies.
Blood was collected on day 21 after immunization, and sera were heat inactivated at 56°C for 30 min. IgG, IgG1, and IgG2a antibodies specific for HEL were measured using an ELISA (Yoshino and Ohsawa, 1997Go). In brief, 96-well flat-bottomed microtiter plates were incubated with 100 µl/well HEL (100 µg/ml) at 37°C for 1 h and washed three times with PBS. The wells were then blocked by incubation with 100 µl PBS containing 1% ovalbumin (Sigma) at 37°C for 1 h. After washing, the plates were incubated with 100 µl of a 1:10,000 dilution of each serum sample at 37°C for 30 min. The plates were washed, and 100 µl/well of a 1:1,000 dilution of rat antimouse IgG, IgG1, or IgG2a labeled with alkaline phosphatase (PharMingen, San Diego, CA) was added and incubated at 37°C for 1 h. After washing, 100 µl of 3 mM p-nitrophenylphosphate (Bio-Rad Laboratories, Hercules, CA) was added per well, and the plates were incubated in the dark at room temperature for 15 min. Absorbance was then measured at 405 nm in a Titertec Multiscan spectrophotometer (EFLAB, Helsinki, Finland). The results were expressed as absorbance units at OD405 ± SEM.

Proliferation assay.
Spleens were removed on day 21 and cell suspensions were prepared (Yoshino, 1998Go). Erythrocytes in the cells were lysed with Tris-NH4Cl. A total of 5 x 106 cells/ml in 100 µl RPMI 1640 (Flow Laboratories, Inc., McLean, VA) containing 1 mM glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin, 5x10–5 M 2-mercaptoethanol and 1% heat-inactivated autologous mouse serum were added to each microwell, followed by the addition of 100 µg/ml HEL. The cells were cultured for 72 h. Each well was pulsed with 0.5 µCi tritiated thymidine, and the cells were cultured for another 16 h. The cultures were harvested onto fiberglass filters using a multiharvester and counted using standard liquid scintillation techniques.

Cytokine measurement.
Single-cell suspensions from spleens were prepared as described above and 5 x 106 cells/ml were cultured in 1-ml aliquots in 24-well tissue culture plates with 100 µg/ml HEL. Forty-eight hours later, supernatants were harvested and stored at –70°C until assayed. Secretion of IFN-{gamma} and IL-4 was quantified using sandwich ELISA techniques. The ELISA kits for these cytokines were commercially available from Funakoshi Co., Tokyo, Japan.

Statistics.
To analyze data statistically, the Mann-Whitney U test was used as a nonparametric statistical methods because sample sizes in our experiments were small; therefore, the normality obtained was poor.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Effect of DEP Extracts on Anti-HEL IgG Antibody Production in Orally Tolerized Mice
To investigate the effect of DEP extracts on anti-HEL antibody production in orally tolerized mice, the animals were intranasally given each DEP extract immediately after each feeding of HEL on days –5, –4, –3, –2, and –1. The results are shown in Table 1Go. HEL feeding was followed by marked suppression of anti-HEL IgG antibody production. Coadministration of DEP as well as DIC-, AMM-, and UNE-DEP blocked the suppression of the antigen-specific IgG antibody production. Giving HEL/HEX-, BEN-, and MET-DEP showed serum levels of anti-HEL IgG antibodies similar to those in animals administered with HEL/PBS.


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TABLE 1 Effect of DEP Extracts on the Suppression of Anti-HEL IgG Antibody Production by Feeding the Antigen
 
Effect of DEP Extracts on Proliferative Responses to HEL in Orally Tolerized Mice
The effect of DEP extracts on proliferative responses to HEL in mice fed the antigen was examined in vitro. HEL feeding was followed by marked suppression of the proliferation of spleen cells to HEL (Table 2Go). When DEP, HEL/DIC-, AMM-, and UNE-DEP, but not HEL/HEX-, BEN-, and MET-DEP, were administered, suppression of HEL-specific cell proliferation was significantly prevented.


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TABLE 2 Effect of DEP Extracts on the Suppression of Proliferative Responses to HEL by Feeding the Antigen
 
Effect of DEP Extracts on Anti-HEL IgG2a and IgG1 Antibody Production in Orally Tolerized Mice
Anti-HEL IgG2a and IgG1 antibodies were measured to examine the effects of HEL plus DEP extracts given orally on Th1 (Burnstein and Abbas, 1993Go) and Th2 (Isakson et al., 1982Go) cell-mediated immune responses, respectively. The results are shown in Table 3Go. Markedly decreased production of anti-HEL IgG2a and IgG1 antibodies was observed in mice given HEL/PBS. Administration of HEL/DEP, HEL/DIC-, and UNE-DEP significantly blocked the suppression of anti-HEL IgG2a antibody production by the oral antigen. HEL/HEX-, BEN-, MET-, and AMM-DEP failed to modulate the orally induced suppression of the antigen-specific IgG2a production. On the other hand, the suppression of anti-HEL IgG1 antibody production seen in orally tolerized mice was blocked by HEL/AMM-DEP as well as HEL/DEP and HEL/DIC-DEP, but not HEL/HEX-, BEN-, MET-, and UNE-DEP.


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TABLE 3 Effect of DEP Extracts on the Suppression of Anti-HEL IgG2a and IgG1 Antibody Production by Feeding the Antigen
 
Effect of DEP Extracts on IFN-{gamma} and IL-4 Secretion in Orally Tolerized Mice
INF-{gamma} and IL-4, known as Th1 and Th2 cytokines (Diamantstein et al., 1988Go; Mu and Sewell, 1994Go), respectively, were also measured to examine whether the blockade by DEP and their extracts of the suppression of immune responses to HEL in orally tolerized mice was associated with secretion of these cytokines. HEL feeding suppressed secretion of both IFN-{gamma} and IL-4, although suppression of IFN-{gamma} appeared to be much greater than that of IL-4 (Table 4Go). Treatment with HEL/DEP and HEL/DIC-DEP significantly blocked the suppression of both IFN-{gamma} and IL-4 production seen after HEL feeding. In contrast, HEL/UNE- and AMM-DEP significantly prevented the suppression of IFN-{gamma} and IL-4 production alone, respectively. Neither HEL/HEX-, BEN-, nor MET-DEP modulated the orally induced suppression of IFN-{gamma} and IL-4 secretion.


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TABLE 4 Effect of DEP Extracts on the Suppression of IFN-{gamma} and IL-4 Secretion by Feeding the Antigen
 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This study shows that not only DEP but also their extracts, including DIC-, AMM-, and UNE-DEP, blocked the suppression by oral HEL administration of production of anti-HEL IgG antibodies as well as the proliferation of spleen cells to the antigen. All other DEP extracts, including HEX-, BEN-, and MET-DEP, failed to affect the induction of oral tolerance. Therefore, DIC-, AMM-, and UNE-DEP but not other DEP extracts appear to contain compounds responsible for abrogating oral tolerance to the fed antigen. Because DEP were consecutively extracted with HEX, BEN, DIC, MET, and AMM, compounds present in the diesel engine–derived particles responsible for the blockade of oral tolerance appear to be not strongly hydrophobic. Although our previous studies showed that DEP blocked oral tolerance, no extraction of the airborne particulates was carried out to investigate the characterization of their components responsible for the blockade of oral tolerance (Yoshino et al., 1998Go).

In addition, our studies also demonstrate that DIC-DEP as well as DEP appear to block induction of both Th1 and Th2 oral tolerance, as they diminished the suppression by oral HEL of secretion of the Th1 cytokine IFN-{gamma} (Diamantstein, 1988) as well as the Th2 cytokine IL-4 (Mu and Sewell, 1994Go). Furthermore, our results showed that UNE-DEP seemed to contain chemicals that weakened induction of Th1 but not Th2 oral tolerance, as suppression of IFN-{gamma} but not IL-4 secretion was diminished by the DEP extract. In contrast, AMM-DEP might have compounds modulating Th2 but not Th1 oral tolerance, as significant blockade of suppression of IL-4 but not IFN-{gamma} was observed following the administration of this extract. Because IFN-{gamma} plays a role in IgG2a antibody production (Burnstein and Abbas, 1993Go), the blockade by DEP, DIC-, and UNE-DEP of suppression of IFN-{gamma} secretion might have led to the enhancement of production of anti-HEL IgG2a. The abrogation of suppression of anti-HEL IgG1 antibody production by DEP, DIC-, and AMM-DEP may be due to the blockade of suppression of IL-4 secretion by this DEP extract, as IL-4 is involved in IgG1 antibody production (Isakson et al., 1982Go).

Oral tolerance is thought to contribute to the prevention of food allergy (Mowat, 1994Go). Therefore, the blockade of oral tolerance by the exposure to DEP and their extracts may lead to the cause of adverse immunologic reactions to food proteins. It is of note that food allergy is associated with 6% of patients with asthma and 5–6% of patients with atopic dermatitis in which Th2 responses appear to be involved (Sabbah et al., 1997Go). Furthermore, we recently found that exposure to DEP enhanced Th1-dominant autoimmune arthritis in mice, a model of rheumatoid arthritis in humans (Yoshino and Sagai, 1999bGo), suggesting that exposure to DEP may also modulate autoimmune disorders caused by the breakdown of tolerance to autoantigens. However, no components from DEP have been demonstrated that play a central role in Th1- and Th2-mediated diseases. This study indicates that UNE-DEP may contain compounds affecting human autoimmune diseases, whereas AMM-DEP may have chemicals associated with the development of asthma and atopic dermatitis. Compounds from DIC-DEP may modulate Th1- as well as Th2-dominant diseases.

Precise compounds contained in DEP are unknown, as the airborne particulates consist of a vast number of organic chemicals different in hydrophobicity, such as polyaromatic hydrocarbons, nitroaromatic hydrocarbons, heterocyclics, quinones, aldehydes, and aliphatic hydrocarbons (Draper, 1986Go; Schuetzle, 1983Go), and metals such as iron, copper, chromium, and nickel (Vouk and Piver, 1983Go). Therefore, extensive studies are required for the isolation and the identification of components contained in DEP that are responsible for the blockade of Th1 and/or Th2 oral tolerance. However, there are some studies demonstrating that polyaromatic hydrocarbons from DEP enhance Th2 responses including IgE production (Takenaka et al., 1995Go; Tsien et al., 1997Go), although which DEP extract used in our studies contains the organic compounds is unknown.

Although the exact mechanism underlying induction of oral tolerance is unclear, possibilities include deletion (Chen et al., 1995Go), anergy (Whitacre et al., 1991Go), and suppression by inhibitory cytokines including IL-4 (Chen et al., 1994Go), depending on the dosage and the nature of antigen fed and the frequency of antigen administration. For example, low doses (less than 1 mg) of oral antigen upregulate secretion of inhibitory cytokines involved in active suppression, whereas high doses (more than 5 mg) appeared to induce anergy (Friedman and Weiner, 1994Go). However, Garside et al. (1995) demonstrated that feeding 25 mg ovalbumin reduced production of Th2 cytokines, including IL-4, as well as Th1 cytokines such as IFN-{gamma}. Similar results were observed in our previous (Yoshino and Ohsawa, 1997Go) and present studies in which 10 mg HEL was orally administered. Furthermore, Melamed et al. (1996) showed that continuous feeding of ovalbumin decreased secretion of IL-4. Thus, large amounts of antigen appear to suppress IL-4 secretion, although this cytokine appears to be augmented by low doses of antigen given orally.

In summary, DEP, DIC-, AMM-, and UNE-DEP blocked induction of oral tolerance. In addition, DEP as well as DIC-DEP significantly prevented both Th1 and Th2 oral tolerance, whereas UNE- and AMM-DEP blocked Th1 but not Th2, and Th2 but not Th1 oral tolerance, respectively. Because oral tolerance is thought to contribute to the prevention of food allergy (Mowat, 1994Go) and because a significant amount of DEP was observed not only in the lung but also in the gut after exposure to the airborne particulates (Takefuji et al., 1987Go), diesel engine–derived particle components may play a role in adverse Th1 and/or Th2 immunologic responses to food proteins in humans.


    ACKNOWLEDGMENTS
 
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan.


    NOTES
 
1 To whom correspondence should be addressed at Department of Pharmacology, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan. Fax: +81-78-441-7572. E-mail: yoshino{at}kobepharma-u.ac.jp. Back


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