Department of Immunology-178, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030-4009
Received May 23, 2000; accepted August 12, 2000
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ABSTRACT |
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Key Words: jet fuel; JP-8; immune suppression; prostaglandin E2; interleukin-10; interleukin-12; cytokines; immunotoxicity.
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INTRODUCTION |
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JP-8 is also immunotoxic, and it appears that immune function is very sensitive to its toxic effects. Short-term pulmonary exposure to relatively low doses of aerosolized JP-8 (100 mg/m3 for 7 days) decreased immune organ weights, decreased the number of viable cells recovered, and suppressed the ability of T cells to respond to mitogenic stimulation (Harris et al., 1997b). The effect of JP-8 on immune organ weights was noted 24 h after treatment, and the suppressed T cell mitogenesis persisted for up to 4 weeks post-exposure (Harris et al., 1997a
). The immunotoxic effects of JP-8 were noted after dosing schedules that failed to induce pulmonary toxicity, leading Harris et al. (1997a) to suggest that immune function is the most sensitive indicator of JP-8-induced toxicity.
Our observation that a single dermal application of JP-8 is immune suppressive supports this hypothesis (Ullrich, 1999). Besides inhalation of aerosolized vapors, the other major route of JP-8 exposure is dermal contact. Dermal application of undiluted JP-8 to mice, either multiple small exposures (50 µl for 5 days) or a single large exposure in excess of 250 µl resulted in immune suppression. The induction of contact hypersensitivity (CHS) was suppressed regardless of whether the contact allergen was applied directly to the jet fuel-treated skin or applied at a distant untreated site. In addition, the ability of splenic T cells from JP-8-treated mice to proliferate in response to plate-bound anti-CD3 monoclonal antibody was significantly suppressed.
The mechanism underlying the induction of systemic immune suppression by dermal application of JP-8 is unclear, but the appearance of the immune modulatory cytokine, interleukin (IL)-10 in the serum of JP-8-treated mice (Ullrich, 1999) suggests that immune-suppressive biological-response modifiers may play a role. The focus of the experiments reported here was to test the hypothesis that the systemic immune suppression observed following dermal exposure to JP-8 is driven by immune modulatory cytokines. We concentrated on prostaglandin E2 (PGE2) and IL-10 because they are known to suppress cell-mediated immune reactions and are secreted by epidermal cells.
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MATERIALS AND METHODS |
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Application of JP-8.
The jet fuel (lot # 3509) was supplied to us by the Operational Toxicology Branch, Air Force Research Laboratory, Wright Patterson Air Force Base, Dayton, OH. The fuel was stored and used in a chemical fume hood. Nitrile rubber-based gloves (Touch N Tuff, Fisher Scientific Co.) were used in the place of normal latex gloves, due to their superior performance in preventing the penetration of JP-8. The standard protective clothing worn in the SPF-barrier animal facility, Nytex coveralls, surgical bonnets, and masks also afforded protection for the investigators against accidental dermal exposure to JP-8. Different amounts of the undiluted fuel (50 to 300 µl) were applied directly to the dorsal skin of the animals. The mice were held individually in the hood for 3 h after exposure, to prevent cage mates from grooming and ingesting the fuel. Also, the jet fuel was placed high up on the back of each mouse, immediately behind the head, to prevent the animals from grooming themselves and ingesting the fuel. In every experiment a control group treated with acetone was handled in the identical manner. After 3 h all the residual fuel was either absorbed or evaporated, and the animals were returned to standard housing in an SPF barrier facility.
T-cell proliferation in vitro.
At various times after JP-8 treatment, the mice were killed, their spleens removed, and single cell suspensions prepared. Contaminating erythrocytes were lysed with ammonium chloride (0.83% in 0.01 M TrisHCl, pH 7.2); and the cells were washed and resuspended in RPMI-1640 supplemented with 5% newborn calf serum (HyClone, Logan, UT). A T-cell enriched population was prepared by passing the spleen cells over a nylon wool column (Julius et al., 1973). The cells were then resuspended in medium supplemented with 10% newborn calf serum, 5 x 105 M 2-mercaptoethanol, 100 units/ml streptomycin, 2 mM L-glutamine, 10% sodium pyruvate, 10 mM HEPES buffer, 1 x vitamins and 1 x non-essential amino acids (GIBCO-BRL, Grand Island, NY). The cells (2 x 105/well) were then cultured at 37°C in an atmosphere of 5% CO2, 95% air for 5 days in 96-well tissue culture plates coated with monoclonal anti-CD3 (100 µl of a 10 µg/ml solution overnight prior to culture; PharMingen, San Diego, CA). During the last 18 h of culture, 1 µCi of tritiated thymidine (ICN Radiochemicals, Irvine, CA) was added to each well. The cells were harvested onto glass-fiber filters (Tomtec Harvester, Orange, CT) and the incorporation of the radioisotope into newly synthesized DNA was determined by liquid scintillation counting (1205 Betaplate, LKB Wallac, Gaithersburg, MD). Background responses were determined by culturing the cells in wells devoid of anti-CD3. Cells from each different group were cultured in triplicate. The means and standard deviations of the triplicates were calculated, and statistical differences between controls (acetone-treated) and experimental (JP-8-treated) groups were determined by use of a 2-tailed Student's t-test, with a probability of less than 0.05 considered significant. Each experiment was repeated 3 times.
Effect of JP-8 on antibody production in vivo.
Various amounts of JP-8 (100 to 300 µl) were applied to the dorsal skins of the mice. Three h later the animals were immunized by subcutaneous injection of 100 µg of keyhole-limpet hemocyanin (KLH) and emulsified in complete Freund's adjuvant (Pierce Immunochemicals, Rockford, IL). One week later the JP-8 application was repeated, and the mice were boosted with 100 µg of KLH emulsified in incomplete Freund's adjuvant. One week after the boost, the mice were deeply anesthetized and exsanguinated, and the serum was collected. An enzyme linked immunoabsorbent assay (ELISA) was used to measure antibody titers (Ullrich and Fidler, 1992). Triplicate serum samples (diluted 1:100, 1:1000, and 1:10,000 in PBS) from the JP-8-treated and acetone-treated controls were added to the wells of a 96-well ELISA dish coated with KLH and incubated at 37°C for one h. After washing, the amount of KLH-specific antibody bound to the antigen was measured by using biotinylated rat anti-mouse IgM, IgG1, and IgG2b (PharMingen, Inc., San Diego, CA) as the detecting antibodies. Generally, 100 µl of a 1:2000 dilution of each antibody was added to the wells and incubated for 90 min at room temperature. After washing, 100 µl of a 1:10,000 dilution of horseradish peroxidase-conjugated streptavidin (Pierce Immunochemicals) was added to each well. Thirty min later the plates were washed, and 100 µl of the substrate (2,2'-azino-bis(3-ethylbenzthiazoline-o-sulfonic acid, Pierce Immunochemicals) was added. Color was allowed to develop for 30 min, at which time the optical density at 410 nm was measured with a Dynatech MR 5000 Microplate reader (Dynatech Labs, Chantilly, VA). Positive-control mice were shaved and treated with acetone before immunization. Negative controls were shaved and treated with acetone but were not immunized. There were 5 mice per group and the serum from each animal was assayed individually. The data represent the mean optical density and standard deviations from the group of 5 mice. Statistically significant differences between the antibody titers in the controls and the JP-8-treated mice were determined by use of the Student's t-test, with a probability of less than 0.05 considered significant. Each experiment was repeated at least 3 times.
Contact hypersensitivity (CHS).
The dorsal hair of the mice was removed with electric clippers, and a micropipete used to apply the JP-8 directly to the dorsal skin, as described above. Control mice were shaved and treated with acetone. Three h later, the mice were sensitized by painting 50 µl of a 0.3% (w/v) solution of dinitroflurobenzene (DNFB) in acetone onto the shaved abdominal skin. Six days after sensitization the thickness of each ear was measured, recorded, and the mice were challenged by applying 10 µl of a 0.2% solution of DNFB in acetone to each ear. Eighteen to 24 h later, the thickness of each ear was measured again, and a mean ear thickness for each mouse (left ear thickness + right ear thickness ÷ 2) was calculated. The specific ear swelling for each mouse was then calculated as described above. There were 5 mice per group; the data is expressed as specific ear swelling ± the standard deviation. Statistical differences between the controls and experimental groups were determined by use of a 2-tailed Student's t-test, with a probability of less than 0.05 considered significant. Each experiment was repeated at least 3 times.
To determine whether prostaglandin E2 or IL-10 production was involved in the induction of immune suppression, we used monoclonal antibodies or specific enzyme inhibitors to neutralize their activity or block their production in vivo. To block PGE2 secretion in vivo, the selective cyclooxygenase-2 (COX-2) inhibitor, SC 236, was employed (a gift from Dr. Peter Isakson, G. D. Searle & Company, St. Louis, MO). SC 236 selectively inhibits the enzymatic action of COX-2, thus preventing the production of PGE2. Because SC 236 has no effect on the enzymatic activity of COX-1, its use is devoid of the side effects (i.e., gastric bleeding) usually associated with in vivo use of non-specific inhibitors of the cyclooxygenase pathway (Seibert et al., 1994). Generally, SC236 was diluted in PBS and 0.1 ml of a 2 µg/ml solution was injected ip 2 h prior to JP-8-treatment.
Interleukin-10 activity was neutralized in vivo by injecting the JP-8-treated mice with 100 µg of monoclonal anti-IL-10 (JES5-2A5.11, rat IgG). The hybridoma-secreting anti-IL-10 was provided to us by Dr. Anne O'Garra (DNAX Research Institute, Palo Alto, CA). The hybridoma cells were grown in RPMI-1640 tissue-culture medium supplemented as described above. The supernatants were collected, the IgG fraction was enriched by 33% ammonium sulfate precipitation, and the IgG was purified by passage over protein A/G columns (Pierce Immunochemicals). Protein concentration was determined by use of bicinchoninic acid (BCA protein assay kit, Pierce Immunochemicals). Control rat IgG was purchased from Sigma (St. Louis, MO). Dr. Stanley Wolf, Genetics Institute Inc., Cambridge, MA generously provided us with recombinant IL-12. It was diluted in PBS prior to use.
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RESULTS |
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DISCUSSION |
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We also examined and further characterized the timing and duration of the immune suppression induced by a single acute exposure to JP-8. The observation that 3 to 4 days must elapse between JP-8-treatment and the induction of immune suppression is consistent with cytokine release as the mechanism behind immune suppression. From our previous work we know that maximal serum IL-10 secretion occurs 24 to 48 h after JP-8 exposure (Ullrich 1999). We propose that it takes 2 to 3 days for immune suppressive cytokines, such as IL-10 and PGE2 to be produced, enter the circulation, and interact with the target cells, thus inducing immune suppression. The exact identity of the target cells is not clear at this time, but based on the fact that IL-10 and PGE2 down-regulate the action of antigen-presenting cells (Fiorentino et al., 1991
; Kalinski et al., 1998
), we suspect that antigen-presenting cells are targeted by JP-8-induced IL-10 and PGE2. Experiments are now in progress to test this hypothesis.
The other major route of toxin exposure is via inhalation of aerosolized JP-8. It is of interest to note the similarities between the immune suppression induced by dermal exposure and inhalation of jet fuel. In both cases, T cell function is suppressed, immune suppression first appears 3 to 4 days after initial exposure and the effect lasts for 3 to four weeks (Harris et al., 1997a,b
). These findings are alarming because, in the course of their duties on a typical Air Force base, fuel handlers, engine mechanics, and flight line personnel are in daily contact with JP-8 (Pleil et al., 2000
). This suggests that the induced immune suppression may be of longer duration than demonstrated here. Alternatively, repeated JP-8 exposure may have a chronic dampening effect on the immune reaction of affected individuals. Whether this translates into increased susceptibility to infection remains to be seen.
Our findings indicate, however, that the consequence of JP-8 exposure is not global immune suppression. Rather JP-8 has a selective effect on the immune response. We base this conclusion on the fact that exposure to JP-8 has no effect on antibody formation. When we exposed mice to doses of JP-8 (300 µl) that caused 95 to 100% suppression of cell-mediated immune reactions (Fig. 1, Table 1
), we noted no suppression of antibody formation. These data, coupled with the observation that IL-12 blocks JP-8-induced immune suppression, indicate to us that JP-8 is selectively suppressing T helper-1-driven, cell-mediated immune reactions. This would suggest that immune reactions driven by T helper-1 cells, such as delayed-type hypersensitivity and immunity to intracellular microorganisms, might be more susceptible to the toxic effects of JP-8.
In one of the classic papers of immunotoxicity, Luster and colleagues suggested that a multi-tiered approach was the best way to detect immunotoxic compounds. Further they presented data to indicate that one of the best tests for determining immunotoxicity was suppression of antibody formation (Luster et al., 1992). We have used a similar multi-tiered approach in our study of the immunotoxicity of JP-8. Although cell-mediated immune reactions, such as delayed and contact hypersensitivity and CD3-driven T cell proliferation, were suppressed by jet-fuel exposure, antibody formation was not. Does the failure to suppress antibody formation suggest that JP-8 is not immunotoxic? We think not, but rather we propose that some immune toxins may have a more subtle and selective effect on the immune response than those originally described by Luster and colleagues. During the past decade, immunologists identified different subclasses of T-helper cells and demonstrated that T helper-1 cells generally help cell-mediated immune reactions and T helper-2 cells help antibody formation (Mosmann and Sad 1996
). Furthermore, distinct classes of antigen-presenting cells have been described: one that presents antigen to T helper-1 cells and one that presents to T helper-2 cells (Rissoan et al., 1999
; Siegal et al., 1999
). Our data strongly suggest that JP-8 exposure only targets T helper-1 cell function. In this regard, the immune regulation induced by JP-8 is similar to that found after exposure to the ubiquitous environmental immune toxin, ultraviolet radiation, which preferentially suppresses T helper-1 cell function (Brown et al., 1995
). If, in either of these studies, we concentrated only on the ability of either toxin to suppress the direct plaque-forming cell function, which is a measure of IgM production, the immunotoxicity of JP-8 or ultraviolet radiation would have been missed. Thus, the findings presented here further reconfirm the need for a multi-tiered approach in determining immunotoxicity, as suggested by Luster et al. (1992). However, they further suggest that different classes of immunotoxins are present and that these toxins may not function via the same suppressive mechanism as those described by Luster and colleagues.
Perhaps the most important finding reported here is the prevention of JP-8-induced immunotoxicity by IL-12, monoclonal anti-IL-10, and the selective COX-2 inhibitor. These findings are important because they provide insight into the mechanisms involved in JP-8-induced immune suppression but more importantly provide insight into preventing JP-8-induced immunotoxicity in the field. Of the 3 agents used, monoclonal anti-IL-10 is the most specific, and the specificity of antibody treatment in blocking JP-8-induced immune suppression is a compelling argument for a role of IL-10 in jet fuel induced immunotoxicity. Due to its specificity, antibody treatment would be ideal in preventing JP-8-induced immune suppression in individuals who come into contact with this toxin; however, the overall lack of humanized monoclonal antibodies makes this approach impractical.
Blocking JP-8 immune suppression by IL-12 is also an important observation regarding the mechanisms involved. Because IL-12 is the primary cytokine involved in activating T helper-1 cells in vivo, the blocking of immune suppression, as demonstrated here, in combination with the type of immune reactions suppressed (cell-mediated immunity versus humoral immunity) argues that JP-8 is interfering with T helper-1-cell-driven immune reactions. In addition, we recently demonstrated that IL-12 blocks IL-10 secretion in vivo, primarily by interfering with the transcription of the gene (Schmitt et al., 2000). Therefore, it is possible that IL-12 is blocking IL-10 production in JP-8-treated mice, which probably contributes to the prevention of immune suppression. Unfortunately, the use of IL-12 to block JP-8-induced immune suppression in humans is risky because of the severe toxicity associated with its use (Car et al., 1999
).
Using the selective COX-2 inhibitor to prevent immune suppression in Air Force personnel who come in contact with JP-8 during the course of their duties holds the most promise. Selective COX-2 inhibitors are commercially available and in use clinically for the treatment of chronic aliments such as arthritis (Megeff and Strayer, 2000) and colon cancer (Rao et al., 1995
). They are well tolerated with minimal side effects Kaplan-Machlis and Klostermeyer, 1999). Their use here provides compelling evidence to suggest the involvement of PGE2 in the immune suppression induced by JP-8. Furthermore, blocking the production of PGE2 may have the added benefit of inhibiting a cascade of events ultimately resulting in IL-10 production. In a study of the immune suppression induced by ultraviolet radiation, we documented that PGE2 induces a cytokine cascade involving IL-4 and IL-10 that ultimately suppresses cell-mediated immune reactions. Pertinent to the results presented here was the finding that blocking COX-2 activity in vivo with SC 236 prevented the secretion of IL-4 and IL-10. Moreover, injecting PGE2 into normal mice resulted in IL-4 and IL-10 production (Shreedhar et al., 1998
). If the same result happens after JP-8 exposure and the suppression of JP-8-induced immune suppression by SC 236, coupled with the secretion of IL-10 into the serum following JP-8-treatment, suggests that it might, then using a selective COX-2 inhibitor will have the added benefit of blocking down stream events. Thus, the selective COX-2 inhibitor may prevent a cascade of events in vivo and may be, due to its limited toxicity and potent restorative effect, the ideal way to overcome the immunotoxicity of JP-8.
In summary, the data presented here indicate that JP-8 exposure has a selective effect on immune function. T helper-1 cell-driven cell-mediated immune reactions, such as DTH, CHS, and T-cell proliferation are susceptible to the effects of JP-8, whereas antibody formation is not suppressed. The mechanism through which dermal JP-8 application induces systemic immune suppression appears to be via cytokine release, in particular PGE2 and IL-10. Furthermore, injecting JP-8-treated mice with a selective COX-2 inhibitor, which suppresses PGE2 production in vivo with minimal side effects, totally restores immune function. These findings suggest that interfering with cycloooxygenase-2 activity in vivo may provide a reasonable method of suppressing JP-8-induced immunotoxicity in exposed personnel.
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ACKNOWLEDGMENTS |
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NOTES |
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