* National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505; and
Department of Pharmacology & Toxicology, Medical College of Virginia of Virginia Commonwealth University, Richmond, Virginia 23298
Received September 9, 1999; accepted January 28, 2000
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ABSTRACT |
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Key Words: mouse; latex; allergy; IgE; topical; respiratory; plethysmography; NRL; Hev B; PENH; bronchoconstriction.
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INTRODUCTION |
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While the majority of the literature supports a latex allergy prevalence of less than 2% in the general public (Turjanmaa, 1987; Moneret-Vautrin et al., 1993
; Bernardini et al., 1997; Cremer et al., 1998
; Liss et al., 1999), increased risk has been associated with several occupations and medical conditions. Numerous reports have suggested that between 817% of healthcare workers (HCW, e.g., physicians, nurses, dentists) may be allergic to NRL (Hamilton et al., 1994
; Yassin et al., 1994
; Sussman et al., 1995
; Sussman et al., 1997; Tarlo et al., 1997
). Persons employed in the manufacture of latex products have also been linked with a heightened prevalence (11%) of occupational allergies toward NRL (Tarlo et al., 1990
). Furthermore, young patients with disorders which require repeated surgical procedures have been associated with an increased risk of latex allergy. While HCW are primarily exposed to latex proteins dermally and by inhalation, surgical patients are additionally exposed subcutaneously. For example, up to 70% of spina bifida (SB) patients have been diagnosed with IgE-mediated latex allergy (Kelly et al., 1994
; Nieto et al., 1996
; Cremer et al., 1998
), and a positive correlation between the number of surgical procedures and latex allergy prevalence has been demonstrated within these patient populations (Chen et al., 1997
; Porri et al., 1997
).
Despite the increased prevalence of latex allergy over the past decade, isolated cases of IgE-mediated reactions to NRL products were reported as early as 1927 (Stern, 1927). Implementation of "Universal Precautions" in the late 1980's correlate with the sudden rise in latex allergy prevalence. Although the prevalence of latex allergy has increased, the primary route(s) of sensitization, and the complete spectrum of latex proteins which result in allergic responses remains unclear. Immunological assays have provided evidence that HCW demonstrate higher recognition for water soluble latex proteins while SB patients exhibit increased recognition of rubber-associated proteins (Alenius et al., 1993
; Hamilton et al., 1996
; Reunala et al., 1996
; Yeang et al., 1996
; Posch et al., 1998
). Latex proteins can aerosolize (Swanson et al., 1994
) or penetrate the skin (Hayes et al., 1999
) and potentially sensitize HCW, while physiological fluids from surgical patients who come in contact with NRL products may elute additional latex proteins allowing for exposure to a unique set of proteins. The objective of these studies was to evaluate the role which sensitization route plays in the development of latex allergy using murine models representative of potential exposure routes by which health care workers (topical and respiratory) and spina bifida patients (subcutaneous) may be sensitized.
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MATERIALS AND METHODS |
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Latex Test Materials
Latex proteins were prepared from raw non-ammoniated latex (NAL), kindly provided by Dr. Che Hasma Hashim of the Rubber Research Institute of Malaysia (RRIM). Raw latex was tapped from a rubber tree and immediately diluted 1:2 with a Goodyear Preservative (50% glycerol/67 mM NaHCO3/2 mM L-cysteine buffer). Upon receipt, the latex/glycerol solution was centrifuged for 40 min @ 14,400xg to separate the rubber fraction from the aqueous protein phase. Collection of the aqueous layer underneath the rubber fraction was accomplished using an 18 gauge needle and a 10-cc syringe. The aqueous fraction was then centrifuged twice more at 40,000xg for 1 h per spin. The final protein extract was filtered through a 0.45 micron bottle top filter and stored at 80°C. Total protein concentration of the NAL extract was determined to be approximately 7 mg/ml using a modified Lowry Assay (ASTM, 1998; Standard D571295). Figure 1 shows the protein profile of the NAL extract following centrifugation and filtration. This protein extract was utilized for all sensitization and challenge exposures, with the exception of respiratory challenges performed for plethysmography evaluations.
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Topical exposures.
NAL dosing solutions were prepared in Goodyear preservative and then diluted 1:1 in acetone for all topical studies. A 1520% gradient SDSPAGE gel suggested that the NAL protein profile was unaffected by acetone (data not shown). Each mouse was anesthetized (methoxyflurane; Schering-Plough Animal Health Corporation, Omaha, NE) and dorsal thorax or lumbar regions were clipped once per week (Mondays). The clipped surface was treated with Nair® hair removal lotion for up to 1 min and the back was washed with warm water and dried. The exposure site was abraded via tape stripping with 10 stripping discs (D-Squanme® Stripping Discs, 14 mm or 22 mm, Cuderm Corp., Dallas, TX). As demonstrated by histology, the stratum corneum of a mouse is largely removed following tape stripping with 10 discs (data not shown). Mice were dosed 5 days/week with 50 µl containing 0150 µg NAL; all topical exposures were non-occluded.
As non-occluded, topically exposed mice were group housed (5/cage), the possibility of animals receiving an oral exposure following topical application of NAL existed. An experiment was therefore conducted to address the potential for IgE production due to oral exposure following topical applications. Mice were administered 10 µl of NAL solution 5 days per week by placing doses on the tongue using a 20 µl Gilson pipetman. Mice fed three different concentrations (1.2 ng, 78 ng, and 50 µg) of NAL did not demonstrate elevations in total IgE by day 79 (data not shown).
Intranasal exposures.
Unanesthetized, BALB/c mice were instilled intranasally (i.n.) with NAL proteins (050 µg) diluted in glycerol buffer and PBS. Mice were administered 5 µl/nostril for 5 days per week over 72 days. Vehicle-treated mice received glycerol buffer diluted in PBS.
Intratracheal exposures.
Intratracheal (i.t.) aspirations were performed similar to that described by Keane-Myers et al. (1998). Mice were anesthetized via methoxyflurane inhalation and restrained in a vertical position on a plexiglass stand by the upper and lower teeth. The tongue was withdrawn using padded forceps, and 50 µl of NAL/glycerol buffer/PBS dosing solution was pipetted into the back of the oral cavity. The tongue was held, to prevent swallowing, until the dose was aspirated from the oro-pharyngeal cavity. Vehicle groups received glycerol buffer diluted in PBS. Mice were dosed every 5th day for 4 weeks with NAL doses ranging from 050 µg.
I.t. and i.n. aspirations of 0.5% Evans blue were used to demonstrate the distribution of test article in the respiratory tract. Within 10 min following i.t. aspiration of 50 µl, blue dye was visible in the trachea and the right and left lungs, including the cranial, medial, and caudal lobes of the right lung. Evans blue was also observed in the bronchi of the accessory lobe of the right lung. Conversely, i.n. instillation with 10 µl of Evans blue dye demonstrated no signs of lower respiratory tract exposure. Blue dye, however. was visible in the stomach of animals within 10 min of i.n. instillation.
Total IgE ELISA
Prior to and following NAL protein exposures, mice were tail-bled weekly or biweekly and total IgE serum levels were measured as described by Manetz and Meade (1999). Serum samples were serially diluted and then added to 96-well flat bottom microtiter plates (Immulon-2), which had been coated overnight with the rat anti-mouse IgE monoclonal antibody. Bound mouse IgE was quantified using a two step addition of a biotin conjugated rat anti-mouse IgE, followed by strepavidin-alkaline phosphatase (Sigma Chemical). P-nitrophenyl phosphate tablets diluted in substrate buffer were added and plate absorbency was determined within 30 min at 405 nm. IgE concentrations for each serum sample were interpolated from a standard curve using a multipoint analysis. Monoclonal antibodies used during the ELISA were previously characterized by Keegan et al. (1991) and Liu et al. (1980), and were purified from hybridomas kindly provided by Dr. Daniel Conrad (Virginia Commonwealth University, Richmond, VA).
In vitro Splenocyte Proliferation Assay
In light of the fact that the total IgE response is not indicative of a specific immune response, splenocyte proliferation was evaluated following in vitro challenge with NAL to demonstrate antigen specificity. Spleens from latex-exposed mice were collected aseptically and placed in sterile Hank's Balanced Salt Solution (pH 7.2; 15 mM HEPES). Single cell suspensions were prepared using frosted microscope slides and splenocyte counts were determined using a Z2 Coulter® Counter. Splenocytes (2x105) from latex-treated and control mice were incubated with either RPMI media or increasing concentrations of latex proteins (0.1 20 µg/ml) in RPMI at 37µC and 6% CO2 for 72 h. RPMI media contained 15 mM HEPES, 0.225% Sodium Bicarbonate, 2 mM Glutamine, 100 U/ml Pen G, and 100 µg/ml Streptomycin Sulfate. 10% FBS and 50 µM 2-Mercaptoethanol were added just prior to incubation. Concanavalin A (1 µg/ml) and LPS (10 µg/ml) were added to control wells as positive control mitogens to assure splenocyte responsiveness. Twenty µl of 3H-thymidine (5 µCi/mM) diluted 1:20 in RPMI media were added 18 h prior to cell harvesting. Cells were harvested onto filter pads. 3H-thymidine uptake by splenocytes was determined via beta liquid scintillation counting and served as an indicator of splenocyte proliferation and a measure of specific allergen stimulation.
Immunoblot Analysis (AlaBLOTTM)
Pooled sera from vehicle- or NAL (50 µg)-exposed mice were evaluated for latex-specific IgE using AlaBLOTTM latex-specific allergen strips (DPC®, Los Angeles, CA). Sera from NAL exposed mice were diluted between 1:21:5 with AlaBLOTTM sample diluent to normalize total IgE content (~1,500 ng), then incubated with latex allergen strips (nitrocellulose) for two h at room temperature. Sera from vehicle-treated mice were diluted 1:2 with sample diluent prior to incubation with allergen strips. Bound murine IgE was subsequently identified by the step-wise addition of rat anti-mouse IgE-HRP (Southern Biotech, Birmingham, AL), diluted 1:500 for one h, followed by 500 µl of BCIP/NBT substrate solution (AlaBLOTTM Universal Kit substrate) for up to 15 min. To further demonstrate specificity of the IgE produced by mice exposed to latex proteins, sera inhibition with NAL and ovalbumin was performed prior to immunoblot analysis. Test sera (250 µl) were incubated with an equal volume of NAL (1 mg), ovalbumin (1 mg), or AlaBLOTTM sample diluent for 2 h at 37°C prior to addition to latex allergen strips, as described above. Normalized band intensities were determined on scanned images of immunoblot strips using Gel Expert 97 (version 2.0). Latex protein or ovalbumin-inhibited allergen strips were compared to sample diluent treated strips to determine percent reduction in band intensities.
Whole Body Plethysmography
To determine pulmonary reactivity, enhanced pause (PENH), an indicator of bronchoconstriction (Drazen et al. 1999), was evaluated in naïve, vehicle, and latex- sensitized mice using whole body plethysmography following respiratory challenge with NAL protein (300 µg). Glycerol-free, lyophilized NAL protein was kindly provided by Dr. Donald Beezhold of the Guthrie Research Institute (Sayre, PA) and was reconstituted in PBS (pH 7.2) for use as the respiratory challenge solution. Prior to i.t. challenge, sensitized mice were placed into plethysmograph chambers (Buxco Electronics, Sharon, CT) and monitored for five min to determine baseline PENH values. Mice were then anesthetized (methoxyflurane) and challenged by i.t. aspiration, as described previously. Immediately following aspiration of NAL into the trachea, mice were placed into plethysmograph chambers and monitored for 25 min. The mean enhanced pause was reported over a period of 20 breaths and was calculated for each breath as follows:
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PENH values for individual mice were averaged for each minute over 25 min and recorded. The percent increase over baseline was subsequently calculated and plotted versus time for each mouse. The area under the curve for percent increase was determined for individual mice using Graph Pad Prism, version 2.01 (San Diego, CA). Group means and standard errors were calculated.
Statistics
Statistics were conducted using Graph Pad Prism, version 2.01. Total serum IgE levels, in vitro splenocyte proliferation, and PENH data from vehicle and NAL protein exposed mice were analyzed by one-way ANOVA. When significant differences were detected (p 0.05), test groups were compared to the controls using a Dunnett's test. PENH data were also evaluated using the Prism software's Linear Trend Test. Correlation between total IgE and PENH responses were evaluated using a two-tailed, Pearson's correlation calculation. Unpaired t-tests were used to perform pair-wise comparisons of PENH data between NAL-challenged and PBS-challenged mice, between NAL-sensitized and vehicle control groups, and between naive mice and vehicle control groups.
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RESULTS |
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In vitro Splenocyte Proliferation
Splenocytes from mice sensitized with NAL demonstrated dose-responsive proliferation following in vitro challenge with latex proteins. Figure 5 shows a representative dose response following challenge of splenocytes from animals sensitized s.c. with 6.25 µg NAL. While in vitro stimulation of murine splenocytes with vehicle resulted in approximately 1,000 c.p.m./2 x 105 spleen cells, splenocytes challenged with 10 or 20 µg/ml NAL exhibited greater than 6,000 c.p.m./2 x 105 splenocytes. Splenocytes from vehicle-exposed mice challenged in vitro with 20 µg/ml NAL exhibited proliferative responses that were not different than RPMI challenged controls. Splenocytes challenged in vitro with Concanavalin A (1 µg/ml) or LPS (10 µg/ml) demonstrated splenocyte proliferation within historical positive values for this assay.
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Enhanced Pause (PENH)
Whole body plethysmography was used to evaluate pulmonary responses of sensitized mice following respiratory challenge with NAL. To confirm the specificity of the PENH response, naive mice, mice administered vehicle i.t., and i.t. NAL (50 µg)-sensitized mice were monitored for bronchoconstriction following respiratory challenge with either PBS or 300 µg NAL. Naive mice and mice administered vehicle i.t. did not demonstrate bronchoconstriction following i.t. challenge with PBS (Fig. 7). Conversely, mice sensitized with NAL via i.t. aspiration demonstrated an almost 2
-fold increase in bronchoconstriction following PBS challenge (p
0.05). Naive and vehicle-treated mice challenged i.t. with NAL protein exhibited statistically significant bronchoconstriction as compared to PBS-challenged mice. Enhanced pause following NAL challenge of mice i.t. sensitized with latex protein was almost 4
-fold higher (p
0.05) than the PENH response in naive and vehicle mice not previously exposed to NAL.
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Respiratory challenge of mice exposed i.n. to high-dose NAL (50 µg/ml) demonstrated almost a 4-fold increase in mean enhanced pause compared to vehicle i.n. mice (p < 0.01). Animals in this group were the only ones to demonstrate an elevation in serum total IgE (1,248 ng/ml) and the only ones to demonstrate bronchoconstriction following respiratory challenge. Mice sensitized i.t. with 50 µg NAL demonstrated an approximate 2-fold increase in enhanced pause compared to vehicle mice following respiratory challenge. The responses by the 50 µg group may have been negatively skewed; five days prior to PENH determinations, mice from this group demonstrated signs of bronchoconstriction upon dosing. Several studies investigating rat mast cell degranulation and morphology suggest that mast cells require between 14 days and 1 month to fully recover from a degranulating stimulus (Kruger et al., 1981; Hammel et al., 1989
; Levi-Schaffer et al., 1990
). Additionally, one mouse from the 50 µg dose group anaphylaxed following dosing and was sacrificed prior to the termination of the study. Surprisingly, the low-dose group (0.049 µg) demonstrated signs of bronchoconstriction with almost a 2-fold increase in PENH following respiratory challenge. The remaining groups did not show any evidence of bronchoconstriction and exhibited PENH values similar to vehicle mice.
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DISCUSSION |
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Protein from NAL was used as the test material due to the improved homogeneity in protein profiles as compared to ammoniated latex or NRL glove extracts; this allowed for more direct comparisons amongst sensitization routes without introducing variability due to test articles. Furthermore, NAL extracts have been shown to possess comparable diagnostic sensitivity and specificity in comparison to AL and glove extracts, and an NAL preparation is under consideration by the FDA as a standardized skin prick test reagent (Hamilton et al., 1996, 1998
). The concentrations of latex proteins chosen for evaluation in these studies were consistent with potential human exposure levels. A number of laboratories have described the elution of latex proteins from NRL gloves (Alenius et al., 1994
; Slater, 1994
; Yunginger et al., 1994
; Tomazic et al., 1995
). Approximately 75% of the powdered gloves evaluated by these investigators had greater than 100 µg of latex protein per gram of glove; therefore, a latex glove weighing 8 grams could contain 800 µg of protein. Swanson et al. (1994) quantified between 8978 ng/m3 latex aeroallergens in several areas of a medical center where powdered gloves were used. Approximately 34% of the airborne particles collected were respirable (
7 µm). Based on human minute ventilation rates, a 40-h work week could result in respiratory tract exposure up to 10 µg of latex proteins per week.
The stratum corneum is considered to be the major barrier between topical antigens and the dermal immune system, but it is frequently compromised in HCW due to dermatitis caused by extensive glove usage and hand washing. Using in vitro diffusion cells, Hayes et al. (1999) demonstrated that, following 24 h of exposure to a single dose of 100 µg latex proteins, approximately 26% of NAL penetrated into or through tape stripped human skin, while less than 1.5% of the applied dose penetrated intact, non-abraded skin samples. Skin abrasion not only improves penetration of proteins through the skin but contributes to the ensuing immune response. Tape stripping of skin has been reported to increase Langerhans cell expression of MHC II and CD86 (Nishijima et al., 1997), and induce Th2-dominant cytokine responses in the skin of BALB/c mice (Kondo et al., 1998
). Consistent with these factors, serum IgE became elevated more quickly in animals which had been tape stripped to remove the stratum corneum. However, by day 50, the effects of tape stripping appeared minimal, as IgE levels were comparable between tape stripped and non-tape stripped animals.
The skin and lungs are considered good anatomical locations for IgE production following antigen exposure (Wu et al., 1996; Frazer et al., 1999) and, while topical and i.t. administration of latex proteins resulted in marked increases in IgE, i.n. instillation elicited a much lower response. The low IgE response following i.n. administration of latex proteins may be due to the limited antigen distribution in the lower respiratory tract. Robinson et al. (1996) demonstrated that only an approximate 30% of an i.n. administered 60 µl dose of 125I BSA was recovered from the lungs of mice, with the majority being recovered from the nasal cavity and gastro-intestinal tract.
A recent report demonstrated a significant correlation between specific IgE levels and both the incidence and severity of asthma and urticaria following latex challenges in humans (Kim et al., 1999). Studies have described altered pulmonary function in mice sensitized with ovalbumin by one route (topical or i.p.), and challenged either i.t. or by nebulization (Saloga et al., 1994; Keane-Myers et al., 1998
). Thakker et al. (1999) demonstrated altered pulmonary conductance and compliance in mice sensitized i.n. with latex proteins and challenged with allergen intravenously. In these studies, mean total IgE levels correlated with PENH responses (p
0.05) following topical (r2 = 0.87), i.n. (r2 = 0.73), and i.t. (r2 = 0.66) sensitization. Conversely, mice sensitized s.c. demonstrated the highest serum total IgE response (14,390 ng/ml), but showed no signs of bronchoconstriction as measured by enhanced pause.
Evidence that HCW and SB patients have a higher prevalence of sensitization to particular latex proteins has emerged. While the rubber associated proteins Hev b 1 (14 kDa) and Hev b 3 (2227 kDa) are recognized more frequently by IgE from SB patients, Hev b 2 (3536 kDa), Hev b 4 (100110 kDa), and Hev b 6.01, 6.02, and 6.03 (20 kDa, 5 kDa, and 14 kDa, respectively) are freely soluble proteins to which a higher percentage of allergic HCW develop antibodies (Alenius et al., 1993; Hamilton et al., 1996
; Reunala et al., 1996
; Yeang et al., 1996
; Posch et al., 1998
). Realizing that molecular weights alone can not be relied upon to identify specific latex proteins (Hev b 1, Hev b 6.03, and Hev b 8 have similar molecular weights), the different latex-specific IgE profiles observed in these studies following distinct sensitization routes is consistent with the hypothesis that the route of sensitization contributes to the varied specific antibody production among latex allergic patients (i.e., HCW and SB patients).
These studies suggest that NRL sensitization may occur following s.c., respiratory, and topical exposure to latex proteins. Mice sensitized to latex proteins demonstrated immunological responses which are consistent with those described for latex allergic patients. Sensitized mice demonstrated in vitro splenocyte proliferation consistent with that described for latex allergic patients by multiple laboratories (Murali et al., 1994; Raulf-Heimsoth et al., 1996
; Ebo et al., 1997
). Peripheral blood mononuclear cells purified from allergic individuals and stimulated with latex proteins (0.520 µg/ml) for 57 days showed stimulation indexes between 2.514 at optimal in vitro challenge concentrations. Additionally, mice showed elevations in total and latex-specific IgE, as well as in vivo bronchoconstriction following respiratory challenge with latex protein. Differences in latex-specific IgE profiles and pulmonary function following sensitization of mice by four different routes suggest that exposure routes leading to NRL sensitization may play a role in determining the primary allergens and the clinical manifestation of the immune response. These murine models of latex allergy appear to be representative of human latex allergy and should be useful in developing and evaluating new intervention techniques and strategies.
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NOTES |
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1 To whom correspondence should be sent at MS 4020, 1095 Willowdale Road, Morgantown, WV 26505. Fax: (304) 285-6126. E-mail: bhm8{at}cdc.gov.
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