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*
Lung Pharmacology Group, Department of Respiratory Medicine and Allergology, Göteborg University, Gothenburg, Sweden; and
Gene Therapy Core Center, Cardiovascular Research Institute, Department of Laboratory Medicine, University of California, San Francisco, CA 94143.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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. In addition, hIL-17
increased the expression of hIL-8 mRNA in bronchial epithelial cells.
Conditioned medium from hIL-17-treated bronchial epithelial cells
increased human neutrophil migration in vitro. This effect was blocked
by an anti-hIL-8 Ab. In vivo, intratracheal instillation of hIL-17
selectively recruited neutrophils into rat airways. This recruitment of
neutrophils into the airways was inhibited by an anti-hIL-17 Ab and
accompanied by increased levels of rat macrophage inflammatory
protein-2 (rMIP-2) in bronchoalveolar lavage (BAL) fluid. The BAL
neutrophilia was also blocked by an anti-rMIP-2 Ab. The effect of
hIL-17 on the release of hIL-8 and rMIP-2 was also inhibited by
glucocorticoids, in vitro and in vivo, respectively. These data
demonstrate that hIL-17 can specifically and selectively recruit
neutrophils into the airways via the release of C-X-C chemokines from
bronchial epithelial cells and suggest a novel mechanism linking the
activation of T-lymphocytes to recruitment of neutrophils into the
airways. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Activated CD4+ T lymphocytes may play a central role in airway inflammation 6, 7, 8, 9 . This is indicated by the ability of anti-CD4+ Abs to inhibit the influx of eosinophils and neutrophils into murine airways 9 . In the case of eosinophils, IL-5 is considered to link the activation of CD4+ to the influx of eosinophils 10 . However, until now, there has been little evidence indicating which cytokine might mediate recruitment of neutrophils induced by activated CD4+ cells.
hIL-17 was recently discovered and is a 16-kDa protein that can be released from activated human CD4+ T lymphocytes in vitro 11 . Rat (r) and mouse (m) IL-17 display a 60–70% homology with hIL-17 12 . All three of these forms of mammalian IL-17 have a highly conserved site for glycosylation, suggesting that interspecies cross-reactivity is possible 12 . IL-17 has specific receptors in several types of cells, including lung cells 13 . In response to hIL-17, human fibroblasts release IL-8 in vitro 14 . However, at present, it is not known whether human airway cells, such as bronchial epithelial cells and venous endothelial cells, release hIL-8 in response to hIL-17, or whether hIL-17, via the release of a C-X-C chemokine, can induce significant neutrophil recruitment into the airways in vivo.
To evaluate whether hIL-17 can induce neutrophil recruitment via C-X-C chemokine production, the current study characterized the effect of hIL-17 on hIL-8 protein release and mRNA levels in human bronchial epithelial and venous endothelial cells in vitro. The chemotactic activity of conditioned medium from the bronchial epithelial cells was tested using human neutrophils in vitro, with and without an anti-hIL-8 Ab. A rat model was utilized to evaluate the effect of hIL-17 on neutrophil recruitment into the airways in vivo. This model was also used to study the effect of hIL-17 on airway release of the rat C-X-C chemokine correlate to hIL-8, macrophage inflammatory protein-2 (rMIP-2) 15 . The study also examined the effect of an anti-rMIP-2 Ab on neutrophil recruitment into rat airways induced by hIL-17.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Transformed human bronchial epithelial (16HBE140-,
abbreviated as 16HBE) cells 16 were utilized because of their ability
to release hIL-8 in response to inflammatory stimuli similar to that
observed for primary human bronchial epithelial cells 17 . Another
human airway epithelial-like cell line (Calu-3) 18 , obtained from the
American Type Culture Collection (Manassas, VA), was also used. HUVEC
cells 19 were also utilized for their ability to release hIL-8 in
response to inflammatory stimuli 5 . HUVEC cells, EGM Bulletkit
(endothelial cell basal medium and supplements), trypsin-EDTA solution,
trypsin neutralizing solution, and HBSS were obtained from Clonetics
(San Diego, CA). Recombinant hIL-17, goat neutralizing anti-hIL-17
Ab, recombinant hIL-8, mouse neutralizing anti-hIL-8 Ab,
recombinant hTNF-, and hIL-8 ELISA kits were obtained from R&D
Systems (Minneapolis, MN). Penicillin-streptomycin,
L-glutamine, PBS, amphotericin B, BSA, and
hydrocortisone were purchased from Sigma (St. Louis, MO). Fibronectin
(human) and collagen (bovine, type I) were obtained from Becton
Dickinson Labware (Bedford, MA), and MEM Earle-Eagle was from Life
Technologies (Inchinnan, Scotland, U.K.). Ketamine hydrochloride
(Park-Davis, Barcelona, Spain), xylazine chloride (Bayer Sverige,
Göteborg, Sweden), dexamethasone (Sigma), pentobarbit-one
(Apoteksbolaget, Umeå, Sweden), rabbit anti-rMIP-2 Ab (Serotec,
Oxford, U.K.), and rMIP-2 ELISA kit (BioSource International,
Camarillo, CA) were also obtained commercially.
In vitro experiments
Cell culture conditions.
16HBE cells were grown in MEM Earle-Eagle medium with FCS (10%), 2 mM
L-glutamine, 100 U/ml penicillin, 100 g/ml
streptomycin, and 5 µg/ml amphotericin B on collagen and
fibronectin-coated dishes 20 . Calu-3 cells were grown in MEM Eagle,
supplemented with 10% FCS, 100 U/ml penicillin, 100 µg/ml
streptomycin, and 5 µg/ml amphotericin B. HUVEC cells were grown in
endothelial cell basal medium, supplemented with 6% FCS, 1 µg/ml
hydrocortisone, 0.01 µg/ml recombinant human epidermal growth factor,
25 µg/ml gentamicin, 0.025 µg/ml amphotericin B, and 12 µg/ml
bovine brain extract. All cells were grown to confluence in 6-well
plastic plates (Becton Dickinson, Mountain View, CA). At 18 h
before the experiments, the concentration of FCS was reduced to 1% in
16HBE and Calu-3 cells and to 2% in HUVEC cells to minimize the basal
(inherent) hIL-8 release. Before the addition of stimuli, the cells
were washed twice with PBS and placed in fresh medium with 1% (16HBE
and Calu-3) or 2% (HUVEC) of FCS. PBS supplemented with 0.35% BSA was
used to deliver hIL-17 and hTNF-. The corresponding concentration of
BSA (total concentration including BSA in cytokines equal to 0.45%)
was used as a vehicle.
Effect of hIL-17 on hIL-8 protein release. Conditioned media were removed from cells and frozen at the end of each experiment. Thawed samples were centrifuged (4000 rpm for 10 min.) to pellet cells and cell debris. The supernatants were analyzed using an ELISA for hIL-8 according to the manufacturer’s instructions.
Effect of hIL-17 on hIL-8 mRNA levels. Total RNA was isolated and analyzed using RT-PCR. Simultaneously, amplification of ß-actin was done as an internal standard for RT-PCR 21 . 16HBE cells were grown to confluence in 6-well plates and treated with hIL-17 or vehicle. Two hours later cells were harvested by scraping, were washed with PBS, and then suspended in RNA STAT-60 (Tel-Test B, Friendswood, TX).
Total RNA was isolated from 16HBE cells by a single-step method with the RNA STAT-60 kit according to the manufacturer’s instructions. The isolate was treated with RQ1 RNase-free DNase (Promega, Madison, WI) and then extracted. The concentration and purity of isolated RNA was determined spectrophotometrically.
Reverse transcription involved incubation of 2 µg of total RNA and random hexamer (Pharmacia, Uppsala, Sweden) with dNTPs (Pharmacia), RNase inhibitor (Promega), superscript reverse transcriptase (Life Technologies, Gaithesburg, MD, USA), first strand buffer (Life Technologies), and diethyl pyrocarbonate-treated water (DEPC-H2O) for 1 h at 42°C. The reaction was terminated by heating at 70°C for 10 min.
PCR amplification utilized commercially available primers to hIL-8 and
ß-actin (Clontech Laboratories, Palo Alto, CA) and was performed in
the presence of AmplyTaq Gold DNA Polymerase, PCR buffer, and 2.0 mM
MgCl2 (all from Perkin-Elmer Cetus, Norwalk CT), dNTP mix
(Pharmacia), and sterile water. The PCR was conducted in a Perkin-Elmer
Cetus GeneAmp PCR System 9600 starting with a 12-min incubation at
95°C, followed by 24 cycles of denaturation at 94°C for 45 s,
annealing at 65°C for 45 s, and extension at 72°C for 2 min.
The final extension was at 72°C for 7 min. The PCR products were
separated on a 3% agarose gel (SeaKem and NuSieve, FMC BioProducts,
Rockland, MA) containing ethidium bromide.
X147/HaeIII-digested DNA (Life Technologies) was used as
a molecular size marker. Gels were photographed under UV light and
images were scanned (StudioScan II/si; Agfa, Mortcel, Belgium)
for densitometric analysis, i.e., bands were quantified in terms of
position, height and area in two dimensions. This "volume" analysis
was performed with IPLab Gel software for Macintosh (BioSystematica,
Plymouth, U.K.). Results were expressed as a ratio calculated from the
volume of the amplified cytokine mRNA product divided by the volume of
the amplified housekeeping (ß-actin) mRNA.
Effect of hIL-17 on human neutrophil chemotaxis. Neutrophils were isolated from peripheral blood of healthy, adult volunteers. Whole blood was sedimented in the presence of 4.5% dextran T500 solution (Pharmacia) to remove RBC, monocytes, and lymphocytes 22 . The residual erythrocytes were lysed (0.8% NH4Cl + 0.1% KHCO3), and the remaining neutrophils were washed twice with HBSS. The neutrophils were brought to the final concentration of 3 x 106 cells/ml in HBSS containing 1% BSA. To analyze the chemotactic activity of conditioned medium from the 16HBE cells, neutrophils were suspended in MEM Earle-Eagle. The chemotaxis assay was performed in a 48-well microchemotaxis chamber (Neuroprobe, Cabin John, MD) as previously described 23 . Briefly, the solutions and equipment were brought to 37°C before onset of the experiment. The bottom wells of the chamber were filled with 25 µl of fluid containing either the chemotactic stimulus, the control solution, or conditioned medium from 16HBE cells. A polycarbonate filter with pore size of 3 µm (Nucleopore, Pleasanton, CA) was placed over the bottom wells. The silicon gasket and upper piece of the chamber were applied, and 50 µl of neutrophil suspension were pipetted into upper wells as triplicate samples. The chamber was incubated in humidified air with 5% CO2 at 37°C for 20 min, then disassembled, and the filter was removed. The filter was then fixed, stained with Diff-Quick dyes (Svenska Labex, Helsingborg, Sweden), and mounted on a glass slide. Neutrophils that completely migrated through the filter were counted in five random, high power fields (HPF) (x1000) from each well. Triplicate wells were used for each data point. The chemotactic response was defined as the mean number of migrating cells per HPF.
The negative control used was HBSS with 1% BSA which caused migration of 8.7 ± 2.7 neutrophils/HPF (n = 4). Pure hIL-8 (1 x 10-9) and FMLP (1 x 10-7) were utilized as positive "technical" controls and caused migration of 148 ± 21.2 and 168.5 ± 26.9 neutrophils/HPF respectively (n = 4). If no response to these stimuli was observed, the experiment was excluded. Inhibition of hIL-8-mediated neutrophil recruitment involved 10 µg/ml of anti-hIL-8 Ab added to the stimuli 15 min before experiment. This concentration of Ab showed 89 ± 3% (n = 4) inhibition of neutrophil recruitment caused by 1 x 10-9 M of hIL-8 and had no effect on chemotaxis induced by 1 x 10-7 of FMLP. In the experiments with conditioned media from 16HBE cells, the conditioned medium from vehicle-treated 16HBE cells served as a negative control. This kind of stimulus resulted in migration of 17.3 ± 2.7 neutrophils/HPF and was not affected by adding an anti-hIL-8 Ab (17.8 ± 1.8 neutrophils/HPF, Student’s paired t test, two-way: p = 0.9, n = 4).
In vivo experiments
Animals. Brown Norway rats (male, 250–300 g, Harlan, Oxon, U.K.) were used under conditions approved by the animal ethics committee in Göteborg University (Dno 134/95).
BAL. Animals were anesthetized with ketamine (50 mg/kg i.m.) and xylazine (5 mg/kg i.m.). The trachea was intubated with a cannula (OD 2.8 mm Portex, Smiths Industries, Middlesex, U.K.), and the solution with hIL-17 (1 µg in 50 µl of vehicle) was instilled intratracheally (i.t.). An equivalent volume of vehicle (PBS containing 0.45% BSA) was administered correspondingly in the control animals. After the administration of hIL-17 or vehicle, the animals regained consciousness.
For time course experiment, animals were treated i.t. with hIL-17 or vehicle. BAL was collected at 2, 4, 6, and 8 h after the administration of IL-17 or vehicle.
To evaluate whether the effect of IL-17 is specific in vivo (i.e., not due to unspecific protein deposition), hIL-17 protein solution (1 µg in 50 µl of vehicle) was coincubated with an anti-hIL-17 Ab (30 µg in 50 µl of vehicle) at 37°C for 15 min and installed i.t. An equivalent volume of corresponding vehicle (100 µl of PBS containing 0.45% BSA and 1 ng LPS) or IL-17 (1 µg in 100 µl of PBS with BSA and LPS) was utilized as negative and positive control, respectively. BAL was collected 6 h later.
To establish whether 6 h of incubation with hIL-17 increases the release of MIP-2 in rat airways, rMIP-2 protein level were determined in BAL fluid by ELISA.
To determine whether endogenous MIP-2 released by hIL-17 (1 µg/rat i.t.) contributes to neutrophil recruitment in rat airways, anti-rMIP-2 Ab was instilled i.t. before administration of hIL-17. Animals were pretreated with: 1) anti-rMIP-2 Ab (100 µg/rat i.t.) 15 min before administration of hIL-17, 2) an equivalent volume of vehicle for MIP-2 (PBS) before administration of hIL-17, and 3) vehicles of both anti-rMIP-2 and hIL-17. BAL was performed 6 h after administration of hIL-17 or vehicle. In separate experiments, an anti-MIP-2 Ab (100 µg/rat i.t.) had no effect on "basal" neutrophil recruitment compared with animals treated with vehicle for the anti-MIP-2 Ab (0.1 ± 0.05 vs 0.08 ± 0.03 x 106/animal, respectively, Student’s t test, two-way: p = 0.7, n = 4).
To test whether a glucocorticoid inhibits hIL-17-induced neutrophil recruitment, animals were treated with: 1) the vehicle for dexamethasone (2-hydroxypropyl-ß-cyclodexin) 1 h before addition of the vehicle for hIL-17, 2) the vehicle for dexamethasone prior hIL-17 administration, and 3) dexamethasone (3 mg/kg i.p.) 1 h before hIL-17 administration. BAL was performed 8 h after administration of hIL-17 or vehicle.
At the indicated time-points (see
Figs. 5–7
), animals were euthanized
by pentobarbitone (100 mg/kg i.p.). The airway was cannulated through a
tracheostoma and lavaged with 5 x 4 ml of PBS at room
temperature. BAL fluid was centrifuged (200 x g for 10
min at 4°C), and the cell pellet was resuspended in washing buffer
(sterile PBS containing 0.35% BSA and 0.1% glucose). Total BAL cell
counts were determined in haemocytometer using Türks staining.
For differential BAL cell counts, cytospin preparations were made and
stained using the May-Giemsa method. Differential cell counts were
conducted according to standard morphology criteria using oil immersion
microscopy (magnification, x1000). Cell counts were conducted on 300
cells and the absolute number of each cell type was calculated. The
cell-free BAL fluid was collected and stored at -80°C.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Effect of hIL-17 on hIL-8 protein release.
In the concentration range of 1–1000 ng/ml, hIL-17 increased hIL-8
levels in conditioned medium from Calu-3 and 16HBE cells in a
concentration-dependent fashion (Fig. 1A). Coincubation with an
anti-hIL-17 Ab blocked the hIL-17-induced hIL-8 increase in medium
from 16HBE cells (Fig. 1A). In Calu-3 and HUVEC cells, there
was a time-dependent effect of hIL-17 on the increase in hIL-8 during
2–18 h (100 ng/ml) (Fig. 1B). At a hIL-17 concentration of
100 ng/ml, hydrocortisone significantly inhibited hIL-8 increase in
both Calu-3 and HUVEC cells (Fig. 1B). Cotreatment of cells
with a concentration of hIL-17 (100 ng/ml) that caused a submaximum
response plus hTNF- (20 ng/ml) resulted in a potentiated increase in
hIL-8 in conditioned medium from 16HBE cells when compared with the sum
of the increase observed with hIL-17 alone or hTNF- alone (Fig. 2). By comparison, the hIL-8 increase
caused by cotreatment with hIL-17 (100 ng/ml) plus hTNF- was
significantly higher (Student;s t test, paired, two-way:
p < 0.05, n = 6) than that observed
after treatment with a maximum-effective concentration of hTNF-
alone (100 ng/ml) (4957 ± 605 and 3574 ± 406 pg/ml,
respectively). In addition, hydrocortisone inhibited the increase in
hIL-8 levels caused by hIL-17 in the conditioned medium from 16HBE
cells (Fig. 2).
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). An anti-hIL-8 Ab blocked this
effect on neutrophil migration (Fig. 4). By contrast, human IL-17 had
no significant direct chemotactic effect on neutrophil migration in the
concentration range of 1–1000 ng/ml (peak migration with 10 ng/ml:
146 ± 56% of migration induced by vehicle, Student’s
t test, paired, two-way: p = 0.5,
n = 4). In addition, hIL-17 (10 ng/ml) had no additive
effect (115 ± 23%) on neutrophil chemotaxis caused by 3 x
10-10 M of hIL-8 (Student’s t test, paired,
two-way: p = 0.5, n = 4, compared with
hIL-8 alone).
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Neutrophil recruitment induced by hIL-17.
hIL-17 significantly and selectively (Fig. 5
) increased the absolute number of
neutrophils in rat BAL fluid at 4, 6, and 8 h after instillation
i.t. (Fig. 6). No such increase in
neutrophils was detected after 2 h. The effect of hIL-17 on
neutrophil recruitment was significantly inhibited by an
anti-hIL-17 Ab at 6 h after instillation (Fig. 7A).
Pretreatment of animals with an anti-rMIP-2 Ab blocked the increase
in neutrophil numbers in BAL fluid from rats given IL-17 i.t. (Fig. 7B). Also, a significant increase in the level of rMIP-2 was
detected in BAL fluid after exposure to hIL-17 (136 ± 31 ng/ml
for vehicle and 565 ± 162 ng/ml for hIL-17, p <
0.05 according to Student’s unpaired, two-way t test,
n = 9).
Pretreatment with dexamethasone significantly decreased the number of
neutrophils in BAL fluid from rats given hIL-17 i.t. as well (Fig. 7C).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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or IL-1ß, which
subsequently increase adhesion molecule expression and chemokine
release 25, 26 . However, T cells are not the dominating source of
TNF- or IL-1ß 25 , and therefore other cytokines may be involved
in mediating the effect of T cells on neutrophils.
The current study now demonstrates that hIL-17, a cytokine derived from
activated CD4+ cells, increases the release of the major
human neutrophil chemoattractant, the C-X-C chemokine, IL-8, in human
bronchial epithelial and venous endothelial cells in vitro. The
inhibition of hIL-8 release caused by cotreatment with hIL-17 plus an
anti-hIL-17 Ab indicates a specific effect exerted by hIL-17 (i.e.,
not an effect due to protein deposition). The fact that hIL-8 mRNA
expression is increased by hIL-17 in epithelial cells strongly
indicates that hIL-17 induces de novo synthesis of hIL-8, and this is
in line with recent data showing that hIL-17 activates NF-
B, a
transcription factor initiating C-X-C chemokine expression 27 . The
functional relevance of the hIL-8 production in hIL-17 induced
neutrophil recruitment in vitro is confirmed by the observation that
conditioned medium from airway epithelial cells treated with hIL-17
causes neutrophil chemotaxis, whereas hIL-17 alone does not.
The current study also demonstrates that, in vivo, i.t. installation of hIL-17 causes selective recruitment of neutrophils into rat airways. This recruitment is inhibited by an anti-hIL-17 Ab, thus proving the specific effect of hIL-17 in vivo. The IL-17-induced neutrophil recruitment is accompanied by an increased level of the rat functional analogue of hIL-8, rMIP-2, in BAL fluid. In addition, an anti-rMIP-2 Ab inhibits this hIL-17-induced neutrophil recruitment. The time course of neutrophil recruitment in vivo induced by hIL-17 supports an indirect effect of hIL-17 via chemokine release. The 4-h lag in recruitment is consistent with the time required for de novo synthesis and release of C-X-C chemokines and subsequent neutrophil recruitment in the airways 28 . We do not find it likely that there is a problem with interspecies cross-reactivity for hIL-17 and rat cells because separate experiments have demonstrated that mIL-17, given i.t. to Sprague Dawley rats, produces virtually the same level of selective neutrophil recruitment as does hIL-17 (unpublished data), and rIL-17 and mIL-17 display a 90% homology. Also, mIL-17 and rIL-17, as well as hIL-17 induce cytokine release in mouse stromal cells 29 , which provides further support of interspecies cross-reactivity at the IL-17 receptor.
The notion that hIL-17 can recruit neutrophils via C-X-C chemokine release is consistent with the recent in vitro finding that hIL-17 releases hIL-8 from fibroblasts 14 . Furthermore, a recent study has demonstrated the release of the neutrophil-activating protein, hIL-6, caused by hIL-17 in airway epithelial cells 13 . It is thus possible that IL-17 is indirectly involved in both chemotaxis and activation of neutrophils in the airways.
The level of the proinflammatory cytokine, hTNF-, is increased in
sputum of patients with airway inflammation 30 . In addition to its
ability to increase the expression of ICAM-1 in endothelial cells,
hTNF- also increases the production of other cytokines such as hIL-6
and hIL-8 26 . In the current study, the potentiating effect on the
release of hIL-8 in airway epithelial cells caused by cotreatment with
hIL-17 plus hTNF- implies another potential mechanism for neutrophil
recruitment. In fact, the effect of this combined treatment with hIL-17
and hTNF- by far exceeded the effect caused by the maximally
effective concentration of hTNF- alone. The two pro-inflammatory
cytokines IL-17 and TNF- may therefore cooperate in causing C-X-C
chemokine release from airway cells and, as a result, potentiate the
subsequent neutrophil recruitment.
Glucocorticoids are widely utilized to inhibit inflammation in the airways. One important anti-inflammatory mechanism for this class of drugs is inhibition of cytokine production 31 . In this study, a glucocorticoid (hydrocortisone) potently inhibited the release of IL-8 caused by hIL-17 in human bronchial epithelial and venous endothelial cells in vitro. Correspondingly, in vivo, another glucocorticoid (dexamethasone) also attenuated the neutrophil influx into rat airways caused by hIL-17. These observations indicate that glucocorticoids down-regulate C-X-C chemokine release and are consistent with previous findings using stimuli other than hIL-17 31, 32 . However, it cannot be excluded that glucocorticoids also reduce the number of IL-17 receptors present on bronchial epithelial or endothelial cells.
In conclusion, this study demonstrates that hIL-17, a cytokine released
from activated CD4+ cells, exerts a specific,
pro-inflammatory effect by increasing C-X-C chemokine release in airway
cells. As indicated by the neutrophil recruitment induced by hIL-17
both in vitro and in vivo, the IL-17-induced release of C-X-C
chemokines is functionally significant in airways. In the case of
hIL-8, the in vitro data indicate that the hIL-17 induced release is
due to de novo synthesis. The in vitro data also indicate that hIL-17
potentiates the effect of the proinflammatory cytokine hTNF- on
hIL-8 release. Thus, if released in airways, IL-17 may link
T-lymphocyte activation to the recruitment of neutrophils in airway
inflammation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Associate Professor Anders Lindén, Lung Pharmacology Group, Göteborg University, Guldhedsgatan 10A, S-413 46 Gothenburg, Sweden. E-mail address:
3 Abbreviations used in this paper: BAL, bronchoalveolar lavage; h, human; r, rat; m, mouse; MIP-2, macrophage inflammatory protein-2; HPF, high power field; i.t., intratracheally.
Received for publication September 29, 1998. Accepted for publication November 5, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Immunology 77:330.[Medline]
field. Int. Arch. Allergy Immunol.
111:199.27.
ß TCR+ CD4-CD8- T cells. J. Interferon Cytokine Res. 16:611.[Medline]
in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am. J. Respir. Crit. Care Med. 153:530.[Abstract]
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