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Department of Respiratory Diseases, University Hospital, B-9000 Ghent, Belgium; and
Laboratoire de Biologie et Thérapeutique de Pathologies Immunitaires, Centre National de la Recherche Scientifique ERS 107, Hôpital de la Pitié-Salpêtrière, 75651 Paris Cedex 13, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the lung, the network of airway DC is particularly well developed to capture inhaled Ag (10, 11, 12). Its location above the basement membrane of the airway epithelium ensures accessibility to inhaled Ag. Upon encounter with inhaled Ag, airway DC migrate to the draining lymph nodes of the lung, up-regulate expression of costimulatory ligands, and interact with naive T lymphocytes, inducing a primary immune response (13, 14, 15). However, no data exist on whether DC are critical in the presentation of inhaled Ag to previously activated or memory T cells. We have addressed this question in a T cell-driven mouse model of asthma. We have previously reported that inhalational challenge with OVA aerosol in OVA-sensitized mice leads to Th2 cytokine-dependent eosinophilic airway inflammation, bronchial hyperreactivity, and IgE production, findings highly characteristic of human allergic asthma (16, 17, 18). In this study, we have used transgenic (TG) mice expressing the herpes simplex virus type 1 thymidine kinase (TK) suicide gene in the cells of the myeloid DC lineage, allowing the conditional ablation of DC by treatment with the nucleoside analogue ganciclovir (GCV) (19). This suicide gene technique allows a well-controlled time window of DC depletion during which experiments can be performed in a GCV-free environment. By depleting DC before challenge with inhaled Ag, we show that DC are essential for the presentation of Ag to previously activated T cells and are critical for the subsequent development of chronic allergic airway inflammation. These findings have important implications for understanding the APC requirements for reactivation of memory T cells. The requirement for functional DC for the development of eosinophilic airway inflammation in sensitized mice suggests that DC may provide a useful target for future anti-asthma therapy.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TG mice carrying the TK transgene under the HIV-LTR promoter (19) were from the 12th backcross to C57BL/6 mice. As these mice show an early wasting syndrome after treatment with GCV, most probably due to ectopic transgene expression in cells of the intestinal epithelium, we performed all experiments using irradiated (13 Gy) C57BL/6 hosts reconstituted with TG bone marrow, referred to as TK-TG (20). Wild-type (WT) C57BL/6 mice and C57BL/6 mice that had received bone marrow from nontransgenic (N-TG) littermates served as controls. All animals were housed in sterile microisolator units under specific pathogen free (SPF) conditions.
Sensitization and challenge with OVA
On day 0, mice (n = 8–10 per group) were actively immunized with OVA (grade III, Sigma Chemical, St. Louis, MO) by the i.p. injection of 10 µg OVA adsorbed to 100 µg of alum adjuvant. Sham-sensitized animals received i.p. PBS. From day 16 to day 20 after immunization, animals were exposed daily for 30 min to an aerosol of 1% (w/v) OVA in PBS. Groups of 10 mice were placed in an exposure chamber connected to the outlet of an ultrasonic nebulizer that delivers an aerosol of particles with a mean diameter of 3.5 µm (Microvernebler R80, Microvernebler, Zurich, Switzerland).
Depletion of dendritic cells by treatment with GCV
On day 9, mice were anesthetized by the i.p. injection of avertin (2.5% in PBS) (Sigma). Miniosmotic pumps (ALZET model 2001, Alza, Palo Alto, CA), delivering a dose of 50 mg/kg/day of GCV (Cymevene, Syntex, Brussels, Belgium) over a 7-day time period, were implanted s.c. In control experiments, PBS-filled pumps were implanted. On day 15 of the experiment, the miniosmotic pumps were removed.
To verify the depletion of airway DC in these mice, we modified a protocol to visualize the rat airway DC network (21). In brief, animals were anesthetized and perfused with 1% paraformaldehyde fixative in PBS (pH 7.4) for 2 min through the ascending aorta. Tracheas were removed, opened by a midline incision and pinned flat on silicone-coated petri dishes (Sylgard 184, Dow Corning, Midland, MI). After permeabilization in PBS containing 0.3% Triton X-100 (Sigma), tissues were preblocked with rabbit serum, incubated with M5/114 mAb (rat IgG2, anti-I-A, and I-Eb,d,k, Boehringer Mannheim, Indianapolis, IN) for 36 h at room temperature, followed by incubation with rabbit anti-rat F(ab')2 fragments conjugated to horseradish peroxidase (Serotec, Oxford, U.K.) for 24 h. Signal was developed by incubation for 20 min in 0.05% diaminobenzidine (DAB) in Tris-buffered saline (pH 7.6). Tissues were dehydrated in serial alcohol steps and cleared in toluene. The entire trachea was mounted in D.P.X. mounting medium (Nustain, University Hospital, Nottingham, U.K.). The cellular density of the airway DC network (cells/mm2) was calculated using the Impact image analysis system (Alcatel, TITN Answare, Oberkochen, Germany).
Bronchoalveolar lavage (BAL)
On day 21 of the experiment, 24 h after the last aerosol
challenge, mice were sacrificed by sodium pentobarbital overdose (60
mg/kg body weight). BAL was performed with 2 x 1 ml of
Ca2+- and Mg2+-free HBSS supplemented with 0.05
mM sodium EDTA, as described (17). The BAL fluid was centrifuged (10
min, 4°C, 700 x g), and supernatant was collected
and stored at -80°C until analysis of cytokine content. After
resuspension in HBSS, cells were counted in a hemocytometer (Coulter
Counter, Hertfordshire, U.K.). Differential cell counts were performed
on cytospin preparations (Cytospin 2, Shandon, Cheshire, U.K.) stained
with May-Grünwald-Giemsa by classification of 300 cells on
standard morphologic criteria. The cytokine content in unconcentrated
BAL fluid was determined using commercially available cytokine ELISA
kits. The ELISA test for determination of murine IFN-
and IL-2 had a
sensitivity of 2 pg/ml and 3 pg/ml, respectively (Quantikine M, R & D
Systems, Abingdon, U.K.). The ELISA tests for determination of murine
IL-4 and IL-5 had a sensitivity of 5 pg/ml (Biotrak, Life Science,
Amersham, U.K.).
Flow cytometric analysis of BAL fluid cells
Monoclonal antibodies conjugated to phycoerythrin or FITC were
purchased from PharMingen (San Diego, CA). All reactions were performed
on ice in staining buffer (PBS, 1% BSA, and 0.02% sodium azide).
Aliquots of 2 x 105 BAL cells were incubated for 15
min with 2.4G2 mAb at 5 µg/ml to reduce nonspecific binding via the
FcRII(CD32). After washing in staining buffer, cells were stained
with anti-CD3-phycoerythrin (clone 145-2C11) and anti-CD4-FITC
(clone H129.19), anti-CD8
-FITC (clone 53-6.7) or anti-B cell
mAb B-220-FITC (CD45R, clone RA3-6B2) at 1 µg of mAb/106
cells for 30 min. Controls were generated by staining cells under
identical conditions with fluorochrome-conjugated irrelevant myeloma
Igs. Cells were fixed in 1% paraformaldehyde in PBS and analyzed on a
FACS-Vantage flow cytometer (Becton Dickinson Immunocytometry Systems,
San Jose, CA). Data were acquired in list mode on
1 x 104 cells and analyzed using Cell Quest software
(Becton Dickinson).
Airway histology
After BAL was performed, fixative (4% paraformaldehyde in PBS) was gently infused through the lavage catheter by a continuous release pump under pressure- and volume-controlled conditions. The lungs were resected and fixed for an additional 4 h. After routine paraffin embedding, 4-µm sections were stained with May-Grünwald-Giemsa and hematoxylin-eosin and examined by light microscopy for histologic changes.
Measurement of serum IgE
Blood was drawn by cardiac puncture for measurement of serum IgE by isotype-specific ELISA as described previously (18). Briefly, total serum IgE was determined by coating 96-well plates overnight with monoclonal rat anti-mouse IgE LO-ME-3 (H. Bazin, Experimental Immunology Unit, Brussels, Belgium). After blocking with 1% BSA, sample dilutions and known IgE standard were incubated, followed by biotin-conjugated monoclonal rat anti-mouse IgE LO-ME-2 (H. Bazin) and peroxidase-streptavidin conjugate. The detection limit of the assay was 0.05 µg/ml.
OVA-specific IgE was determined by coating plates overnight with OVA grade V (Sigma). Serial dilutions of serum were applied, followed by biotin-conjugated anti-mouse IgE. A serum pool of OVA-sensitized mice was used as internal laboratory standard. A 1:100 dilution of this pool was chosen as arbitrary unit. The lower detection limit of this assay is 0.00165 U/ml.
Statistical analysis
Total and and OVA-specific IgE levels were logarithmically transformed before calculation of the mean ± SEM. Comparison of means between different groups was performed with the Mann-Whitney U test for unpaired data using the Spreadware Statistics (Spreadware, Palm Desert, CA) statistical package (22). Differences were considered significant if p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine whether DC could be depleted from the airways of
TK-TG mice, animals were treated with a continuous release infusion of
GCV delivered via miniosmotic pumps, as previously described (19). The
cellular density of the network lining the airways was visualized in
tracheal whole mounts. The pattern of MHC class II staining in the
airways of WT mice revealed a network of strongly positive cells with a
dendritic morphology in the upper layers of the respiratory epithelium
(Fig. 1
, A and B).
The density of the network decreased from the upper to the lower
trachea (Fig. 1D). Administration of GCV for 6 days to TK-TG
mice led to a disappearance of more than 95% of airway DC (Fig. 1, C and D), a reduction maintained for at least 4
or 5 days after discontinuation of GCV treatment (not shown). After the
same treatment regimen of 6 days, the cellular composition of BAL fluid
of unimmunized TK-TG mice was identical in GCV- and PBS-treated animals
(Table I).
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In initial experiments, WT C57BL/6 mice were sensitized to OVA by
i.p. injection of OVA in alum and challenged 2 wk later with
OVA-aerosol. The cellular composition of BAL fluid was measured as an
indicator of airway inflammation. The total number of BAL fluid
eosinophils was significantly higher in actively sensitized animals
compared with sham-sensitized animals (p <
0.05) (Fig. 2A). The absolute
numbers of BAL CD3+, CD4+, and CD8+
T lymphocytes and B lymphocytes were significantly higher in actively
sensitized compared with sham-sensitized animals
(p < 0.05) (Fig. 2, B and
C). The Ag-induced changes in BAL fluid were not affected by
treating WT animals with GCV (Fig. 2, A to C).
Moreover, the cellular changes observed in BAL fluid were identical in
PBS-treated TK-TG and WT mice, illustrating that there was no
intrinsic difference in the response of TG mice. However, when TK-TG
mice were treated with GCV to deplete DC, there was a significant
reduction in the number of CD3+, CD4+,
CD8+, and B cells in BAL fluid compared with PBS-treated
TK-TG and GCV-treated WT mice (p < 0.01) (Fig. 2, B and C). This effect of GCV was not observed
in control N-TG chimeric mice, which developed similar changes in BAL
fluid as WT animals. The number of eosinophils induced by OVA aerosol
was reduced to background levels by GCV treatment (Fig. 2A).
However, considerably more T lymphocytes were recovered from lavage in
DC-depleted OVA-sensitized animals compared with sham-sensitized
animals, illustrating the presence of a primary immunization effect in
OVA-sensitized TG animals (p < 0.01). Alveolar
macrophages constituted 88% of cells in the BAL fluid of GCV-treated
TK-TG mice.
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Histologic analysis of the lungs of sensitized and
challenged mice revealed that OVA-aerosol challenge in OVA-sensitized
mice led to the development of peribronchial and perivascular
inflammatory lesions characterized by a predominance of eosinophils and
mononuclear cells, as previously described (Fig. 3, B and
C) (16). Occasionally, giant
cells were seen in the infiltrates. These changes were absent from the
lungs of sham-sensitized mice (Fig. 3A). Similar tissue
lesions were observed in WT mice treated with GCV and TK-TG mice
treated with PBS (Fig. 3, D and E). However, when
DC were depleted by GCV treatment in TK-TG mice, the tissue response to
secondary challenge with OVA was suppressed such that no peribronchial
and perivascular infiltrates were seen (Fig. 3F).
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To determine the type of immune response (Th1 vs Th2) being
induced in the airways of sensitized mice, we measured BAL fluid
cytokine levels using commercially available ELISA. BAL fluid contained
measurable cytokines after aerosol challenge of sensitized WT mice in
only 4 out of 10 mice, but revealed a predominance of Th2 cytokines
IL-4 and IL-5 (Table II). We used
unconcentrated BAL fluid, which probably explains why some of the
samples had concentration levels of cytokines below the detection
limits of the assay. No Th1 cytokines were detected. All
sham-sensitized mice had undetectable levels of both Th1 and Th2
cytokines. Treatment with GCV in WT mice did not affect the pattern of
cytokine synthesis inasmuch as 5 of 8 mice had measurable Th2 cytokines
and the range of reactivity found was similar to PBS-treated WT
animals. Treatment with GCV in TK-TG mice reduced the number of animals
with measurable Th2 cytokines from 4 of 10 to 1 of 9 and the IL-4
concentration was the lowest overall.
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In view of the association of allergic disorders with the presence
of detectable levels of IgE, we measured both total and OVA-specific
serum IgE by ELISA. Active sensitization by i.p. injection of OVA in
alum and subsequent challenge with OVA aerosol led to an increase in
both total and OVA-specific IgE levels, compared with sham-sensitized
mice (p < 0.05 and p < 0.01)
(Fig. 4, A and B).
GCV treatment of WT mice did not influence the levels of IgE. Treatment
with GCV to deplete DC led to a significant reduction in the levels of
both total and OVA-specific IgE compared with PBS-treatment in TK-TG
mice (p < 0.05 and < 0.001). This effect
of GCV was not seen in control N-TG chimeric mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). The typical morphology of these cells, combined with the
previous observation that all MHC class II staining in the airways of
SPF-reared mice is attributable to DC (10, 12), indicates that these
cells constitute the DC population. After discontinuation of GCV
treatment, DC gradually replenish the airways, allowing for a time
window of DC depletion in which experiments can be performed in a
GCV-free environment. Since GCV is toxic only to dividing cells, the
depletion of DC in TK-TG mice by 6-day treatment with GCV indicates a
rapid turnover rate of airway DC in mice, consistent with the previous
report of a turnover rate of about 2 or 3 days in rats (23).
We have previously studied the selectivity of the GCV-induced depletion
of various populations of APC in TK-TG mice (19, 20). We found no
effect on the number of monocytes and B cells in the peripheral blood
of animals given an identical treatment regimen of GCV. FACS analysis
of spleen and lymph nodes of these animals revealed an identical
percentage of Mac-1-positive macrophages and B-220-positive B cells.
Immunohistochemical analysis of spleen and lymph node sections of TK-TG
mice treated with GCV has demonstrated a complete depletion of
CD11c-positive marginal zone DC, without effects on red pulp
macrophages, marginal metallophilic macrophages (MOMA-1+),
and marginal zone macrophages (24). Moreover, the CD8+
NLDC-145+ population of interdigitating DC were not
affected by treatment with GCV, suggesting that these cells have a
separate lymphoid lineage or turnover rate, as recently shown by others
(24, 25). In our experiments, GCV treatment in TK-TG mice had no effect
on the numbers of alveolar macrophages and B cells recovered from
lavage. However, the depletion of DC in the airways of GCV-treated
TK-TG mice was almost complete.
As the HIV LTR-promoter sequence used to drive the expression of TK in DC can also be transcribed in activated T cells, we have also addressed the question of whether T cell function is normal in GCV-treated animals at the time of antigenic stimulation (i.e., 24 h after the discontinuation of GCV). Under these experimental conditions, T cell responses are not affected as assessed by the generation of a normal CTL response after challenge with lymphocytic choriomeningitis virus (R. Zinkernagel, B. Salomon, and D. Klatzmann, unpublished observations). Moreover, TK-TG mice demonstrated normal proliferation in Vß8.1-2 T cells 48 h after the i.v. injection of staphylococcal enterotoxin B superantigen. CD4+ Vß8.1-2 cells increased from 15 to 25% and CD8+ Vß8.1-2 cells from 24 to 35% (Salomon, unpublished observations). These experiments also demonstrate that other non-DC APCs must be functional during the period of GCV-induced DC depletion.
Having established that DC could be efficiently depleted from the airways of TK-TG mice, we used these mice in an existing model of allergic airway inflammation in which WT C57BL/6 mice are actively sensitized to OVA and subsequently develop eosinophilic peribronchial and perivascular inflammation, demonstrable by analysis of BAL fluid eosinophil content and lung histology, in response to inhalational challenge with OVA (16, 17, 18). This is accompanied by increased numbers of BAL fluid T lymphocytes secreting Th2 cytokines. Furthermore, challenge of sensitized animals increases the number of B cells recovered in BAL fluid and systemic production of total and OVA-specific IgE. In view of the dependence of IgE synthesis on IL-4 and of the development of tissue eosinophilia on IL-5, these results in WT mice indicate that systemic sensitization and aerosol reexposure to OVA induce a Th2-associated eosinophilic airway inflammation (26). Brusselle et al. have previously shown that this response is critically dependent on the presence of T lymphocytes and IL-4 (18) and can be inhibited by the systemic administration of IL-12 during sensitization (17), further strengthening the hypothesis that the development of airway inflammation in the mouse is controlled by and dependent on Th2 lymphocytes, as has been suggested for human asthma (1).
We next verified that airway inflammation developed normally in response to aerosol challenge in TK-TG mice that had been subjected to high dose irradiation and bone marrow reconstitution (see Materials and Methods). Since GCV is administered via miniosmotic pumps, TK-TG mice were implanted with identical PBS-filled pumps. These mice developed a comparable degree of airway inflammation to WT mice and had similar cytokine profiles in BAL fluid and similar systemic levels of IgE. Thus, the development of eosinophilic airway inflammation was unaffected in chimeric TK-TG mice implanted with PBS-filled pumps. Since the conditional depletion of DC in TK-TG mice involves the administration of GCV, we also verified that this drug did not modify the overall development of allergic airway inflammation in WT mice, as has recently been described for its structural analogue acyclovir in a guinea pig model of calcium ionophore-induced eosinophilic inflammation (27). Treatment with GCV before the OVA challenge in sensitized mice did not affect the Ag-induced changes observed in airway histology, BAL fluid cytokine profiles, or IgE levels.
We then tested whether the absence of DC during secondary exposure to OVA influenced the development of eosinophilic airway inflammation. Sensitized animals were challenged with OVA aerosol during the period in which DC were depleted from the airways after the discontinuation of GCV treatment. Compared with PBS treatment, GCV treatment in TK-TG mice significantly decreased the number of eosinophils, CD4+ and CD8+ T lymphocytes, and B lymphocytes recovered from BAL fluid. IL-4 was detected in only 1 out of 9 BAL fluid samples tested compared with 4 out of 10 in the controls. On histologic analysis, GCV treatment led to the disappearance of aerosol-induced peribronchial and perivascular eosinophilic infiltrates. The levels of both total and OVA-specific IgE were significantly lower in GCV-treated compared with PBS-treated TK-TG mice, suggesting that T cell help for IgE synthesis was deficient. These effects of GCV treatment were not apparent in transgene-negative littermate controls, indicating that the depletion of myeloid DC was specifically implicated in the suppression of eosinophilic airway inflammation.
These data strongly suggest that depletion of DC during secondary exposure to inhaled Ag affects presentation of Ag to memory Th2 cells, leading to the suppression of Th2 effector functions. Although in vitro experiments suggest that memory T cells are less dependent than naive T cells on costimulatory signals derived from the APC, and can respond to a variety of professional APC such as resting B cells and macrophages (8, 9), our results suggest that the requirements for costimulation of resting memory T cells may be more stringent in vivo. Thus DC appear to be required for generation of effector function by cells exposed to Ag 16 days previously. This interpretation is consistent with recent studies showing that lung DC constitutively express costimulatory ligands and up-regulate their expression upon maturation (15) and that aerosol-induced effector function in memory T cells can be inhibited by blocking the function of these costimulatory ligands B7-1 (28) or B7-2 (29, 30). It will be interesting to study whether generation of effector function in memory cells in models of infectious or autoimmune diseases are similarly dependent on costimulation and DC function (reviewed in 31 .
An alternative hypothesis is that DC are critical for the transport of inhaled Ag to the draining lymph nodes of the lung, by analogy with the primary response (13, 14). In contrast to previous data suggesting that activated/memory T cells can recirculate via nonlymphoid tissues, possibly reacting to Ag presented by APCs resident in these tissues (32), recent studies have shown that resting memory cells may follow a similar pathway of recirculation as naive T cells, leaving the bloodstream at the high endothelial venules of secondary lymphoid organs (33, 34). Thus it is possible that one of the functions of airway DC in the generation of effector function is to carry Ag to the draining nodes of the lung where recirculating memory cells can be stimulated.
Whatever the mechanism of suppression of airway inflammation by DC depletion, our findings suggest that other APCs are unable to substitute for DC function in the airways. This is further supported by previous studies that have addressed the role of macrophages and B cells in presenting inhaled Ag in sensitized animals. Aerosol-induced inflammatory lung lesions developed to a greater extent and IgE production was higher in animals depleted of alveolar macrophages by administration of toxic liposomes into the trachea before the secondary Ag challenge. Thus alveolar macrophages not only have poor Ag-presenting capacity, but even suppress the activity of other APC (35, 36). Similarly, recent studies using the same experimental model as ours in B cell-deficient mice have indicated that B cells do not appear to play an important role in the induction of airway inflammation (37).
In view of the dependence on DC for the development of eosinophilic airway inflammation in this animal model, targeting DC could provide a novel therapeutic strategy for human asthma. The airways of atopic asthmatics are known to contain increased numbers of DC (38), some of which carry the high affinity receptor for IgE (39); however, their role in the pathogenesis of the disease remains largely unknown (40). It has been shown that treatment with inhaled glucocorticosteroid drugs leads to a reduction in the number of DC in the airways in both man and rodents (38, 41). The current study suggests that this reduction in DC numbers could be an important means by which these drugs reduce eosinophilic airway inflammation. Finding new therapeutic strategies that target the function of the airway DC selectively, without inducing pulmonary or systemic immunodeficiency, will be a major future challenge.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Bart N. Lambrecht, Department of Respiratory Diseases, University Hospital Ghent, De Pintelaan 185, B-9000 Ghent, Belgium.
3 Abbreviations used in this paper: DC, dendritic cell; BAL, bronchoalveolar lavage; GCV, ganciclovir; N-TG, nontransgenic; TK, thymidine kinase; TG, transgenic; WT, wild-type; LTR, long terminal repeat; SPF, specific pathogen free.
Received for publication September 17, 1997. Accepted for publication December 22, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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subunit of the high affinity immunoglobulin E receptor. Clin. Exp. Allergy 26:648.[Medline]
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F. L. Jahnsen, D. H. Strickland, J. A. Thomas, I. T. Tobagus, S. Napoli, G. R. Zosky, D. J. Turner, P. D. Sly, P. A. Stumbles, and P. G. Holt Accelerated Antigen Sampling and Transport by Airway Mucosal Dendritic Cells following Inhalation of a Bacterial Stimulus J. Immunol., November 1, 2006; 177(9): 5861 - 5867. [Abstract] [Full Text] [PDF]
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J. W. Hollingsworth, G. S. Whitehead, K. L. Lin, H. Nakano, M. D. Gunn, D. A. Schwartz, and D. N. Cook TLR4 Signaling Attenuates Ongoing Allergic Inflammation J. Immunol., May 15, 2006; 176(10): 5856 - 5862. [Abstract] [Full Text] [PDF]
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P. Ettmayer, P. Mayer, F. Kalthoff, W. Neruda, N. Harrer, G. Hartmann, M. M. Epstein, V. Brinkmann, C. Heusser, and M. Woisetschlager A Novel Low Molecular Weight Inhibitor of Dendritic Cells and B Cells Blocks Allergic Inflammation Am. J. Respir. Crit. Care Med., March 15, 2006; 173(6): 599 - 606. [Abstract] [Full Text] [PDF]
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T. Koya, T. Kodama, K. Takeda, N. Miyahara, E.-S. Yang, C. Taube, A. Joetham, J.-W. Park, A. Dakhama, and E. W. Gelfand Importance of Myeloid Dendritic Cells in Persistent Airway Disease after Repeated Allergen Exposure Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 42 - 55. [Abstract] [Full Text] [PDF]
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J. Zhang-Hoover, P. Finn, and J. Stein-Streilein Modulation of Ovalbumin-Induced Airway Inflammation and Hyperreactivity by Tolerogenic APC J. Immunol., December 1, 2005; 175(11): 7117 - 7124. [Abstract] [Full Text] [PDF]
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K. Okunishi, M. Dohi, K. Nakagome, R. Tanaka, S. Mizuno, K. Matsumoto, J.-i. Miyazaki, T. Nakamura, and K. Yamamoto A Novel Role of Hepatocyte Growth Factor as an Immune Regulator through Suppressing Dendritic Cell Function J. Immunol., October 1, 2005; 175(7): 4745 - 4753. [Abstract] [Full Text] [PDF]
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K. Vermaelen and R. Pauwels Pulmonary Dendritic Cells Am. J. Respir. Crit. Care Med., September 1, 2005; 172(5): 530 - 551. [Abstract] [Full Text] [PDF]
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 P. G. Holt Pulmonary Dendritic Cells in Local Immunity to Inert and Pathogenic Antigens in the Respiratory Tract Proceedings of the ATS, August 1, 2005; 2(2): 116 - 120. [Abstract] [Full Text] [PDF]
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T. Murakawa, M. M. Kerklo, M. R. Zamora, Y. Wei, R. G. Gill, P. M. Henson, F. L. Grover, and M. R. Nicolls Simultaneous LFA-1 and CD40 Ligand Antagonism Prevents Airway Remodeling in Orthotopic Airway Transplantation: Implications for the Role of Respiratory Epithelium as a Modulator of Fibrosis J. Immunol., April 1, 2005; 174(7): 3869 - 3879. [Abstract] [Full Text] [PDF]
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L. S. van Rijt, S. Jung, A. KleinJan, N. Vos, M. Willart, C. Duez, H. C. Hoogsteden, and B. N. Lambrecht In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma J. Exp. Med., March 21, 2005; 201(6): 981 - 991. [Abstract] [Full Text] [PDF]
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H. Kuipers, C. Heirman, D. Hijdra, F. Muskens, M. Willart, S. van Meirvenne, K. Thielemans, H. C. Hoogsteden, and B. N. Lambrecht Dendritic cells retrovirally overexpressing IL-12 induce strong Th1 responses to inhaled antigen in the lung but fail to revert established Th2 sensitization J. Leukoc. Biol., November 1, 2004; 76(5): 1028 - 1038. [Abstract] [Full Text] [PDF]
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J. A. Long, M. Fogel-Petrovic, D. A. Knight, P. J. Thompson, and J. W. Upham Higher Prostaglandin E2 Production by Dendritic Cells from Subjects with Asthma Compared with Normal Subjects Am. J. Respir. Crit. Care Med., September 1, 2004; 170(5): 485 - 491. [Abstract] [Full Text] [PDF]
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H. J. de Heer, H. Hammad, T. Soullie, D. Hijdra, N. Vos, M. A.M. Willart, H. C. Hoogsteden, and B. N. Lambrecht Essential Role of Lung Plasmacytoid Dendritic Cells in Preventing Asthmatic Reactions to Harmless Inhaled Antigen J. Exp. Med., July 6, 2004; 200(1): 89 - 98. [Abstract] [Full Text] [PDF]
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 C. S. Robbins, D. E. Dawe, S. I. Goncharova, M. A. Pouladi, A. G. Drannik, F. K. Swirski, G. Cox, and M. R. Stampfli Cigarette Smoke Decreases Pulmonary Dendritic Cells and Impacts Antiviral Immune Responsiveness Am. J. Respir. Cell Mol. Biol., February 1, 2004; 30(2): 202 - 211. [Abstract] [Full Text] [PDF]
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 H. Hammad, H. J. de Heer, T. Soullie, V. Angeli, F. Trottein, H. C. Hoogsteden, and B. N. Lambrecht Activation of Peroxisome Proliferator-Activated Receptor-{gamma} in Dendritic Cells Inhibits the Development of Eosinophilic Airway Inflammation in a Mouse Model of Asthma Am. J. Pathol., January 1, 2004; 164(1): 263 - 271. [Abstract] [Full Text] [PDF]
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G. Pynaert, P. Rottiers, A. Haegeman, S. Sehra, T. Van Belle, J. Korf, and J. Grooten Antigen Presentation by Local Macrophages Promotes Nonallergic Airway Responses in Sensitized Mice Am. J. Respir. Cell Mol. Biol., November 1, 2003; 29(5): 634 - 641. [Abstract] [Full Text]
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H. Kuipers, D. Hijdra, V. C. de Vries, H. Hammad, J.-B. Prins, A. J. Coyle, H. C. Hoogsteden, and B. N. Lambrecht Lipopolysaccharide-Induced Suppression of Airway Th2 Responses Does Not Require IL-12 Production by Dendritic Cells J. Immunol., October 1, 2003; 171(7): 3645 - 3654. [Abstract] [Full Text] [PDF]
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D.-J. Chiang, Y.-L. Ye, W.-L. Chen, Y.-L. Lee, N.-Y. Hsu, and B.-L. Chiang Ribavirin or CpG DNA Sequence-Modulated Dendritic Cells Decrease the IgE Level and Airway Inflammation Am. J. Respir. Crit. Care Med., September 1, 2003; 168(5): 575 - 580. [Abstract] [Full Text] [PDF]
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K. Vermaelen and R. Pauwels Accelerated Airway Dendritic Cell Maturation, Trafficking, and Elimination in a Mouse Model of Asthma Am. J. Respir. Cell Mol. Biol., September 1, 2003; 29(3): 405 - 409. [Abstract] [Full Text] [PDF]
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K. Y. Vermaelen, D. Cataldo, K. Tournoy, T. Maes, A. Dhulst, R. Louis, J.-M. Foidart, A. Noel, and R. Pauwels Matrix Metalloproteinase-9-Mediated Dendritic Cell Recruitment into the Airways Is a Critical Step in a Mouse Model of Asthma J. Immunol., July 15, 2003; 171(2): 1016 - 1022. [Abstract] [Full Text] [PDF]
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J. C. Huh, D. H. Strickland, F. L. Jahnsen, D. J. Turner, J. A. Thomas, S. Napoli, I. Tobagus, P. A. Stumbles, P. D. Sly, and P. G. Holt Bidirectional Interactions between Antigen-bearing Respiratory Tract Dendritic Cells (DCs) and T Cells Precede the Late Phase Reaction in Experimental Asthma: DC Activation Occurs in the Airway Mucosa but Not in the Lung Parenchyma J. Exp. Med., July 7, 2003; 198(1): 19 - 30. [Abstract] [Full Text] [PDF]
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Q. Ye, P. W. Finn, R. Sweeney, E. K. Bikoff, and R. J. Riese MHC Class II-Associated Invariant Chain Isoforms Regulate Pulmonary Immune Responses J. Immunol., February 1, 2003; 170(3): 1473 - 1480. [Abstract] [Full Text] [PDF]
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A.-S. Charbonnier, H. Hammad, P. Gosset, G. A. Stewart, S. Alkan, A.-B. Tonnel, and J. Pestel Der p 1-pulsed myeloid and plasmacytoid dendritic cells from house dust mite-sensitized allergic patients dysregulate the T cell response J. Leukoc. Biol., January 1, 2003; 73(1): 91 - 99. [Abstract] [Full Text] [PDF]
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 L. S. van Rijt, J.-B. Prins, P. J. M. Leenen, K. Thielemans, V. C. de Vries, H. C. Hoogsteden, and B. N. Lambrecht Allergen-induced accumulation of airway dendritic cells is supported by an increase in CD31hiLy-6Cneg bone marrow precursors in a mouse model of asthma Blood, November 15, 2002; 100(10): 3663 - 3671. [Abstract] [Full Text] [PDF]
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N. Omata, M. Yasutomi, A. Yamada, H. Iwasaki, M. Mayumi, and Y. Ohshima Monocyte Chemoattractant Protein-1 Selectively Inhibits the Acquisition of CD40 Ligand-Dependent IL-12-Producing Capacity of Monocyte-Derived Dendritic Cells and Modulates Th1 Immune Response J. Immunol., November 1, 2002; 169(9): 4861 - 4866. [Abstract] [Full Text] [PDF]
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F. K. Swirski, D. Sajic, C. S. Robbins, B. U. Gajewska, M. Jordana, and M. R. Stampfli Chronic Exposure to Innocuous Antigen in Sensitized Mice Leads to Suppressed Airway Eosinophilia That Is Reversed by Granulocyte Macrophage Colony-Stimulating Factor J. Immunol., October 1, 2002; 169(7): 3499 - 3506. [Abstract] [Full Text] [PDF]
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H. Hammad, B. N. Lambrecht, P. Pochard, P. Gosset, P. Marquillies, A.-B. Tonnel, and J. Pestel Monocyte-Derived Dendritic Cells Induce a House Dust Mite-Specific Th2 Allergic Inflammation in the Lung of Humanized SCID Mice: Involvement of CCR7 J. Immunol., August 1, 2002; 169(3): 1524 - 1534. [Abstract] [Full Text] [PDF]
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 M. F. Lipscomb and B. J. Masten Dendritic Cells: Immune Regulators in Health and Disease Physiol Rev, January 1, 2002; 82(1): 97 - 130. [Abstract] [Full Text] [PDF]
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C. A. Byersdorfer and D. D. Chaplin Visualization of Early APC/T Cell Interactions in the Mouse Lung Following Intranasal Challenge J. Immunol., December 15, 2001; 167(12): 6756 - 6764. [Abstract] [Full Text] [PDF]
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 F L Jahnsen, E D Moloney, T Hogan, J W Upham, C M Burke, and P G Holt Rapid dendritic cell recruitment to the bronchial mucosa of patients with atopic asthma in response to local allergen challenge Thorax, November 1, 2001; 56(11): 823 - 826. [Abstract] [Full Text] [PDF]
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 B.N. Lambrecht, J-;B. Prins, and H.C. Hoogsteden Lung dendritic cells and host immunity to infection Eur. Respir. J., October 1, 2001; 18(4): 692 - 704. [Abstract] [Full Text] [PDF]
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B. U. Gajewska, F. K. Swirski, D. Alvarez, S. A. Ritz, S. Goncharova, M. Cundall, D. P. Snider, A. J. Coyle, J.-C. Gutierrez-Ramos, M. R. Stampfli, et al. Temporal-Spatial Analysis of the Immune Response in a Murine Model of Ovalbumin-Induced Airways Inflammation Am. J. Respir. Cell Mol. Biol., September 1, 2001; 25(3): 326 - 334. [Abstract] [Full Text] [PDF]
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T Tschernig, A S Debertin, F Paulsen, W J Kleemann, and R Pabst Dendritic cells in the mucosa of the human trachea are not regularly found in the first year of life Thorax, June 1, 2001; 56(6): 427 - 431. [Abstract] [Full Text]
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C. Tang, M. D. Inman, N. van Rooijen, P. Yang, H. Shen, K. Matsumoto, and P. M. O'Byrne Th Type 1-Stimulating Activity of Lung Macrophages Inhibits Th2-Mediated Allergic Airway Inflammation by an IFN-{{gamma}}-Dependent Mechanism J. Immunol., February 1, 2001; 166(3): 1471 - 1481. [Abstract] [Full Text] [PDF]
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 N. Yamamoto, S. Suzuki, Y. Suzuki, A. Shirai, M. Nakazawa, M. Suzuki, T. Takamasu, Y. Nagashima, M. Minami, and Y. Ishigatsubo Immune Response Induced by Airway Sensitization after Influenza A Virus Infection Depends on Timing of Antigen Exposure in Mice J. Virol., January 1, 2001; 75(1): 499 - 505. [Abstract] [Full Text]
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K. Y. Vermaelen, I. Carro-Muino, B. N. Lambrecht, and R. A. Pauwels Specific Migratory Dendritic Cells Rapidly Transport Antigen from the Airways to the Thoracic Lymph Nodes J. Exp. Med., January 1, 2001; 193(1): 51 - 60. [Abstract] [Full Text] [PDF]
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P. G. HOLT Antigen Presentation in the Lung Am. J. Respir. Crit. Care Med., October 1, 2000; 162(4): S151 - 156. [Abstract] [Full Text] [PDF]
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J. C. KIPS, K. G. TOURNOY, and R. A. PAUWELS Gene Knockout Models of Asthma Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): S66 - 70. [Full Text] [PDF]
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J. Reibman, A. T. Talbot, Y. Hsu, G. Ou, J. Jover, D. Nilsen, and M. H. Pillinger Regulation of Expression of Granulocyte-Macrophage Colony-Stimulating Factor in Human Bronchial Epithelial Cells: Roles of Protein Kinase C and Mitogen-Activated Protein Kinases J. Immunol., August 1, 2000; 165(3): 1618 - 1625. [Abstract] [Full Text] [PDF]
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K. HAMADA, C.-A. GOLDSMITH, A. GOLDMAN, and L. KOBZIK Resistance of Very Young Mice to Inhaled Allergen Sensitization Is Overcome by Coexposure to an Air-Pollutant Aerosol Am. J. Respir. Crit. Care Med., April 1, 2000; 161(4): 1285 - 1293. [Abstract] [Full Text]
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B. N. Lambrecht, R. A. Pauwels, and B. Fazekas de St. Groth Induction of Rapid T Cell Activation, Division, and Recirculation by Intratracheal Injection of Dendritic Cells in a TCR Transgenic Model J. Immunol., March 15, 2000; 164(6): 2937 - 2946. [Abstract] [Full Text] [PDF]
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D. A. Mark, C. E. Donovan, G. T. De Sanctis, H. Z. He, M. Cernadas, L. Kobzik, D. L. Perkins, A. Sharpe, and P. W. Finn B7-1 (CD80) and B7-2 (CD86) Have Complementary Roles in Mediating Allergic Pulmonary Inflammation and Airway Hyperresponsiveness Am. J. Respir. Cell Mol. Biol., March 1, 2000; 22(3): 265 - 271. [Abstract] [Full Text]
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G. P. ANDERSON Interactions between Corticosteroids and beta -Adrenergic Agonists in Asthma Disease Induction, Progression, and Exacerbation Am. J. Respir. Crit. Care Med., March 1, 2000; 161(3): S188 - 196. [Full Text] [PDF]
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A. Braun, M. Lommatzsch, A. Mannsfeldt, U. Neuhaus-Steinmetz, A. Fischer, N. Schnoy, G. R. Lewin, and H. Renz Cellular Sources of Enhanced Brain-Derived Neurotrophic Factor Production in a Mouse Model of Allergic Inflammation Am. J. Respir. Cell Mol. Biol., October 1, 1999; 21(4): 537 - 546. [Abstract] [Full Text]
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A. Kaser, S. Dunzendorfer, F. A. Offner, T. Ryan, A. Schwabegger, W. W. Cruikshank, C. J. Wiedermann, and H. Tilg A Role for IL-16 in the Cross-Talk Between Dendritic Cells and T Cells J. Immunol., September 15, 1999; 163(6): 3232 - 3238. [Abstract] [Full Text] [PDF]
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B. N. Lambrecht, I. Carro-Muino, K. Vermaelen, and R. A. Pauwels Allergen-Induced Changes in Bone-Marrow Progenitor and Airway Dendritic Cells in Sensitized Rats Am. J. Respir. Cell Mol. Biol., June 1, 1999; 20(6): 1165 - 1174. [Abstract] [Full Text]
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M. Korsgren, C. G.A. Persson, F. Sundler, T. Bjerke, T. Hansson, B. J. Chambers, S. Hong, L. Van Kaer, H.-G. Ljunggren, and O. Korsgren Natural Killer Cells Determine Development of Allergen-induced Eosinophilic Airway Inflammation in Mice J. Exp. Med., February 1, 1999; 189(3): 553 - 562. [Abstract] [Full Text] [PDF]
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C. Masurier, B. Salomon, N. Guettari, C. Pioche, F. Lachapelle, M. Guigon, and D. Klatzmann Dendritic Cells Route Human Immunodeficiency Virus to Lymph Nodes after Vaginal or Intravenous Administration to Mice J. Virol., October 1, 1998; 72(10): 7822 - 7829. [Abstract] [Full Text] [PDF]
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