 Negatively Regulates Airway
Hyperresponsiveness through   T Cells
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
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Tumor necrosis factor (TNF)-
is a potent cytokine with immunomodulatory, proinflammatory, and pathobiologic activities. Although TNF- is thought to play a role in mediating airway inflammation and airway hyperresponsiveness (AHR), its function is not
well defined. TNF--deficient mice and mice expressing TNF- in
their lungs because of a TNF- transgene placed under the control
of the surfactant protein (SP)-C promoter (SP-C/TNF--transgenic mice) were sensitized to ovalbumin (OVA) and subsequently challenged with OVA via the airways; airway function in response to
inhaled methacholine was monitored. In the TNF--deficient mice,
AHR was significantly increased over that in controls. In contrast,
the transgenic mice failed to develop AHR. In addition, sensitized/ challenged TNF--deficient mice had significantly increased numbers of eosinophils and higher levels of interleukin (IL)-5 and IL-10 in their bronchoalveolar lavage fluid than were found for control mice. However, in SP-C/TNF--transgenic mice, both the numbers of eosinophils and levels of IL-5 and IL-10 were significantly lower
than in sensitized/challenged transgene-negative mice. 
T cells
have been shown to be activated by TNF- and to negatively regulate AHR. Depletion of T cells in the TNF--transgenic mice in
the present study increased AHR, whereas depletion of these cells
had no significant effect in TNF--deficient mice. These data indicate that TNF- can negatively modulate airway responsiveness,
controlling airway function in allergen-induced AHR through the
activation of T cells.
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METHODS
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Keywords: TNF-; T cells; airway hyperresponsiveness; inflammation
Allergic asthma is a complex syndrome associated with airway
hyperresponsiveness (AHR) and airway inflammation, and is
characterized by an influx of activated eosinophils and T lymphocytes into the airways (1). The selective accumulation of
these cells at allergic inflammatory sites depends on the interactions between adhesion molecules on the infiltrating cells
and endothelial cells, and a number of pivotal cytokines, including interleukin (IL)-4 and IL-5. Tumor necrosis factor
(TNF)- is a multifunctional cytokine with widespread proinflammatory and antineoplastic activities. It was originally
identified as the factor induced in mice exposed to bacterial
endotoxin that caused the hemhorragic necrosis of certain tumors (4). TNF- is now implicated in the pathogenesis of
other chronic inflammatory diseases such as rheumatoid arthritis, and is thought to be an important mediator of inflammation in endotoxin-induced shock and ischemia/reperfusion
injury (5). TNF- has also been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), and TNF- messenger RNA (mRNA) and protein have been detected in the
lungs of IPF patients. In mouse models, TNF- depletion protects against pulmonary fibrosis induced by exposure to bleomycin and silica (6). Therefore, several lines of evidence
indicate that TNF- may play a significant role in airway inflammation, but its role in asthma remains to be defined.
TNF- is secreted mainly from monocytes, alveolar macrophages (AM), mast cells, neutrophils, and T lymphocytes, depending on the conditions or stimulus used (12). In previous
studies, the effects of TNF- on AHR have been inconsistent.
TNF- was reported to increase responsiveness to electrical
field stimulation, albeit to a low level, in nonsensitized human
bronchial tissue as compared with control tissue; however, this
effect was not dose-dependent, and TNF- had no effect on
sensitized human bronchial tissue (16). In a rat model, TNF-
inhalation induced AHR to 5-hydroxytryptamine, but to a lower
degree than observed after administration of lipopolysaccharide (LPS), despite an increase in neutrophil numbers in bronchoalveolar lavage fluid (BALF) (17). On the other hand, the
pulmonary pathology of surfactant protein (SP)-C/TNF--
transgenic mice, whose expression of TNF- mRNA was limited to the lungs, consisted of a chronic mononuclear cell infiltrate with a predominance of T lymphocytes, and an increase in neutrophils in lavage fluid. This lymphocytic pneumonitis in time led to air space enlargement and emphysematous changes
(8, 18). The affected animals also had an increase in T cells in their lungs (19).
TNF- has also been identified as a mediator of early T-cell
activation, but may differentially influence the response of 
and T cells. Greater responsiveness of T cells to TNF- has
been correlated with higher levels of the inducible TNF- receptor p75 (20). We recently reported that T cells down- regulate
AHR through an T-cell-independent mechanism (21). To
clarify the significance of TNF- and the role of T cells in controlling the development of allergen-induced AHR, we examined both TNF--deficient mice and SP-C/TNF--transgenic
mice after sensitization and challenge to ovalbumin (OVA). We
monitored airway function in response to inhaled methacholine
(MCh), and inflammatory cell infiltration in the airways.
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METHODS
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DISCUSSION
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Animals
Mice genetically deficient in TNF- (22, 23) were a gift from Dr. John
Harty of the University of Iowa, Iowa City, IA. These mice were originally derived from intercrosses of (129Sv × C57BL/6)F1 mice heterozygous for the mutated 129/Sv TNF- gene, and have been maintained since 1996 as a line of mixed 129/B6-genetic-background mice
homozygous for the mutation. Intercrossed mice not expressing the
mutated TNF- gene served as controls. Mice expressing the TNF-
gene under the control of the SP-C promoter (SP-C/TNF--transgenic mice) (8) were a gift from Dr. Yoshitaka Miyazaki of the Department of Clinical Immunology, Medical Institute of Bioregulation,
Kyushu University, Beppu, Japan. The transgenic founder mice
(C57BL/6xDBA/2 F1) were backcrossed with C57BL/6 mice to generate F1 hybrid transgenic mice, and have been maintained as a heterozygous line by repeated backcrossing since 1995. All transgenic
mice were identified by polymerase chain reaction (PCR) analysis of
genomic DNA as previously described (8). Littermate transgene-negative
mice were used as controls. The mice were maintained on OVA-free diets.
Antibodies
Monoclonal anti-murine T cell receptor (TCR)- antibodies (GL3 and
403A10) were gifts from Drs. Leo LeFrançois (24) and Susumu Tonegawa (25). The antibody is panspecific for TCR-. The dose administered
was optimized for T cell depletion, and routinely depleted more than
90% of splenic and pulmonary / T cells (21). Monoclonal antibodies
(mAbs) were prepared from antibody-secreting hybridoma cell lines.
Antibodies were purified on affinity columns and quantified.
Sensitization and Airway Challenge
Each strain of mouse was grouped on the basis of the following treatments (4 mice/group/experiment): (1) airway challenge (×3) with OVA nebulization alone (N group); and (2) intraperitoneal sensitization with OVA and OVA airway challenge (IPN group). Mice were sensitized by intraperitoneal injection of 20 µg of OVA (Grade V; Sigma, St. Louis, MO) emulsified in 2.25 mg of alum (AlumImuject; Pierce, Rockford, IL) in a total volume of 100 µl on Days 0 and 14. Mice were challenged via the airways with OVA (1% in saline) for 20 min on Days 28, 29, and 30 by ultrasonic nebulization (particle size 1 to 5 µm; De Vilbiss, Somerset, PA). Lung resistance (RL) and dynamic compliance (Cdyn) were assessed 48 h after the last allergen challenge, and the mice were killed to obtain tissues and cells for further assay.
Determination of Airway Responsiveness
RL and Cdyn were determined as changes in airway function after inhaled MCh challenge (21, 26). After each aerosolized MCh challenge, the data were continuously collected for 1 to 5 min, and maximum values of RL and minimum values of Cdyn were taken to express changes in these functional parameters.
Cytokine Levels in BALF
After assessment of RL and Cdyn, lungs were lavaged once via the tracheal tube with Hank's balanced salt solution (1 ml, 37° C). Cytospin slides (Shandon, Sewickley, PA) were stained with Leukostat (Fisher Diagnostics, Pittsburgh, PA) and cells were differentiated in a blinded fashion by counting at least 300 cells under light microscopy.
Cytokine levels (IL-4, IL-5, IL-10, and interferon [IFN]-) in
BALF supernatants were measured with enzyme-linked immunosorbent assays (ELISAs) as described (27), and IL-12 (p70) was also assayed with an ELISA (R&D Systems, Minneapolis, MN) according to
the manufacturer's recommendations. Cytokine levels were determined by comparison with known standards. The limits of detection
were 4 pg/ml.
T Cell Purification and Fluorescence Activated Cell Sorter Analysis
Lung cells were isolated as previously described (28), and were passed through nylon wool columns to yield an enriched T cell preparation containing > 90% CD3+ cells as previously described (29).
For cytofluorographic analysis, mAbs were conjugated with N-hydroxysuccinimidobiotin (Sigma) and/or fluorescein isothiocyanate isomer I on Celite (Sigma), and were analyzed on an XL2 cytofluorograph (Coulter, Miami, FL). We used streptavidin-phycoerythrin (diluted at 1:100 per 1 × 106 cells; Tago Immunologicals Biosource, Camarillo, CA) for the biotin-conjugated antibodies in order to enhance detection as described (30).
Anti-TCR- mAb Depletion of T Cells
T cell depletion was achieved after injection of 200 µg hamster monoclonal anti-TCR- IgG antibody (1:1 mixture of GL3 and 403A10) into
the tail vein of mice 3 d before the first OVA challenge (21). Sham depletion was done with hamster IgG (Jackson Laboratories, Bar Harbor, ME).
Measurement of Serum Anti-OVA Antibody and Total Ig Levels
Anti-OVA IgE antibody levels and total IgE were measured with ELISAs as previously described (31). The limits of detection were 100 pg/ml for IgE.
Histologic and Immunohistochemistry Studies
After obtaining BALF, we inflated lungs through the tracheal tube with 2 ml of air and fixed them in 10% formalin. Portions of lung tissue were cut around the main bronchus and embedded in paraffin blocks. Tissue sections 5 µm thick were cut, deparaffinized, stained with hematoxylin and eosin (H&E), and examined under light microscopy. The examiner was masked with regard to the treatment group.
Cells containing major basic protein (MBP) in lung sections were identified by immunohistochemical staining and quantitated as described, using a rabbit antimouse-MBP antibody (provided by Dr. James J. Lee of Mayo Clinic, Scottsdale, AZ) (28).
Statistical Analysis
Values for all measurements were expressed as the mean ± SEM. Student's two-tailed unpaired t test was used to determine the levels of difference between two experimental groups. Analysis of variance (ANOVA) was used to compare percent changes of RL and Cdyn in different groups with the same treatment. Significance was set at p < 0.05.
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INTRODUCTION
METHODS
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AHR Is Increased in the Absence of TNF-
We first assessed airway responsiveness to inhaled MCh in
TNF--deficient mice. Both OVA-sensitized and nonsensitized TNF--deficient mice were challenged with an aerosol
of OVA on three consecutive days, in parallel with TNF--
sufficient controls. After OVA sensitization and challenge,
TNF--sufficient mice developed significant increases in RL
and decreases in Cdyn in an MCh dose-dependent manner, as compared with mice only challenged with OVA (Figure 1).
Mice genetically deficient in TNF- developed AHR to a (significantly) greater extent than did the control animals. In both
naive and nonsensitized mice undergoing airway challenge
alone, there were no significant differences in airway responsiveness between the two strains.
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/To further extend these results and directly compare the
results of allergen challenge in sensitized mice, we sensitized
both TNF--sufficient and -deficient mice to OVA (together
with alum) on Days 0 and 14, and exposed them to phosphate
buffered saline (PBS) or OVA by aerosol challenge on Days
28, 29, and 30. As shown in Table 1, challenge with OVA increased RL with increasing concentrations of inhaled MCh in a
dose-dependent manner (as compared with exposure to PBS)
in both TNF--sufficient and -deficient mice, and the increases in RL were significantly greater in the TNF--deficient animals.
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The numbers and types of inflammatory cells in the airways
of TNF--sufficient and -deficient mice were measured in
BALF (Figure 2). In TNF--sufficient mice, sensitization and
challenge with OVA resulted in a marked increase in inflammatory cell numbers as compared with challenge alone. TNF--deficient mice showed a similar inflammatory cell response,
but the numbers of eosinophils in their BALF were significantly lower than in that of the TNF--sufficient mice (Figure 2).
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We also examined the inflammatory cell response in lung
tissue. In mice that underwent challenge alone, very little inflammatory cell infiltration was detected, whereas intraperitoneal sensitization and subsequent challenge with OVA via the
airways increased the number of eosinophils and lymphocytes
at these sites (Figure 3). The inflammatory cell response in
sensitized and challenged TNF--deficient mice was similar to
that in sensitized and challenged TNF--sufficient animals
(Figure 3), including numbers of tissue eosinophils, despite the differences in BALF cell numbers (Figure 4).
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SP-C/TNF--Transgenic Mice Fail to Develop AHR
In view of the heightened airway responses in TNF--deficient mice, we investigated airway responsiveness in TNF--
transgenic mice. Baseline responsiveness in the transgenic
mice was not significantly different from that in the transgene-negative or TNF--deficient mice, and there were no significant differences between the two strains of mice in airway responsiveness under naive conditions or with challenge alone.
Surprisingly, SP-C/TNF--transgenic mice failed to develop
significant changes in RL and Cdyn after OVA sensitization
and challenge (Figure 5).
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The numbers of neutrophils and lymphocytes in the BALF
of transgenic mice were significantly increased over those of
control mice. However, the numbers of eosinophils in the
BALF of transgenic mice were significantly decreased as compared with those in the transgene-negative mice (Figure 6).
Histologic sections of the lungs of transgenic mice that underwent challenge alone showed an inflammatory cell infiltration,
especially by lymphocytes, within the thickened alveolar septa
and under the pleura (Figure 3). Neutrophils were also observed in the same sites. Despite this apparent increase over
the background level in the inflammatory infiltrate in the
lungs of nonsensitized TNF--transgenic mice, there was no
AHR. After OVA sensitization and challenge the SP-C/TNF--transgenic mice also showed a decrease in eosinophil numbers as compared with the transgene-negative mice (Figure 4).
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Cytokine Levels in BALF in TNF--Deficient and
Transgenic Mice
Concentrations of IL-4, IL-5, IL-10, and IFN- in BALF
supernatants were measured with ELISA. OVA sensitization
and challenge significantly enhanced IL-4, IL-5, IL-10, and
IFN- levels in BALF over the levels in mice that underwent
challenge alone in both the TNF--sufficient (Figure 7) and
TNF- transgene-negative mice (Figure 8). BALF from
OVA-sensitized and -challenged TNF--deficient mice contained increased levels of IL-4, IL-5, and IL-10 as compared with the levels in the nonsensitized group. The IL-10 levels in TNF--deficient mice were significantly higher than those in
the TNF--sufficient controls, whereas IFN- levels were significantly lower (Figure 7). In contrast, IL-5 and IL-10 levels in the SP-C/TNF--transgenic mice were significantly decreased as compared with those of transgene-negative mice,
whereas IFN- levels were increased; IL-4 levels were similar in the two groups (Figure 8). IL-12 levels were also measured in the BALF, and paralleled those of IFN- (Table 2). For
each group, sensitization and challenge resulted in an increase
in IL-12 levels. The increases in the TNF--sufficient mice were significantly greater than in the TNF--deficient mice, and the levels in the sensitized and challenged transgenic mice were
the highest, exceeding those in the transgene-negative mice.
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Serum Anti-OVA IgE Antibody Levels in TNF--Deficient and
Transgenic Mice
Anti-OVA IgE and total IgE levels in the sera of sensitized
and challenged TNF--sufficient mice, TNF--deficient mice,
transgene-negative mice, and SP-C/TNF--transgenic mice
were not significantly different from one another (Table 3).
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T Cells in SP-C/TNF--Transgenic Mice
An increased frequency of T cells has been demonstrated
in SP-C/TNF--transgenic mice (19). We therefore investigated the effects of monoclonal anti-TCR- antibody on the
T cell populations in the lungs of OVA-sensitized and -challenged, TNF--deficient and transgenic mice. The number of
T cells in the lung in TNF--deficient mice was significantly lower than in TNF--sufficient mice (Figure 9). In contrast, the number of T cells in the transgenic mice was significantly increased as compared with that in littermate transgene-negative mice. Injection of monoclonal anti-TCR-
antibody significantly suppressed the numbers of T cells in
the lung in sensitized and challenged transgenic mice, as well
as in TNF--sufficient and transgene-negative mice; the low
T cell numbers in the TNF--deficient mice did not change
significantly upon antibody treatment (Figure 9).
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Airway Responsiveness in TNF--Transgenic Mice after
T Cell Depletion
We recently demonstrated that T cells play a role in the
regulation of airway responsiveness (21). In view of the increased number of T cells in TNF--transgenic mice
(19), and the finding that T cells may be activated by
TNF- (20), we examined whether activated T cells
might play a role in the failure of TNF--transgenic mice to
develop AHR. To deplete T cells, we treated mice with
monoclonal anti-TCR- antibody 3 d before the first challenge with OVA. TNF--deficient mice given anti-TCR- antibody failed to show any further increase in AHR, although TNF--sufficient mice showed some increase, as
previously reported (Figures 10A and 10B). The response
in SP-C/TNF--transgenic mice depleted of T cells was
striking, with significant increases in RL and decreases in
Cdyn that approached those of the transgene negative
mice. The transgene-negative mice also showed some increase in AHR after T cell depletion, as predicted by
earlier studies (21) (Figures 10C and 10D). This effect on
AHR was not correlated with changes in cellular inflammatory response: neither OVA-sensitized and -challenged
TNF--deficient nor transgenic mice showed any significant differences in the composition of inflammatory cells in
their BALF after depletion of T cells (Figure 11).
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TNF- is produced in response to numerous stimuli and by
a variety of cells (15), and is implicated in the pathogenesis of a number of chronic inflammatory diseases (5). The
connection between TNF- and inflammatory responses in
patients with asthma has not been clearly defined, nor have
the effects of TNF- on tissue and smooth muscle been consistent (16, 32, 33). In the present study, we examined genetically manipulated mice in an attempt to define the
physiologic importance of TNF- in the development of allergen-induced AHR. Although the TNF--deficient mice
and the transgenic mice in our study differed in genetic background, such differences are not likely to have played
a substantive role in defining the activity of TNF- in the
primary sensitization model used in our study. Direct comparison of controls (challenge alone, Figures 1 and 4) with
the TNF--deficient or transgenic mice (challenge alone)
revealed little difference between the four groups of mice
as compared with the differences in airway responsiveness
after sensitization and challenge with OVA. The results indicated that TNF- negatively modulates AHR in the
model we used; OVA sensitization and challenge of TNF--deficient mice resulted in significant increases in AHR in
response to inhaled MCh in a dose-dependent manner as
compared with the changes seen in sensitized and challenged
control mice. In contrast, SP-C/TNF--transgenic mice,
which have lung concentrations of TNF- that are more
than 300 times higher than those of transgene-negative
mice (34), failed to develop increases in RL and Cdyn after
sensitization and airway challenge.
After sensitization and challenge, TNF--deficient mice
demonstrated increased numbers of eosinophils and higher
levels of IL-5 in BALF than did mice that underwent challenge alone, but the levels were lower than in sensitized and
challenged TNF--sufficient mice. Interestingly, another
study found that administration of anti-TNF- antibody to
mice receiving antigen-specific T helper type 1 (Th1) and
Th2 cells reduced BALF eosinophil numbers by about 30%
(35), indicating only limited control of eosinophil recruitment
by TNF-, in keeping with the results in our TNF--deficient mice. In contrast, after sensitization and challenge, the TNF- transgene-expressing mice in our study exhibited lower levels of IL-5 and eosinophil numbers but increased levels of IFN-
and IL-12. It is important to note that the present study evaluated the role of TNF- in a primary sensitization model.
Therefore, in the TNF--transgenic mice, TNF- may have
influenced initial Th1/Th2 development as a result of the increased release of IL-12 and IFN-. IL-10 levels in BALF of
the TNF--deficient mice were significantly increased, whereas
the levels in TNF--transgenic mice were decreased as compared with those of sensitized and challenged controls. On one
hand, IL-10 may limit eosinophilic inflammation, whereas on
the other hand we demonstrated a requirement for IL-10 in
the development of AHR (36); mice deficient in IL-10 failed to develop AHR, and only after reconstitution of the IL-10
gene could development of AHR be restored (36). The role of
IL-10, however, is complex, with its requirement described
both for AHR (36) and for the inhibition of AHR (37, 38).
Some of these differences may be related to the timing and extent of allergen exposure.
TNF- has been implicated in the recruitment of neutrophils to the lungs under different conditions. The kinetics of
neutrophil recruitment to the lung, and its association with development of AHR, are not well delineated. Thomas and colleagues showed that inhaled TNF- significantly induced
AHR in normal subjects, but only at 24 h, and this response
was associated with a neutrophil infiltration found in induced
sputum (39). In rats, LPS induced both local release of TNF-
and AHR, and a neutrophil influx found in BALF (17). Conversely, Lefort and coworkers, using immunologic (anti-TNF-
and anti-granulocyte antibodies) and pharmacologic (dexamethasone and vinblastine) methods, demonstrated that AHR was neither related to the presence of neutrophils in the pulmonary microvasculature nor to the synthesis of TNF- in
C57BL/6 mice (40). TNF- administration has also been
shown to overcome the defect in homing to the lung of IL-4-
deficient Th2 cells that were involved in the induction of mucus production (41). These results, and the increase in cell
accumulation observed in sensitized and challenged TNF--
deficient mice, indicate that although TNF- can affect neutrophil, eosinophil, and lymphocyte recruitment to the lungs
of sensitized and challenged mice, its role is not likely to be an
essential one in the accumulation of these cells.
The lungs of the SP-C/TNF--transgenic mice used in the
current study showed a mononuclear cell alveolitis with lymphocytic infiltration that at 2 mo of age was more prominent
in the interlobular septa around the extraalveolar small vessels and under the pleura. Macrophages numbers appeared to
be increased and neutrophils could be seen within the infiltrates. In older mice (6 mo of age), the alveolar spaces became
enlarged and the inflammatory infiltrate appeared to decrease
(8). TNF- mRNA, which was overexpressed in type II alveolar epithelial cells, was identified only in the lungs, and was
not detected in other tissues (8). Using these transgenic mice,
we showed that beyond the numbers of neutrophils in the
BALF of naive mice, OVA sensitization and challenge further increased the numbers of neutrophils by up to 50%. Despite
this influx of neutrophils, lung resistance to inhaled MCh remained lower than in sensitized and challenged control mice.
Thus, expression of the TNF- transgene is associated with
negative regulation of airway responsiveness. Because of the
finding of decreased airway reactivity in the presence of increased numbers of neutrophils in these mice, it also seems
unlikely that neutrophils directly contribute to AHR after
sensitization and challenge with OVA, a finding that we
previously reported (42).
We recently reported that mice genetically deficient in
T cells and T cell depleted (after treatment with monoclonal anti-TCR- antibody) mice have altered airway function. The studies in which we made these findings further
showed that T cells downregulate AHR through an
T cell-independent mechanism and without changes in inflammatory cell accumulation (21). This mechanism may coexist with
immunoregulatory effects of T cells on T cell-dependent pathways of AHR (21). Several studies have identified
interactions between TNF- and T cells; not only was early
activation of T cells found to be largely dependent on TNF-,
but T cells themselves can produce TNF- (20, 43, 44). Furthermore, Nakama and coworkers demonstrated an increased frequency of T cells in SP-C/TNF--transgenic mice (19), which we confirmed in the present study. In light of these findings, we investigated the effect of depletion in TNF--
transgenic mice. A marked increase in airway responsiveness
to MCh was detected after allergen sensitization and airway
challenge in SP-C/TNF--transgenic mice depleted of T cells,
which was not seen in sham-treated mice. The changes in airway function were similar to those observed in transgene-negative mice. As seen previously with T cell depletion (21),
the effects on AHR were independent of changes in inflammatory cell response. T cell depletion did result in increased
AHR in both TNF--sufficient and transgene-negative mice,
in keeping with previous results (21), but the changes in both
groups were much smaller than in TNF--transgenic mice. Only the TNF--deficient mice failed to show any change in
airway function after T cell depletion, a finding in keeping
with the very low numbers of T cells in these mice. Therefore, T cells seem to play an important role in the mechanism of suppressing airway responsiveness in SP-C/TNF--
transgenic mice. In contrast, antibody treatment directed at
depleting these cells had little effect in altering airway function in the TNF--deficient mice, in which few T cells were
detected and which already showed increased airway responsiveness without T cell depletion.
Because AHR could be restored in the transgenic mice,
these data indicate that the absence of allergen-induced
AHR in these mice is not the result of a developmental defect, but rather reflects the negative control over airway responsiveness exerted by TNF-, presumably via T cells.
These data confirm that T cells play an important role in
the pathophysiology of AHR, and on the basis of data for
the TNF--transgenic mice in our study, suggest a possible
mechanism for this. Thus, interactions between TNF- and
T cells may be central in regulating airway tone after airway exposure to allergen.
In summary, the findings reported here support complex
but important contributions of TNF- to the overall regulation of allergic inflammatory responses in the lung and to
the development of altered airway function, in part through
interactions with T cells. The additional finding that increased levels of TNF- were associated with decreased levels
of IL-10
an important factor in the development of AHR
(36)reveals that suppression of IL-10 may be another mechanism by which TNF- controls airway responsiveness. The possibility that these two mechanisms (increased/
activated T cells and IL-10 suppression) are linked is
currently being explored.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Erwin W. Gelfand, M.D., National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: gelfande{at}njc.org
(Received in original form December 11, 2000 and accepted in revised form May 25, 2001).
Acknowledgments: The authors appreciate the advice of Dr. Rebecca O'Brien throughout these studies. We are grateful to Ms. Diana Nabighian for preparation of the manuscript and Ms. Lynn Cunningham for her help in preparing the tissue slides.
Supported by grants HL-36577 and HL-61005 from the National Institutes of Health, by grant R825702 from the U.S. Environmental Protection Agency, and grant HL-56556 from the Arthritis Foundation, and by the Melvin Garb Fellowship.
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References |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
REFERENCES
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