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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study investigates the presence of CD8+ T lymphocytes and
their possible association with viral infection in bronchi of victims
of fatal asthma. Postmortem samples from the peribronchial region of the lung were obtained from seven patients who died an
asthma death (AD), seven asthmatic patients who died of unrelated causes (AUC), and seven postmortem cases with no history
of lung disease (control subjects). Using immunohistochemical
techniques, the CD8+ cytotoxic T-cell population in peribronchial
tissue was characterized in three patient groups. The percentage
of CD8+ cells expressing the activation marker CD25 was higher in
the AD group than in both the AUC and control groups (11.91 ± 1.92% versus 3.93 ± 1.63% and 1.09 ± 0.56%, respectively (p < 0.001). Perforin expression, a marker of cytotoxicity, was highest
in the AD group (9.16 ± 1.5%) compared with 1.39 ± 0.9; 1.8 ± 0.6% in the AUC and control groups respectively (p < 0.001). Expression of interleukin-4 (IL-4) and interferon gamma (IFN-
) by
CD8+ T cells was higher in the AD group than the control group (p < 0.05). Furthermore, the IFN-/IL-4 ratio in the AD group was less
than half that of the control group (1.46 ± 0.2 versus 3.2 ± 0.1; p = 0.02). Using polymerase chain reaction (PCR), viral genome for
rhinovirus (RV) was detected in lung tissue from three of the
seven cases in the AD group. Two of these cases also had detectable respiratory syncytial virus (RSV). Viral genome for RSV was
detected in five of the AUC group and in one of these cases, RV
was also detected. No viral genome was detected in the lungs of
the control group. In conclusion, this study provides novel evidence of an aberrant CD8+ T-cell population, possibly in response
to viral infection in subjects who die of acute asthma.
Keywords: asthma death; virus; CD8+ T lymphocytes
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Despite recent advances in the understanding of the pathophysiology of asthma and the availability of effective treatment, asthma mortality in the United States increased from 0.8 per 100,000 to 2.0 per 100,000 in the 20-yr period 1977 to 1997 (1). The socioeconomic and psychological factors associated with asthma mortality have been widely described (2); however, the pathologic events that accompany death due to asthma are less well defined.
Several clinical and epidemiologic studies support a role for viral infection in acute exacerbations of asthma. Viral respiratory infections and hospital admissions for asthma in both adults and children are closely correlated and demonstrate similar seasonality (3). Teichtahl and coworkers identified viruses in 80% of adults requiring hospital admission for acute asthma in a 1-yr period (4). In a prospective study of 31 asthmatics followed over 11 mo, 36% of severe exacerbations (defined as greater than a 40% decrease in FEV1) were associated with a viral respiratory tract infection (5). Viral infection has also been implicated as a major precipitant of asthma mortality. In older age groups mortality is greater in winter, a pattern that is suggestive of a viral origin (6). Moreover, in a study of 90 cases of asthma death (AD), respiratory infection was the most frequently recognized trigger of the fatal attack (7).
The precise mechanism by which viral infection exacerbates asthma remains unclear. Current thinking suggests that the immune response to viral infection increases airway inflammation that contributes to the increased airway obstruction and bronchial responsiveness seen in acute asthma (8). Viral infection leads to the release of chemokines and cytokines and local recruitment of inflammatory cells, particularly lymphocytes (9), factors that may enhance preexisting airway inflammation.
Previous work from our laboratory revealed a peribronchial cell infiltrate dominated by CD8+ lymphocytes in postmortem lung tissue of five asthmatics who had suffered an
acute AD (10). Although CD8+ lymphocytes are important
effectors of cell-mediated immunity, their precise role in the
pathogenesis of asthma is unclear. Viral infections characteristically elicit strong CD8+ T-cell lymphocytosis predominated
by cytotoxic, interferon gamma (IFN-)-secreting cells (11).
Therefore, in this study we investigate the presence and phenotype of CD8+ T lymphocytes in peribronchial postmortem
tissue from victims of AD and their possible association with
viral infection.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Postmortem lung biopsies were obtained from seven victims of acute AD, seven asthmatics who died of an unrelated cause (AUC), and seven control subjects with no history or evidence of respiratory disease (C) (Table 1). All asthmatics had a clinical history of asthma as documented by hospital or general practitioner medical records. In addition, AD cases had a clinical history and postmortem report consistent with death due to status asthmaticus. In all AD cases there was an absence of an identifiable precipitating factor, e.g., aeroallergen. None of the subjects had a recent (within 3 mo) change in their asthma medication. Only individuals who died outside of hospital were studied in order to avoid confounding factors of airway intubation or mechanical ventilation, and material was collected within 18 h of death. The local ethics committee of James Connolly Memorial Hospital approved the study.
Sample Collection
Multiple samples (0.5 cm3) of peribronchial material were obtained
from the second-generation right middle bronchi. Samples were placed
in cryo-embed medium (Brights Instrument Co., Huntingdon, UK) on
a small cork disk and immediately snap-frozen in iso-pentane (BDH,
Poole, UK) cooled to 
50° C. The samples were stored in liquid nitrogen. Six-micron sections were cut from the specimens and prepared as
previously described (12).
Immunohistochemistry
T lymphocytes were identified using a cocktail of CD2, CD3, CD5, and CD8 monoclonal antibodies (MoAbs) (T mix) (Royal Free & University College Medical School, London, UK) by an indirect immunoperoxidase method as previously described (12). All slides were coded and counted in a blind fashion by two observers. A minimum of five areas in the subepithelial region (each containing at least 20 cells) were analyzed and the total number of T cells was determined per unit area (104 µm2) using a computerized image analysis system (Seescan, Cambridge, UK).
The CD4:CD8 ratio was established by double immunofluorescence using a mouse anti-human (MAH) CD4+ IgG1 (DAKO A/S, Glostrup, Denmark) and a MAH CD8+ IgM (Royal Free Hospital, London, UK). The second layer contained a mixture of purified goat anti-mouse IgG (conjugated to tetra ethyl rhodamine isothiocyanate [TRITC]) and goat anti-mouse IgM (conjugated to fluorescein isothiocyanate [FITC]), (Southern Biotechnology Association, AL). Sections were examined using a Zeiss fluorescence microscope with epi-illumination and barrier filters for FITC and TRITC. A minimum of five high-power fields (×40) were examined (each containing at least 20 cells), and the total number of CD4+ and CD8+ cells was determined.
CD8 expression of CD25, CD45RO, Bcl-2, and perforin was investigated by double immunofluorescence (12). A mouse anti-human CD8 IgM MoAb (IgG1/IgG2
; DAKO A/S, Glostrup, Denmark) and
a different subclass of the same isotype for CD25 (IgG2, Royal Free
& University College Medical School), CD45RO (IgG2; University
College London Hospital [U.C.L.H.]-1), Bcl-2 (IgG1; DAKO A/S),
and perforin (IgG2b; Neomarkers, Union City, CA) were applied to
sections. The second layer contained goat anti-mouse IgM TRITC
and goat anti-mouse IgG FITC (Southern Biotechnology Associates).
Sections were examined using a Zeiss fluorescence microscope as previously described.
To determine the proportion of T cells and CD8+ T cells that coexpressed interleukin-4 (IL-4) and IFN-, direct immunofluorescence for
T mix/CD8+ was combined with a modified biotin-streptavidin (Southern Biotechnology Associates, Birmingham, AL) fluorescence staining
technique for IL-4 and IFN- as previously described (12). Sections
were viewed under a Zeiss fluorescent microscope as described.
Detection of RNA
Peribronchial RNA was extracted from 500 µl of Trizol (Gibco BRL, Paisley, Scotland) according to the manufacturer's instructions. Reverse transcriptase was then performed as previously described (13). A panel of reverse transcriptase/polymerase chain reaction (RT-PCR) assays based on previously published methods was used to screen postmortem tissue for all common respiratory viruses and atypical bacteria. PCR assays and cycle numbers used were as follows: picornaviruses 40 cycles, respiratory syncytial viruses (RSV) A and B nested PCR 35 and 30 cycles, coronaviruses OC43 and 229E nested PCR 35 and 30 cycles, influenza viruses A and B nested PCR 35 and 35 cycles, parainfluenza viruses 1-3 50 cycles, adenoviruses 50 cycles, Chlamydia pneumoniae nested PCR 35 and 30 cycles, and Mycoplasma pneumoniae 50 cycles.
Confirmation of specificity of the picornavirus PCR products and determination whether rhinovirus (RV) or other picornavirus was performed by restriction digestion (14). Confirmation of RSV PCR products was performed by sequence analysis. For semiquantification of RSV-positive samples, parallel PCR amplifications for RSV and housekeeping gene messenger RNA (mRNA) were performed. Densities of PCR bands on photographs were then determined using Band Reader software version 3.00 (Tech Knowledge, Tel Aviv, Israel) and were expressed as a ratio of RSV/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for each sample.
Data Analysis
Normally distributed data (as assessed by Kolmogorov-Smirnov test)
are expressed as mean ± SE. Differences between the three study groups
were assessed using a one-way analysis of variance and the Tukey test.
Significance was taken at p 
0.05. The statistical calculations were
performed using Sigma Stat 2.0 (Jandel Scientific, San Rafael, CA).
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Viral nucleic acid for RSV and RV was detected in seven of the 21 subjects (Table 2). Three of the AD group had viral genome for RV. Two of these cases also had detectable RSV. In five of the asthmatics who died of a cause unrelated to their asthma, viral genome for RSV could be found, and in one of these cases RV was also detected. In the control group there was no detectable viral genome for any of the panel of eight viruses investigated. Viral load (as assessed by the RSV/GAPDH ratio) was not significantly different between the asthmatic groups (AD: 0.52 ± 0.1; AUC: 0.63 ± 0.1; p = 0.48).
Numbers of T cells (per unit area) were higher in Group AD (14.7 ± 2.5) than Group AUC (6.7 ± 0.9) and the control group (6.5 ± 2.7); (p = 0.02) (Figure 1A). Subset analysis of the T-cell population revealed a preponderance of CD8 cells in Group AD (0.8 ± 0.2) that was not evident in the other two groups (AUC: 1.16 ± 0.4, C: 1.22 ± 0.2; p = 0.58) (Figure 1B).
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CD8+ T-cell phenotype was elaborated using combinations of MoAbs. In Group AD, higher proportions of CD8+ cells expressed CD25 (11.9 ± 1.9%) than Group AUC (3.9 ± 1.6%) and the control group (3.1 ± 0.6%) (p = 0.01) (Figure 2A). There was no significant difference in the number of primed CD8+ cells (as assessed by CD45RO) between the three groups (p = 0.18), although expression of CD45RO was higher in the AD group (AD: 62.7 ± 5.1 versus AUC: 45.8 ± 9, C: 43.3 ± 8.8) (Figure 2B). A tenfold increase in the expression of the cytotoxicity marker perforin, by CD8+ T cells was evident in Group AD compared with the groups AUC and the control group (AD: 9.16 ± 1.5, AUC: 1.39 ± 0.9, C: 1.8 ± 0.6; p = 0.001) (Figure 2C).
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Expression of Bcl-2 by CD8 cells was lower in both the asthmatic groups compared with the control group (AD: 33.7 ± 11.1, AUC: 30.2 ± 8.8, C: 59.6 ± 7.2; p = 0.07) (Figure 2D).
The percentage of T cells positive for IL-4 (AD: 1.83 ± 0.4, AUC: 1.63 ± 0.3, C: 1.55 ± 0.3, p = 0.8) and IFN- (AD: 1.55 ± 0.4, AUC: 1.29 ± 0.3, C: 1.18 ± 0.2, p = 0.8) did not differ between the groups (Figures 3A and 3B). However, when cytokine production was examined in the CD8+ T-cell subset, as
would be expected IFN- production by CD+ cells was greater
than IL-4 (Figures 3C and 3D). There was a significantly higher
percentage of IL-4-producing CD8+ T cells in the AD group
compared with the control group (41.5 ± 9.2 versus 8.7 ± 6.5;
p = 0.02) (Figure 3C). In addition, the IFN-/IL-4 ratio in the
AD group was less than that of the control group (1.46 ± 0.2 versus 3.2 ± 0.1; p = 0.02).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Using postmortem peribronchial tissue samples, we have demonstrated similar rates of infection in victims of AD and asthmatic subjects who die of an unrelated cause (AUC). However, we demonstrate an expanded CD8+ T-cell population, dominated by activated cytotoxic CD8+ lymphocytes in those patients dying as a result of acute asthma.
Application of a virus PCR panel designed to detect common respiratory viruses and atypical bacteria to bronchial tissue revealed the presence of RV and RSV in the asthmatic but not the nonasthmatic control subjects. The results showed a similar prevalence of nucleic acid from these viruses among the asthmatics who died of AD and the asthmatics who died of AUC. Moreover, viral load was similar in both groups. There was no association of a specific virus or combination of viruses with fatal asthma. Macek and coworkers with a similar study design in terms of patient groups could detect virus in 19 of 20 cases and multiple viruses were detected in 14 cases (15). As in the current study, RSV was identified most frequently and RV was present in a third of samples. One significant difference between the Macek study and that described here is the absence of viral genome in any of our nonasthmatic control group. It has been suggested that asthmatics are more susceptible to respiratory infection. Minor and coworkers describe a greater incidence of viral infections in asthmatic children compared with their nonasthmatic siblings (16). In a prospective study, adult asthmatics reported symptomatic respiratory infections more frequently than their nonasthmatic spouses (17). The lack of any viral genome in the control group in the present study would lend support to the hypothesis that asthmatics are more prone to viral infection.
There is little doubt that infections with respiratory viruses such as RSV can extend to and replicate in the lower airways (15). Therefore, it appears that viral replication in the lower airway could trigger a local inflammatory response and directly enhance preexisting airway inflammation. The precise mechanisms by which viral infection increases airway inflammation in asthma are not established; however, disruption of the epithelial barrier likely plays a role (18). Epithelial shedding can lead to significant increases in permeability resulting in airway mucosal edema, a characteristic feature of an acute asthma. Furthermore, it is established that RV infection of pulmonary epithelial cells in vitro induces synthesis of proinflammatory cytokines such as IL-8, IL-6, IL-11, and RANTES (regulated upon activation, normal T-cell expressed and secreted) (19). These chemokines are thought to drive the recruitment of inflammatory cells such as lymphocytes and eosinophils (20).
Although there was no difference in viral burden and the prevalence of viral infection between the two asthmatic groups, the phenotype of their CD8+ T cells, namely an expanded, activated, cytotoxic population was distinctly different. Bronchial biopsy specimens taken from asthmatic and nonasthmatic volunteers postinfection with RV have been shown to contain increased numbers of CD8+ T cells (9). Increases in CD8+ T cells have also been documented in the bronchial mucosa of atopic and nonatopic individuals during the course of a naturally occurring common cold (21) and a trend toward an increase in CD25+ T lymphocytes was observed (21). The current study revealed higher expression of the activation marker CD25 in peribronchial CD8+ T cells in victims of AD than in the asthmatics who died of an unrelated cause or the nonasthmatic control group. This is consistent with studies of peripheral blood of patients with acute severe asthma that show increased numbers of activated (CD25-positive) T cells (22). Notably, CD25 expression by lymphocytes is thought to play a pivotal role in the antiviral immune response as the IL-2 receptor enhances generation of virus-specific cytotoxic T lymphocytes (23).
Perforin expression was higher in peribronchial CD8+ cells from the AD group, compared with the AUC and control groups. Perforin mediates the destruction of virus-infected cells by inserting into plasma membranes of target cells and forming pores, which lead to osmotic lysis of the cell. Although this action is necessary for virus eradication, it also results in the type of tissue inflammation and injury that is seen in postmortem tissue obtained from victims of fatal asthma (24). To limit tissue damage resulting from the expanded cytotoxic CD8+ T lymphocytes, a stringent control mechanism to reestablish cellular homeostasis is crucial. Low expression of Bcl-2 renders cells susceptible to apoptosis. Apoptosis is thought to play a regulatory role in immune responses to acute viral infection (25). Expression of Bcl-2 was lower in both AD and AUC groups as compared with the control group, suggestive of an attempt by the immune system to resolve a viral infection.
Recent studies have demonstrated that a T helper cell, type
2 (Th2) cytokine environment, such as that in the asthmatic
lung, can transform CD8+ cytotoxic T cells into noncytotoxic
IL-5-producing cells in vitro (26) and in vivo (20). This IL-4-dependent switch to CD8+ T cells that secrete IL-5 is thought
to not only promote eosinophilia but also to lead to impaired
viral clearance owing to reductions in IFN- production. In
the current study the percentages of T cells that produced IL-4
and IFN- did not differ between the three groups. However,
when percentages of CD8+ T cells positive for IL-4 and IFN-
were examined, significantly more of these two cytokines were
being produced by the AD group as compared with the nonasthmatic control group. Furthermore, in the AD group, the
increase in IL-4 was proportionally greater than that in IFN-,
resulting in a significantly lower IFN-/IL-4 ratio compared
with the control group. A low IFN-/IL-4 ratio has been documented after mitogen stimulation of peripheral blood mononuclear cells from RSV-infected infants (27). More recently, Bendelja and coworkers have demonstrated increased IL-4
production by peripheral blood CD8+ T cells obtained from
RSV-infected children (28). Together, these studies, and the
current data provide evidence for a viral-induced Th1/Th2
"switch" in vivo that results in both high eosinophil recruitment and impaired viral clearance. However, it should be noted that RSV infection results in relative low levels of IFN- synthesis compared with other viruses.
In conclusion, this study provides the first documentation of an aberrant CD8+ T-cell response in the bronchi of subjects who die of acute asthma. Respiratory viruses among other stimuli, including other microorganisms not investigated in the present study, could induce the observed CD8+ T-cell deviation. It would appear that aberrant T-cell responses, mounted by a subset of asthmatics, perhaps in the context of a viral infection, place them at risk for fatal asthma. The data provide an important new line of inquiry into the pathology of AD.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Siobhán O'Sullivan, Ph.D., Dept. of Clinical Immunology, Royal Free & University College School of Medicine, Pond St., Hampstead, London NW3 2QG, UK. E-mail: sioosu{at}indigo.ie
(Received in original form February 6, 2001 and in revised form April 5, 2001).
Acknowledgments: The authors express their gratitude to Gwen Sanderson for excellent technical assistance and to Dr. Brian Farrell for his cooperation and advice.
Supported by GlaxoSmithKline R&D, UK
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1. Sly R. Decreases in asthma mortality in the United States. Ann Allergy Asthma Immunol 2000; 85: 121-127 [Medline].
2. Hannaway P. Demographic characteristics of patients experiencing near-fatal and fatal asthma: results of a regional survey of 400 asthma specialists. Ann Allergy Asthma Immunol 2000; 84: 587-593 [Medline].
3. Johnston S, Pattemore P, Sanderson G, Smith S, Campbell L, Josephs L, Cunningham A, Robinson S, Myint S, Ward M, et al . . The relationship between upper respiratory infections and hospital admissions for asthma: a time trend analysis. Am J Respir Crit Care Med 1996; 154: 654-660 [Abstract].
4.
Teichtahl H,
Buckmaster N,
Pertnikovs E.
The incidence of respiratory
tract infection in adults requiring hospitalization for asthma.
Chest
1997;
112:
591-596
5.
Beasley R,
Coleman E,
Hermon Y,
Holst P,
O'Donnell T,
Tobias M.
Viral respiratory tract infection and exacerbations of asthma in adult patients.
Thorax
1988;
43:
679-683
6.
Campbell M,
Holgate S,
Johnston S.
Trends in asthma mortality.
Br Med
J
1997;
315:
1012
7. British Thoracic Society. Comparison of atopic and non-atopic patients dying of asthma. Br J Dis Chest 1987;81:30-34.
8. Cheung D, Dick E, Timmers M, De Klerk E, Spaan W, Sterk P. Rhinovirus inhalation causes long-lasting excessive airway narrowing in response to methacholine in asthmatic subjects in vivo. Am J Respir Crit Care Med 1995; 152: 1490-1496 [Abstract].
9. Fraenkel D, Bardin P, Sanderson G, Lampe F, Johnston S, Holgate S. Lower airway inflammation during rhinovirus colds in normal and asthmatic subjects. Am J Respir Crit Care Med 1995; 151: 879-886 [Abstract].
10. Faul J, Tormey V, Leonard C, Burke C, Horne S, Poulter L. Lung immunopathology in cases of sudden asthma death. Eur Respir J 1997; 10: 301-307 [Abstract].
11.
Lukacher A,
Braciale V,
Braciale T.
In vivo effector function of influenza virus-specific cytotoxic T lymphocyte clones is highly specific.
J
Exp Med
1984;
160:
814-826
12.
Cormican L,
O'Sullivan S,
Burke C,
Poulter L.
IFN- but not IL-4 T cells
of the asthmatic bronchial wall show increased incidence of apoptosis.
Clin Exp Allergy
2001;
31:
731-739
[Medline].
13.
Johnston S,
Sanderson G,
Pattemore P,
Smith S,
Bardin P,
Bruce C,
Lambden P,
Tyrrell D,
Holgate S.
Use of polymerase chain reaction
for diagnosis of Picornavirus infection in subjects with and without respiratory symptoms.
J Clin Microbiol
1993;
31:
111-117
14. Papadopoulos N, Hunter J, Sanderson G, Johnston S. Rhinovirus identification by Bgl1 digestion of picornavirus amplicons. J Virol Methods 1999; 80: 179-185 [Medline].
15. Macek V, Dakhama A, Hogg J, Green F, Rubin B, Hegele R. PCR detection of viral nucleic acid in fatal asthma: is the lower respiratory tract a reservoir for common viruses? Can Respir J 1999; 6: 37-43 . [Medline]
16. Minor T, Baker J, Dick E, DeMeo A, Ouellette J, Cohen M, Reed C. Greater frequency of viral respiratory infections in asthmatic children as compared with their normal non-asthmatic siblings. J Pediatr 1974; 85: 472-477 [Medline].
17. Tarlo S, Broder I, Spence L. A prospective study of respiratory infection in adult asthmatics and their normal spouses. Clin Allergy 1979; 9: 293-301 [Medline].
18. Becker S, Soukup J, Yankaskas J. Respiratory syncytial virus infection of human primary nasal and bronchial epithelial cell cultures and bronchoalveolar macrophages. Am J Respir Cell Mol Biol 1992; 6: 369-374 .
19. Subauste M, Jacoby D, Richards S, Proud D. Infection of a human respiratory epithelial cell line with rhinovirus: induction of cytokine release and modulation of susceptibility to infection by cytokine exposure. J Clin Invest 1995; 96: 549-557 .
20.
Coyle A,
Erard F,
Bertrand C,
Walti S,
Pircher H,
Le Gros G.
Virus-specific CD8+ cells can switch to interleukin-5 production and induce
airway eosinophilia.
J Exp Med
1995;
181:
1229-1233
21. Trigg C, Nicholson K, Wang J, Ireland D, Jordan S, Duddle J. Bronchial inflammation and the common cold: a comparison of atopic and non-atopic individuals. Clin Exp Allergy 1996; 26: 665-678 [Medline].
22. Corrigan C, Hartnell A, Kay A. 1988. T lymphocytes activation in acute severe asthma. Lancet 1988; 1: 1129-1131 [Medline].
23. Untermohlen O, Tarnok A, Bonig L, Lehmann-Grube F. T lymphocyte-mediated antiviral immune responses in mice are diminished by treatment with monoclonal antibody directed against the interleukin-2 receptor. Eur J Immunol 1994; 24: 3093-3099 [Medline].
24.
Dunnill M,
Massarella G,
Anderson A.
A comparison of the quantitative anatomy of the bronchi in normal subjects, in status asthmaticus,
in chronic bronchitis and in emphysema.
Thorax
1969;
24:
176-179
25. Soares M, Maini M, Beverley P, Salmon M, Akbar A. Regulation of apoptosis and replicative senescence in CD8+T cells from patients with viral infections. Biochem Soc Trans 2000; 28: 255-258 [Medline].
26.
Erard F,
Wild M-T,
Garcia-Sanz J,
LeGros G.
CD8+ lymphocytes can
develop into non-cytolytic CD8-CD4-cells which produce IL-4, IL-5,
IL-10, and help B cells.
Science
1993;
260:
1802-1805
27.
Roman M,
Calhoun W,
Hinton K,
Avendano L,
Simon V,
Escobar A,
Gaggero A,
Diaz P.
Respiratory syncytial virus infection in infants is associated with predominant Th-2-like response.
Am J Respir Crit Care
Med
1997;
156:
190-195
28. Bendelja K, Gagro A, Bace A, Lokar-Kolbas R, Krsulovic-Hresic V, Drazenovic V, Mlinaric-Galinovic G, Rabatic S. Predominant type-2 response in infants with respiratory syncytial virus (RSV) infection demonstrated by cytokine flow cytometry. Clin Exp Immunol 2000; 121: 332-338 [Medline].
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U. Eriksson, U. Egermann, M. P. Bihl, F. Gambazzi, M. Tamm, P. G. Holt, and R. M. Bingisser Human Bronchial Epithelium Controls TH2 Responses by TH1-Induced, Nitric Oxide-Mediated STAT5 Dephosphorylation: Implications for the Pathogenesis of Asthma J. Immunol., August 15, 2005; 175(4): 2715 - 2720. [Abstract] [Full Text] [PDF]
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 M. J. Holtzman, J. W. Tyner, E. Y. Kim, M. S. Lo, A. C. Patel, L. P. Shornick, E. Agapov, and Y. Zhang Acute and Chronic Airway Responses to Viral Infection: Implications for Asthma and Chronic Obstructive Pulmonary Disease Proceedings of the ATS, August 1, 2005; 2(2): 132 - 140. [Abstract] [Full Text] [PDF]
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S. M. O'Sullivan Asthma Death, CD8+ T Cells, and Viruses Proceedings of the ATS, August 1, 2005; 2(2): 162 - 165. [Abstract] [Full Text] [PDF]
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N. Miyahara, K. Takeda, S. Miyahara, S. Matsubara, T. Koya, A. Joetham, E. Krishnan, A. Dakhama, B. Haribabu, and E. W. Gelfand Requirement for Leukotriene B4 Receptor 1 in Allergen-induced Airway Hyperresponsiveness Am. J. Respir. Crit. Care Med., July 15, 2005; 172(2): 161 - 167. [Abstract] [Full Text] [PDF]
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S.-H. Cho, L. A. Stanciu, S. T. Holgate, and S. L. Johnston Increased Interleukin-4, Interleukin-5, and Interferon-{gamma} in Airway CD4+ and CD8+ T Cells in Atopic Asthma Am. J. Respir. Crit. Care Med., February 1, 2005; 171(3): 224 - 230. [Abstract] [Full Text] [PDF]
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R. K. Kumar, C. Herbert, D. C. Webb, L. Li, and P. S. Foster Effects of Anticytokine Therapy in a Mouse Model of Chronic Asthma Am. J. Respir. Crit. Care Med., November 15, 2004; 170(10): 1043 - 1048. [Abstract] [Full Text] [PDF]
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P. K. Jeffery Remodeling and Inflammation of Bronchi in Asthma and Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2004; 1(3): 176 - 183. [Abstract] [Full Text] [PDF]
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H. Kanazawa, K. Hirata, and J. Yoshikawa Increased Responses to Inhaled Oxitropium Bromide in Asthmatic Patients With Active Hepatitis C Virus Infection Chest, April 1, 2004; 125(4): 1368 - 1371. [Abstract] [Full Text] [PDF]
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M. Castro, S. R. Bloch, M. V. Jenkerson, S. DeMartino, D. L. Hamilos, R. B. Cochran, X. E. L. Zhang, H. Wang, J. P. Bradley, K. B. Schechtman, et al. Asthma Exacerbations after Glucocorticoid Withdrawal Reflects T Cell Recruitment to the Airway Am. J. Respir. Crit. Care Med., April 1, 2004; 169(7): 842 - 849. [Abstract] [Full Text] [PDF]
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J. Schwarze, D. R. O'Donnell, A. Rohwedder, and P. J. M. Openshaw Latency and Persistence of Respiratory Syncytial Virus Despite T Cell Immunity Am. J. Respir. Crit. Care Med., April 1, 2004; 169(7): 801 - 805. [Abstract] [Full Text] [PDF]
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N. Miyahara, K. Takeda, T. Kodama, A. Joetham, C. Taube, J.-W. Park, S. Miyahara, A. Balhorn, A. Dakhama, and E. W. Gelfand Contribution of Antigen-Primed CD8+ T Cells to the Development of Airway Hyperresponsiveness and Inflammation Is Associated with IL-13 J. Immunol., February 15, 2004; 172(4): 2549 - 2558. [Abstract] [Full Text] [PDF]
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E. R. McFadden Jr. Acute Severe Asthma Am. J. Respir. Crit. Care Med., October 1, 2003; 168(7): 740 - 759. [Abstract] [Full Text] [PDF]
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M. J. Holtzman Drug Development for Asthma Am. J. Respir. Cell Mol. Biol., August 1, 2003; 29(2): 163 - 171. [Abstract] [Full Text] [PDF]
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D. J. Adamko, A. D. Fryer, B. S. Bochner, and D. B. Jacoby CD8+ T Lymphocytes in Viral Hyperreactivity and M2 Muscarinic Receptor Dysfunction Am. J. Respir. Crit. Care Med., February 15, 2003; 167(4): 550 - 556. [Abstract] [Full Text] [PDF]
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B. D. Medoff, A. Sauty, A. M. Tager, J. A. Maclean, R. N. Smith, A. Mathew, J. H. Dufour, and A. D. Luster IFN-{gamma}-Inducible Protein 10 (CXCL10) Contributes to Airway Hyperreactivity and Airway Inflammation in a Mouse Model of Asthma J. Immunol., May 15, 2002; 168(10): 5278 - 5286. [Abstract] [Full Text] [PDF]
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H. P. Jones, L. Tabor, X. Sun, M. D. Woolard, and J. W. Simecka Depletion of CD8+ T Cells Exacerbates CD4+ Th Cell-Associated Inflammatory Lesions During Murine Mycoplasma Respiratory Disease J. Immunol., April 1, 2002; 168(7): 3493 - 3501. [Abstract] [Full Text] [PDF]
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M. J. TOBIN Asthma, Airway Biology, and Nasal Disorders in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 598 - 618. [Full Text] [PDF]
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