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ABSTRACT |
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Local cellular immune responses may affect presentation and outcome in tuberculosis (TB). To investigate this hypothesis, we performed bronchoalveolar lavage (BAL) on 30 patients with untreated
pulmonary tuberculosis and assessed the type of cellular inflammatory response and cytokine production. We then correlated BAL findings and cytokine production with clinical findings. We also performed BAL on a subset of patients to examine changes in cytokine production by BAL cells over
time. We found that at presentation patients with less clinically and radiographically advanced TB
(smear-negative, noncavitary disease) had a local immune response characterized by a predominance of lymphocytes. Furthermore, BAL cells from these patients secreted interferon (IFN
), and not
Interleukin-4, suggesting a Th 1-type lymphocytic response. In patients with smear-positive and/or
cavitary disease, macrophages or polymorphonuclear leukocytes were the predominant BAL cell type,
but with treatment and clinical improvement these patients went on to recruit IFN producing cells
to the lung. We conclude that the type of cellular immune response that occurs locally in the lung
may affect presentation and outcome in pulmonary TB, and an understanding of the development of
this response may lead to insights into pathogenesis and novel therapies for TB.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
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Human infection with Mycobacterium tuberculosis can lead to a range of clinical outcomes, from asymptomatic lifelong infection to progressive primary tuberculosis to what has been traditionally regarded as typical reactivation disease, with pulmonary infiltrates and, often, parenchymal lung destruction. The precise clinical manifestations of tuberculosis likely result from a complex interaction between the host and the pathogen (1). As noted above, not all (in fact, a minority of) patients with tuberculosis infection ever develop active disease, and in the prechemotherapy era, an appreciable number of patients recovered without specific treatment. Although it is possible that interstrain virulence differences among M. tuberculosis isolates play a role in outcome after initial infection, the type of active disease that develops is generally tied to the state of the immune system. For example, patients with HIV infection are exceedingly more likely to develop active disease after infection than those whose immune system is intact, and tuberculous mediastinal lymphadenitis (a form of primary tuberculosis usually seen in children) is more commonly seen in the AIDS population than in patients with normal immunity (2).
Key components of the immune response in tuberculosis
include alveolar macrophages and T lymphocytes, particularly
CD4+ (so-called T-helper) cells (3). Macrophages are the primary phagocytic cells in defense against M. tuberculosis, and
T cells are able, among other things, to stimulate a variety of
macrophage effector functions by secreting cytokines such as
interferon (IFN). T lymphocytes are also important components of granuloma formation, and circulating lymphocytes
from patients with tuberculous infection demonstrate the ability to proliferate when stimulated in vitro with tuberculin and
other M. tuberculosis antigens (4). In the lung itself, several
studies have demonstrated that lymphocytic alveolitis is present
in patients with tuberculosis, and bronchoalveolar lavage
(BAL) of these patients has demonstrated increased numbers of activated alveolar macrophages as well (5). However, to date few studies have characterized the specific nature of the cellular immune response locally in the lung or attempted to
correlate particular cellular immune response in tuberculosis
with particular manifestations of the disease. In other disease
states marked by a vigorous cellular immune response, phenotypic CD4+ T-cell differences seem to be related to different
clinical presentations of illness. For example, necrotic, multibacillary lepromatous leprosy lesions contain CD4+ cells that
secrete interleukin-4 (IL-4), IL-5, and IL-10 (a Th 2 response),
while more well-circumscribed paucibacillary lesions of tuberculoid leprosy are populated by CD4+ cells making IL-2 and
IFN (a Th 1 response) (9). Previously, it has been shown that
lung T lymphocytes from some patients with tuberculosis are
capable of expressing IFN mRNA, though actual cytokine
production, the consistency of this finding, and the association
between it and any specific disease pattern have not been studied (10). To evaluate the hypothesis that different clinical manifestations of active pulmonary tuberculosis are associated with
different patterns of cellular immune response locally in the lung,
we used BAL to sample radiographically involved pulmonary segments from a group of patients with a variety of clinical
stages of pulmonary tuberculosis in order to characterize the
number, type, and function of immune cells present in the
lungs of a diverse group of tuberculosis patients.
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METHODS |
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INTRODUCTION
METHODS
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DISCUSSION
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Study Population
The protocol was approved by the Human Subjects Review Committees of New York University Medical Center and Bellevue Hospital. All patients admitted to the Bellevue Chest Service with suspected pulmonary tuberculosis were approached about the study. A tuberculosis suspect was defined as any patient regardless of HIV status with a chest radiograph suggestive of tuberculosis with or without symptoms of cough, fever, and weight loss. Approximately 70 patients were approached regarding the study, of which 31 agreed to participate. One patient was later excluded based on negative sputum cultures and no clinical diagnosis of tuberculosis. A group of 30 patients with active pulmonary tuberculosis were recruited from Bellevue Hospital Chest Service. Fifteen normal volunteers were screened and recruited from NYU Medical Center. All patients and volunteers gave informed consent and the protocol was approved by the Institutional Board of Research Associates at New York University School of Medicine.
Bronchoalveolar Lavage
For each subject, BAL was performed with a flexible bronchoscope with local xylocaine anesthesia. Six 50-ml aliquots of sterile saline solution were instilled and subsequently recovered by gentle suction from radiographically involved and uninvolved segments. Chest radiographs were reviewed prior to bronchoscopy by two pulmonary specialists to determine the areas of involvement and the normal areas. Recordings of the lung subsegment lavaged, the amount of fluid instilled, and the amount returned were kept on all patients. In normal volunteers, two lung subsegments per patient were lavaged, The BAL fluid was coded by number in a blinded fashion. The BAL fluid was filtered through two layers of sterile cotton gauze to remove mucus and centrifuged at 1,000 rpm for 10 min. Supernatants were aliquoted and stored frozen until assay.
Alveolar cell populations were counted in a hemocytometer for
both involved and uninvolved seqments. Cell viabilities was determined by trypan blue exclusion. All recovered cells showed > 90% viability. Cell pellets and supernatants were separated by centrifugation
at 1,000 rpm for 5 min. The BAL cells were washed twice in RPMI
(Gibco BRL, Gaithersburg, MD) and resuspended at 106 cells per ml.
At least 500 BAL cells were counted on a hemocytometer. Cytocentrifuge slides were prepared by spinning 5-10 × 104 cells in 0.5 ml
cytofunnel (Shandon Inc., Pittsburgh, PA) at 500 rpm for 10 min in a
Cytospin 2 (Shandon). Alveolar cells were cultured in suspension for
24 h at 106 cells/ml in serum-free RPMI (GIBCO BRL). Supernatants
were collected upon centrifugation and frozen at 
70° C until assay.
Immunoassays
All BAL fluids were concentrated (3-10×) using Centriprep-10 filters
(Amicon, Beverly, MA) for measurement of IL-1
, tumor necrosis
factor (TNF)
, transforming growth factor (TGF), IL-4, and IFN.
For the assay, the frozen supernatants and BAL fluid were thawed to
room temperature, and all measurements were performed with concentrated BAL fluid aliquots and 24-h cell culture supernatants. IL-1, TNF, TFG, Il-4, and IFN radioimmunoassay kits were purchased (R&D, Minneapolis, MN) and used according to the recommendations of the manufacturer. Standards were prepared for all
assays. Two-hundred microliters of standards and samples were added
to wells of microtiter plates coated with IL-1, TNF, TGF, IL-4,
and IFN. After incubation, the plates were aspirated and washed.
Horseradish peroxidase-conjugated antibodies directed against the
same cytokines were added. After the second incubation, the plates
were again aspirated and washed. A substrate to the horseradish peroxidase was added to detect the cytokine concentration, which is reflected by a color change. The concentrations were determined with a
microtiter plate reader. All samples were assayed in duplicate. Protein
concentrations for BAL fluid measurements were corrected with the
BCA Protein Assay (Pierce, Rockford, IL).
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RESULTS |
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INTRODUCTION
METHODS
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DISCUSSION
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Patient Demographics
Demographic data of the 30 patients recruited from the Bellevue Chest Service are shown in Table 1. Bellevue Hospital is an inner-city municipal hospital with a patient population consisting mostly of indigent patients and immigrants. All patients had abnormal chest radiographs, and the diagnosis of tuberculosis was confirmed in all patients by positive sputum culture. Most of the patients had symptoms of cough, fever, night sweats, and weight loss and reported symptoms of approximately 1 mo duration. All patients had an average of four sputum samples obtained by induction prior to research bronchoscopy. Those patients with negative sputum smears underwent bronchoscopy with biopsy for diagnosis.
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Fifteen normal volunteers were also recruited. Fourteen were men, and none were HIV-infected. Seven of the 15 were smokers.
Bronchoalveolar Lavage Fluid Findings
More cells were recovered from patients with tuberculosis (mean = 120.1 × 104 cells per ml) than from normal control subjects (mean = 30 × 104 cells/ml), although the difference did not reach statistical significance. There were no significant differences in the number of cells recovered from smokers versus nonsmokers. In the patients with tuberculosis, more cells were recovered from patients with cavitary infiltrates on their chest radiographs (533.14 × 104 cells/ml) than noncavitary infiltrates (47.5 × 104 cells/ml; p < 0.01). There were no differences in the number of cells recovered from HIV-infected patients versus non-HIV-infected patients.
Cell differentials determined from cytospin slides prepared from BAL samples revealed three distinct patterns: a lymphocyte-predominant (> 20% lymphocytes) cell differential; a macrophage-predominant (> 80% macrophages) cell differential; and polymorphonuclear cell-predominant (> 20% polymorphonuclear cells) differentials (Table 2).
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Eight patients had a lymphocyte-predominant BAL differential with greater than 20% lymphocytes in the involved lobe (mean 34.4%; range 20-91%). All of the patients in this group were sputum smear-negative at the time of presentation. There are no cavities on chest radiographs in this group. Two patients in this group were HIV-infected.
Thirteen patients had a polymorphonuclear cell-predominant BAL differential (> 20%; mean 66.7%; range 30.9- 99%). Two of the 13 patients were HIV-positive. Almost all (12 of 13) were sputum smear-positive at the time of presentation. Seven of these patients had evidence of cavitary disease on their chest radiographs.
Nine patients had a macrophage-predominant BAL differential with greater than 80% macrophages in the involved lobe. Seven of these nine patients were sputum smear-positive at the time of presentation, and two of the nine were HIV- infected. Two of the patients in this group had cavitary disease on their chest radiograph. Summary data of patient information, total cell counts, and cell differentials in BAL fluid are shown in Table 3.
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Spontaneous Release of Cytokines from BAL Fluid and Cell Culture Supernatants
Levels of TNF, IL-1, IL-4, IFN and TGF were measured
in concentrated BAL samples and supernatants from 24-h cultures of BAL cells. All samples were assayed in a blinded
fashion by a technician with no knowledge of the clinical status of the patients. Both involved lobes and uninvolved lobes
were measured with ELISA kits (R&D). Concentrated BAL
fluid measurements were corrected per milligram of protein.
Results from BAL cell culture supernatants for all tuberculosis patients are shown in Table 4. Elevated levels of cytokines
were measured in both the involved and uninvolved lobe
when compared with normal subjects. Levels of TNF were
equally elevated in both the involved and uninvolved lobes.
IL-1 and IFN levels were increased in the involved lobe
(p = ns). Levels of TGF were measured and not significantly
different in the involved versus the uninvolved lobe. Concentrated BAL fluid showed similar trends, although the levels of
cytokines measured were much lower (data not shown).
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Twenty-four-hour cell culture supernatants from patients
with a lymphocyte-predominant cell differential in their BAL
released increased amounts of TNF, IL-1, and IFN from
the radiographically involved lobe compared with the radiographically uninvolved lobe. Interferon-gamma levels in these
patients were corrected for 106 lymphocytes and were found
to be elevated in the involved lobe compared with the uninvolved lobe. The expression of IFN in the involved lobe was
markedly elevated when compared with that expressed in normal subjects (p < 0.05). In addition, there were no detectable levels of IL-4 in any of these patients. This suggests a Th 1 immune response in this lymphocyte-predominant group of patients. There was no difference in the expressed levels of cytokines in HIV-infected patients compared with the group as a
whole.
Spontaneous Release of Cytokines in Patients Followed over Time
Five patients had BAL performed before and during antituberculous chemotherapy. All concentrated BAL fluids were
assayed at the same time for cytokines using ELISA kits. All
patients had clinical and bacteriological improvement while
on therapy. Four patients underwent three bronchoalveolar
lavages and one patient had two lavages, one at the beginning
and one at the end of therapy. All patients showed decreases
in the level of TNF in the BAL fluid in the involved lobe
over time. Concomitantly there was an increase in the level of
IFN with treatment (Figure 1). Two patients showed no
change in their levels of IFN, despite decreasing levels of
TNF. None of these patients were lymphocyte-predominant at the start of treatment.
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Previously, work from our laboratory as well as others has
demonstrated that a CD4+ lymphocytic alveolitis is present in
many, but not all, patients with active pulmonary tuberculosis.
We have now demonstrated that among a group of patients
with active pulmonary tuberculosis, clinically less advanced
disease (as manifested by negative AFB sputum smears and
lack of cavitary lesions on chest radiographs) in untreated patients was associated with a lymphocytic alveolitis and the secretion by those lymphocytes of significant amounts of IFN,
a Th 1-type cytokine. The Th 2-type cytokine IL-4 was not
produced by these lymphocytes, suggesting that a Th 1-type
lymphocytosis was associated with a more effective host inflammatory response. Furthermore, patients who did not demonstrate an IFN-associated lymphocytic alveolitis initially did so later in their course, and elevated levels of this cytokine were observed as patients improved clinically. Taken
together, these data support an important role for Th 1-type
CD4+ cells and IFN in effective cellular immunity locally in
active pulmonary tuberculosis.
The data obtained in our study help to fill in the evolving picture of local host immune responses in pulmonary tuberculosis. Previously published data support our finding of alveolar lymphocytosis in involved areas of the lung in patients with active pulmonary tuberculosis. Ozaki and colleagues (11) found lymphocytosis in the involved lobe in non-HIV-infected patients with active tuberculosis. Subset analysis revealed an increase in CD4+ T cells. This finding is further supported by our previously published data showing a CD4+ lymphocytic alveolitis in the involved lobes of tuberculosis patients (12). Ainslie and coworkers (13) found alveolar lymphocytosis in 55% of patients with localized pulmonary disease, and there was a switch to CD4+ cells in lavage fluid during successful treatment. Dhand and colleagues (14) reported an alveolar lymphocytosis in patients with minimal pulmonary disease; as symptom duration increased, alveolar lymphocytosis decreased. Similarly, in the present study lymphocytosis was associated with less clinically advanced disease. Although it is possible that the transition between cell populations in BAL was strictly a function of time, the reported symptom duration was similar in all patients in the study, suggesting that true differences in host immunity were present.
The ability of the host immune response to inhibit the
growth of M. tuberculosis seems to depend in large part on the
interaction between T cells and macrophages. A good deal of
attention has been focused on the role of IFN and its ability
to activate macrophages to inhibit mycobacterial growth. A
major role for IFN in mycobacterial host response has been
suggested by a variety of in vitro and animal experiments, and
our present study provides more evidence that this cytokine is
important to a good outcome in patients with pulmonary tuberculosis. Nagasawa and associates (15) added rhIFN to a
culture of human alveolar macrophages and found that glucose consumption and cytotoxicity against HeLa cells was
markedly increased. On the other hand, Douvas and coworkers (16) found that in response to lymphokine supplementation, intracellular mycobacterial replication actually increased.
Rook and colleagues (17), however, found that there was no effect on intracellular growth in the presence of additional rhIFN.
Denis (18) found that the additional of rhIFN to a pool of
human monocytes endowed them with no tuberculostatic activity; however, if calcitrol was added to the lymphokine preparation, there was total stasis of growth of mycobacteria, though
the mechanism by with this interaction between lymphokine and
vitamin occurs is unclear. Using human bone marrow-derived
macrophages, Flesch and Kaufmann (19) found the rhIFN significantly augmented killing of M. Tuberculosis strain Erdman, but this effect was not seen in M. tuberculosis strain Middleburg. Rose and colleagues (20) studied the effect of rhIFN
on growth of mycobacterium avium complex in human alveolar macrophages and found that as a lone agent it had no bacteriostatic effect, but significant killing was achieved when macrophage colony-stimulating factor (MCSF) was added to the
interferon-macrophage preparation. Genetically altered mice
that lack IFN or its receptor are extraordinarily susceptible to
infection with Mycobacterium bovis bacillus Calmette-Guèrin (BCG), though the mechanism of this susceptibility is not precisely determined (21, 22). Jaffe and colleagues (23) demonstrated that aerosol IFN administered to normal human subjects is capable of activating alveolar macrophages, and Holland
and colleagues (24) have used systemically administered IFN
to treat the group of patients with systemic infections caused
by Mycobacteria avium complex and other nontuberculous mycobacteria, and beneficial effects were seen. Additionally, a cohort of patients has recently been described in which a genetic
defect in IFN receptor function is present, leading to infections with usually nonpathogenic mycobacteria (25). Recently,
we have demonstrated in a preliminary study that aerosol IFN
given to patients with multidrug-resistant tuberculosis is associated with conversion of sputum smears, stabilization of weight,
and decrease in cavity size on computed tomography (CT) scans
of the chest (26). Taken together, these experiments do indeed
suggest an important role for IFN in host defense, and it is certainly possible that this cytokine is acting primarily as a macrophage activator. However, it is also possible that some of the
effect of IFN is due to effects other than direct augmentation of the inhibitory effect of the phagocyte. Interferon-gamma
might also improve or augment antigen presentation, leading
to recruitment of CD4+ T lymphocytes and/or cytotoxic T lymphocytes, which may participate in mycobacterial killing.
We found that in patients without alveolar lymphocytosis,
levels of IFN were low at the time of diagnosis. These levels
increased on antituberculous therapy as the patients improved.
This supports Ainslie's finding of increasing CD4+ cells in
patients successfully treated, as those cells are the major producers of this cytokine. Stimulated peripheral blood mononuclear cells from tuberculosis patients have also shown depressed production of IFN at the time of diagnosis (27). In
some of these patients, successful treatment with antituberculous chemotherapy was associated with recovery of IFN responses to stimulation (28).
Thirteen patients in the current study showed a significant increase in the number of polymorphonuclear cells in their BAL. These patients had more advanced pulmonary tuberculosis as evidenced by the large percentage of smear-positive patients with cavitary disease in this group. Six of these 13 patients were smokers but had no other intercurrent respiratory illnesses at the time of the lavage. Our data are consistent with the findings of Dhand and colleagues (29), who performed BAL in tuberculosis patients and found that patients with advanced pulmonary tuberculosis had a higher percentage of neutrophils compared with patients with minimal pulmonary disease. In a study of the utility of BAL in the diagnosis of tuberculosis, Baughman and associates (30) found some patients with increased numbers of polymorphonuclear cells, and this increase was not observed in healthy control subjects who were smokers.
Our finding that neutrophilic alveolitis was associated with more advanced disease fits well with previous reports of the relationship between M. tuberculosis and IL-8, a cytokine that is a potent neutrophil attractant. Our group demonstrated that M. tuberculosis or its cellular components were capable of stimulating both gene expression and protein secretion of IL-8 from alveolar macrophages in vitro (31). Friedland and colleagues (32) recently demonstrated that high levels of IL-8 in plasma were associated with significantly increased risk of death in patients with tuberculosis. Our data provided evidence that neutrophils in the lung represent a response to local tissue damage.
The role of specific cytokines in the control of intracellular
mycobacterial growth is complex. It has previously been reported that TGF inhibits cytokine synthesis by macrophages
and killing of H37Ra by phagocytes (33). It is also found in
pulmonary granulomas and multinucleated giant cells (34).
Rich (35) has found that stimulated alveolar macrophages
produce high levels of TNF compared with TGF and
suggested that the pattern of cytokine production (TNF > TGF) may determine effect on macrophages. In our study, no changes in expression of TGF levels were found across
clinical presentation or BAL findings. In addition, high levels
of TNF and TGF were produced in both the involved and
uninvolved lobe, suggesting that TGF may not exert its inhibitory effects in the presence of high pro-inflammatory cytokines. Its function in the alveolar space in pulmonary tuberculosis remains to be better defined.
In conclusion, our study provides evidence that the type of local immune response in the lung is correlated with different clinical presentations and outcomes. Understanding the precise mediators of these inflammatory responses may lead to new insights into the pathogenesis, presentation, and treatment of tuberculosis.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Neil W. Schluger, M.D., Bellevue Hospital 7N24, First Avenue and 27th Street, New York, NY 10016.
(Received in original form May 19, 1997 and in revised form October 9, 1997).
Acknowledgments: Supported by the National Institutes of Health grants RO1 HL55791, K07 HL03030, and M01 RR00096.
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References |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
REFERENCES
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