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Infection and Immunity, October 2000, p. 5824-5829, Vol. 68, No. 10
Kuzell Institute for Arthritis and Infectious
Diseases at California Pacific Medical Center Research Institute,
San Francisco, California 941151;
Stanford University Blood Center, Palo Alto, California
943042; and Laboratory of Electron
Microscopy, Department of Pediatrics, University of California, San
Francisco, San Francisco, California 941433
Received 8 November 1999/Returned for modification 16 February
2000/Accepted 27 July 2000
The mechanism by which mycobacteria elicit class I-restricted
T-cell responses remains undefined because these organisms have been
shown to reside exclusively within membrane-bound vesicles in
macrophages (M Organisms of the Mycobacterium
avium complex are rarely pathogenic for healthy individuals
(17) but cause disseminated disease in patients with AIDS
(24, 40) and localized pulmonary infection in non-AIDS
patients with underlying chronic lung disease (26). Infection with M. avium poses staggering public health
problems because of the limited susceptibility of this organism to
available antibiotics (12) and the ability of these bacilli
to become resistant to commonly used antituberculosis agents
(19). To develop new strategies for treating M. avium infection, we need to better understand the interactions of
this organism with the host's immune system.
As is the case with other mycobacteria, the importance of
CD8+ T cells in resistance to M. avium is
controversial (6, 27) because the mechanism by which
M. avium-derived molecules gain access to the cytoplasmic
presentation pathway to elicit major histocompatibility complex class
I-restricted T cells remains undefined. It is widely accepted that
M. avium, a facultative intracellular bacillus, impedes
macrophages' (M DC are potent antigen-presenting cells (APC) (35) and show
clear superiority particularly in inducing primary immune responses to
other APC types, including M Our results show that DC, generated from human peripheral blood
mononuclear cells (PBMC) by short-term culture, internalize M. avium. The percentages of apoptotic cells in M. avium-infected DC and M Antibodies.
Monoclonal antibodies (MAb) to CD4
(Leu-3a), CD14 (Leu-M3), CD19 (Leu-12), and HLA-DR (CA141) were
generously provided by Edgar G. Engleman (Stanford University School of
Medicine, Stanford, Calif.). We purchased from Becton-Dickinson
Monoclonal Center (Mountain View, Calif.) and PharMingen (San Diego,
Calif.) phycoerythrin (PE)-conjugated MAb directed at CD3, CD4, CD14,
CD16, CD20, CD33, CD80, CD86, and HLA-DR, as well as PE-labeled
isotype-matched immunoglobulin G. Affinity-purified goat anti-mouse
immunoglobulin G ( Bacteria.
M. avium 101 (serotype 1) was originally
obtained from the blood of an AIDS patient. For the experiments,
M. avium was cultured on Middlebrook 7H10 agar and pure,
transparent colonies were expanded by an additional 5 days' incubation
in 7H9 broth supplemented with oleic acid, dextrose, albumin, and catalase.
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Interaction of Mycobacterium avium with
Human Monocyte-Derived Dendritic Cells
and
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
), their primary host cells. We studied the interaction of M. avium with dendritic cells (DC) because
they are the most potent antigen-presenting cells and are abundant at
M. avium infection sites. We observed that both DC and
M, generated from human peripheral blood monocytes by short-term culture, internalized M. avium. The onset of programmed
cell death and the percentage of apoptotic cells in infected DC and
M were comparable. However, following infection, DC secreted
significantly larger amounts of interleukin-12, but not
interleukin-1
, than infected autologous M. Further analysis of
infected cells showed that while phagosomes failed to acidify in both
M. avium-infected DC and M, bacilli grew more slowly in
DC. Electron microscopy studies revealed that M. avium
resided within endocytic vacuoles in both cell types. The vacuolar
membrane surrounding some bacilli in approximately 10% of the vacuoles
in DC possessed several breaks. The importance of this finding will
have to be addressed in future studies.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
) processing and presentation of antigen by
restricting vacuole maturation (10, 36, 39). In view of the
paradox concerning the involvement of mycobacterium-specific major
histocompatibility complex class I-restricted T cells in the control of
infection and the finding that M. avium remains primarily
within membrane-bound vesicles in M, we analyzed human dendritic
cells (DC) infected in vitro with M. avium for uptake and
intracellular growth of bacilli, apoptotic death, production of
interleukin-12 (IL-12), fusigenicity of bacilli containing vacuoles
with lysosomes, and the intracellular localization of the bacteria. The
belief that M. avium may display behavior in DC different
from its behavior in M was inspired by studies showing that in DC
there is a rapid fusion between the Chlamydia vacuoles and
host cell lysosomes (25). Chlamydia is known to
survive within its primary host cells, epithelial cells, through its
ability to inhibit fusion between the entry vacuoles and host cell
lysosomes (31).
(23, 34). DC are present in
the airway epithelium, lung parenchyma, and visceral pleura (33) and may contribute to generating M. avium-specific CD4+ and CD8+ T-cell
responses. They are among the first cells to encounter a pathogen and
have the capacity to internalize it and process its antigens before
migration to secondary lymphoid organs (1). Cells of
dendritic lineage are also a major source of IL-12 (32). IL-12 favors the development of CD4+ T-helper 1 cells
(38). In mice, endogenous IL-12 is required for resistance
to M. avium infection (28), and administering recombinant IL-12 augmented resistance to M. avium infection
in susceptible mice (11, 20). In keeping with these
findings, the adherent cells from patients with familial disseminated
M. avium complex infection were shown to have a defect in
IL-12 production (14).
were comparable. Following infection
with M. avium, DC secreted higher amounts of IL-12, but not
of IL-1, than autologous M. Like M, the DC phagosomes
containing M. avium did not acidify; however, the organisms
grew more slowly in DC. Electron microscopy studies revealed that
M. avium resided within endocytic vacuoles in both cell types.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
-chain-specific) antibody was purchased from
Caltag Laboratories (Burlingame, Calif.).
Culture medium.
DC were cultured in AIM-V medium (Life
Technologies, Inc., Grand Island, N.Y.) that was supplemented with 5%
human AB serum, 50 µM 2-mercaptoethanol, 1 mM sodium pyruvate, 0.1 mM
nonessential amino acid, 100 µg of streptomycin/ml, 100 U of
penicillin/ml, 2.5 µg of amphotericin B (Fungizone)/ml, 2,000 U of
recombinant human granulocyte-M colony-stimulating factor (rhGM-CSF)
(Immunex, Seattle, Wash.)/ml, and 30 ng of rhIL-4 (Caltag
Laboratories)/ml (hereafter designated DC complete medium [DC-CM]).
were cultured in Macrophage-SFM (Life Technologies, Inc.)
supplemented with 5% human AB serum, 100 µg of streptomycin/ml, 100 U of penicillin/ml, 2.5 µg of amphotericin B/ml, 50 µM
2-mercaptoethanol, 1 mM sodium pyruvate, and 0.1 mM nonessential amino
acid (hereafter designated M complete medium [(M-CM]).
T cells were cultured in AIM-V medium supplemented only with 5% human
AB serum, 100 µg of streptomycin/ml, 100 U of penicillin/ml, 2.5 µg
of amphotericin B/ml, and 2 mM L-glutamine.
Isolation of M and T cells.
PBMC were isolated by
Histopaque-1077 (Sigma) gradient centrifugation from the white-cell
concentrate purchased from the Blood Center of the Pacific (San
Francisco, Calif.). Monocytes were isolated from PBMC by their
differential densities (21). Briefly, PBMC were separated
into low-density and high-density Percoll (Pharmacia Biotech, Uppsala,
Sweden) fractions. Low-density cells (monocytes), collected from the
interface over 51% Percoll solution, were refloated on a second
Percoll gradient for further enrichment.
isolation. This fraction was depleted of B cells, activated
(HLA-DR+) T cells, DC, and M by panning (23)
using a mixture of anti-CD19, anti-HLA-DR, and anti-CD14 MAb. Residual
M were removed from the nonadherent fraction by overnight adherence
in plastic vessels at 37°C. A final positive-selection panning
procedure utilizing anti-CD4 MAb yielded cells that were 
97%
CD4+.
Cell culture.
First, 25 × 106 to 30 × 106 purified monocytes were cultured in T75 flasks
(Costar, Cambridge, Mass.) in 30 ml of either DC-CM or M-CM. After
overnight incubation at 37°C in a humidified atmosphere containing
5% CO2, the medium of each culture was changed to remove the residual nonadherent cells. Thereafter, the medium was replaced every 4 days, and the nonadherent cells, recovered by centrifugation of
the old medium, were added back to the cell culture. After 8 and 12 days, the nonadherent cells were harvested for analysis.
Fluorescence-activated cell sorter analysis. Approximately 2.5 × 105 cells were stained with the indicated PE-conjugated MAb by standard techniques (23). After thorough washing, each sample was fixed with 1% paraformaldehyde and analyzed within 3 days on a FACS Calibur (Becton-Dickinson, San Jose, Calif.). The staining intensity of a particular MAb was evaluated relative to an isotype-matched control MAb by analyzing 5,000 cells. Data were measured in log scale.
Proliferation assay.
All proliferation assays were performed
in round-bottomed microtiter wells in a final volume of 200 µl of
T-cell medium. In these experiments, 50 × 103
cryopreserved autologous (for induction of an autologous mixed lymphocyte reaction) or 50 × 103 allogeneic (for
induction of an allogeneic mixed lymphocyte reaction [MLR])
CD4+ T cells were incubated with varying numbers of
irradiated (3,000 rads from a 137Cs source) DC or M.
Control T cells were incubated in medium alone. All cultures were
carried for 6 days at 37°C in a humidified 10% CO2
atmosphere. Cellular proliferation was measured on the basis of uptake
of [3H]thymidine that was added 16 h before
harvesting. Results are the mean counts per minute ± standard
errors of the means (SEM) of four replicate cultures.
Infection of M and DC.
DC (5 × 105)
were incubated in a Lab-Tek chamber (Nunc, Inc., Naperville, Ill.) in
antibiotic-free DC-CM (rhGM-CSF only) containing 10% nonheated human
AB serum. These cells were infected with 5 × 106
(multiplicity of infection [MOI] of 10) bacteria for 1 or 4 h. After the infection period, the culture supernatant was removed and
monolayers were washed carefully three times with 37°C warmed Hanks
balanced salt solution to ensure removal of the extracellular bacteria.
M were incubated in antibiotic-free M-CM as described for DC. To
determine the M. avium uptake, cells were lysed with sterile
water and 0.25% sodium dodecyl sulfate. The lysate was diluted and
plated onto 7H10 agar as reported (4). In some assays,
extracellular bacteria were removed by washing and intracellular bacteria were allowed to replicate for several days (4). At different times, the assay was stopped by lysing the monolayers, and
serial dilutions of the cell lysate were plated onto 7H10 agar for
quantitation of intracellular bacteria (4).
Cytokine assay.
M and DC monolayers were infected with
M. avium for 24, 48, and 72 h before supernatants were
collected, filtered through a 0.22-µm-pore-size filter, and frozen.
Some control wells were treated with polymyxin B (10 µg/ml) to ensure
that mycobacteria, but not the contaminating lipopolysaccharide (LPS),
stimulated cytokine production. Concentrations of IL-12 (p70) and
IL-1 in the supernatant of cell culture were measured by
enzyme-linked immunosorbent assay (Biosource International, Camarillo,
Calif.). The lowest limit of detection was 5 pg/ml for IL-1 and 10 pg/ml for IL-12. The assays were repeated twice, and three samples were collected in each assay.
pH measurement.
M. avium labeled with
N-hydroxysuccinimide (NHS)-carboxyfluorescein (Sigma
Chemical Co.) was used to infect DC and M as previously described (36). Extracellular bacteria were removed by
washing. The fluorescence of the total cell population was measured
at different times fluorometrically and compared with a standard pH
curve constructed using
N-hydroxysuccinimide-carboxyfluorescein-labeled M. avium in suspension and in nigericin-treated M and DC
(36).
and DC were infected, and the pH probes were added at
different times. Monolayers were washed after 30 min, and the
fluorescence emission was determined. DND-167 was read at
A373 and an emission of 425 nm, while DND-192
was read at A354 and an emission of 454 nm. A
standard curve was constructed in parallel using different pH references.
Phagosome-lysosome fusion. We used the following two assays to determine if M. avium remains within a vacuole following uptake by DC.
(i) DC and M after 8 or 12 days of in vitro differentiation were
transferred into a Lab-Tek chamber before infection with either
M. avium, M. smegmatis, or E. coli.
Two hours after infection, extracellular bacteria were removed by
washing and the medium was replaced. Eighteen hours after infection,
cells were incubated with acridine orange (Sigma Chemical Co.) for 15 min as previously reported (2, 7). After the incubation,
monolayers were washed to remove the excess of acridine orange and then
the slides were rapidly mounted and observed under a light microscope
for 30 min. After 30 min, the intralysosomal acridine orange began to
diffuse to the rest of the cell (2, 7). The number of
bacteria that were stained by the acridine orange (fused vacuoles) was
counted in 200 cells.
(ii) M. avium was used to infect both M and DC monolayers
on coverslips. At several time points the monolayers were fixed with
2% glutaraldehyde and processed for electron microscopy as previously
described (4, 7).
Apoptosis assay.
To determine whether DC infected with
M. avium undergo apoptosis, monolayers of both DC and M
were infected with M. avium, and the number of apoptotic
cells in each culture was determined by both ELISA and terminal
deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling
assay at days 3, 5, and 7 postinfection as previously described
(4, 5).
Electron microscopy.
M. avium-infected DC and M
were fixed with ice-cold 1% glutaraldehyde in phosphate buffer for
1 h and postfixed in 1% aqueous osmium tetroxide for 1 h at
4°C as described (4). They were dehydrated in ethanol at
room temperature, embedded in resin, and polymerized at 52°C.
Ultrathin sections were cut and mounted on carbon-coated grids. The
distribution of bacteria per vacuole was scored by examining 2 to 10 vacuoles for each cell type.
Statistical analysis. The results of the experiments are expressed as means ± SEM. Significance between experimental groups and controls was analyzed by the Student t test. A P value of <0.05 was considered significant.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Characterization of DC and M.
Using a multistep
procedure described by Markowicz and Engleman (21), we
obtained highly enriched monocytes from human peripheral blood.
Cytofluorographic analysis of freshly isolated monocytes (low-density Percoll fraction) indicated that 94% were stained with
anti-CD14 MAb, 95% were stained with anti-HLA-DR MAb, 73% expressed CD33 molecules (a myeloid marker), and 
4% were
CD3+ or CD20+ (data not shown).
(monocytes maintained in culture
in the absence of exogenous cytokines for the same length of time).
Unlike M, a few (3 to 6%) cells in the DC population displayed CD14
molecules. A higher percentage of DC were CD80+ (33% ± 8% versus 3% ± 1%, P < 0.05). DC displayed
significantly (P < 0.01) higher MFI for the CD86
molecule than did M (138 ± 22 versus 31 ± 5). Despite
the wide donor variation in the MFI value for HLA-DR molecules, the
expression of these molecules by DC and M was similar (70 ± 16 and 63 ± 11, respectively).
DC, but not M, were able to induce proliferation in purified
autologous CD4+ T cells (Fig.
1). DC were also more potent stimulators
of allogeneic T-cell proliferation in the MLR (P < 0.01) than were M. This difference was particularly pronounced
at a low stimulator/responder ratio of 1:20 (Fig. 1). The ability of DC
to stimulate T-cell proliferation in MLR depends partly on the
increased expression of the costimulatory molecules CD80 and CD86
(30).
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Fate of M. avium in DC and M.
To compare the
abilities of monocyte-derived DC and M to internalize M. avium, (1.5 ± 0.4) × 106 organisms were
incubated with (1.2 ± 0.3) × 105 cells on
monolayers for 1 and 4 h. Following incubation, monolayers were
washed, cells were lysed, and liberated bacteria were enumerated by
colony count. M consistently ingested greater (but not statistically significant) numbers of bacteria than DC after both 1 h of
incubation [(1.6 ± 0.5) × 105 versus (9.1 ± 0.4) × 104 CFU] and 4 h of incubation
[(4.9 ± 0.3) × 105 versus (2.1 ± 0.4) × 105 CFU] (n = 5). Because the
extent of DC differentiation may influence their functional capacities,
we infected DC from the same blood donor after 8 and 12 days of in
vitro differentiation. The results showed that cells cultured for 12 days ingested numbers of bacteria similar to those ingested by cells
cultured for 8 days (data not shown).
, infected
cells were recultured for 1 to 72 h in fresh antibiotic-free
medium before the number of viable bacilli in each cell type was
determined by colony count. M. avium was able to replicate
within both monocyte-derived DC and M; however, DC markedly
restricted replication of the bacterium compared to M (4-fold
increase in DC versus 10-fold increase in M) (Table
1).
|
Phagosome-lysosome interaction in DC and M.
To determine if
M. avium prevents phagosome-lysosome fusion when taken up by
DC, we infected DC with M. avium for 18 h before staining the monolayers with acridine orange. M infected with M. avium were used as control because restricted
fusigenicity of M. avium vacuoles with lysosomes in these
cells has been reported (36). The numbers of fused vacuoles
were comparable in DC and M, as shown in Fig.
2.
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infected for 18 h with M. smegmatis
or for 4 h with E. coli showed significant fusion of
phagosomes and lysosomes.
M. avium-containing phagosomes in DC are unable to
acidify.
M. avium within M has been observed to live in
vacuoles that do not acidify (36, 39). In this study, we
compared the M. avium environments in DC and M by
measuring the intraphagosomal pH in both cell types at 4, 24, and
48 h after infection. In M, the pH in M. avium
vacuoles did not drop below 6.7 at any time. The vacuoles in DC
infected with M. avium either 8 or 12 days after in vitro
differentiation also failed to acidify (pH of 6.7 ± 0.3 versus
6.9 ± 0.2 in the uninfected DC and M). Within 4 h of
M. smegmatis internalization, the vacuoles in both DC and M had pH values of 5.6 ± 0.1 and 5.4 ± 0.1, respectively
(P < 0.05 compared to that of M. avium-infected cells).
IL-12 production by DC.
To determine if M and DC differ in
their ability to produce IL-12 following M. avium
internalization, DC and M that were allowed to differentiate in
vitro for 8 days were infected with M. avium and the level
of IL-12 in the culture supernatant was measured after 24, 48, and
72 h. Production of IL-1 was assessed as well. We conducted
these experiments because IL-12 production is the centerpiece of the
specific immune response, and APC such as DC and M produce IL-12
upon antigen uptake.
, than did M (Table
2). We carried out a similar experimental
protocol using medium that contained 10 µg of polymyxin B/ml because
contamination with LPS influences IL-12 production. The results showed
that LPS contamination was not responsible for IL-12 production.
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DC apoptosis.
Data from a number of studies have indicated
that M prevent the spread of infection by undergoing apoptosis
following mycobacterial infection (6, 13). We carried out
comparative experiments with DC and M to determine the degree of
apoptosis occurring in these cells over time. As shown in Fig.
3, the percentage of cells undergoing
apoptosis did not differ for DC and M. Twenty percent of DC were
apoptotic after 5 days of infection, compared to 4% of cells in the
noninfected cultures, and the percentage of apoptotic DC increased with
time.
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Electron microscopy.
The information available thus far
indicates that both M. avium and Mycobacterium
tuberculosis live within vacuoles in M (36). We used
transmission electron microscopy to examine if M. avium
behavior in DC was similar to that previously described in M.
Electron micrographs of DC infected for 24 h with M. avium show that mycobacterium-containing vacuoles did not fuse
with lysosomes. M. avium phagocytosed by DC remained in
tightly opposed vacuoles; however, in very few vacuoles of a small
percentage of DC, we observed some sort of fracture of the vacuole
membrane. The meaning of this finding is unknown and will have to be
addressed in the future.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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In this study, we analyzed the interaction between M. avium and DC generated by short-term culture from human peripheral
blood monocytes, and we compared the results with the key features of internalization of M. avium by M. We show that the
ability of DC to take up M. avium and undergo apoptosis is
approximately the same as that displayed by M. Following
internalization of bacilli, DC secreted higher amounts of IL-12, but
not of IL-1, than autologous M (Table 2). Like M, the DC
phagosome containing M. avium did not acidify; however, the
organisms grew more slowly in DC. Although M. avium resided
in tight cytoplasmic vacuoles in both DC and M, the vacuolar
membrane surrounding the bacilli in DC possessed several breaks which
were not observed in M (Fig. 4).
|
Our findings in DC are in agreement with the earlier observations by
Henderson et al. (16), who showed that human
monocyte-derived DC can phagocytose M. tuberculosis and that
infection with this organism results in secretion of IL-1 and IL-12.
The reason for the secretion of higher amounts of IL-12 by M. avium-infected DC than by autologous M is unknown; however,
data suggest a significant role for DC in the host defense against
M. avium. Both in humans and in mice, IL-12 is required for
resistance to M. avium (8, 11, 14, 20, 28). IL-12
augments cell-mediated immunity by stimulating production of gamma
interferon and proliferation of T lymphocytes as well as of NK cells
(9, 15). Infection of M with M. avium does not
result in a strong IL-12 response (D. Wagner, F. J. Sangari, M. Petrofsky, L. S. Young, and L. E. Bermudez, Abstr. 39th
Intersci. Conf. Antimicrob. Agents Chemother., abstr. 1596, 1999).
Infection of DC with M. avium resulted in a significant
increase in apoptotic death from 5 days after infection (Fig. 3), which
is comparable with the onset of apoptosis in M. avium-infected M (4, 5). Fratazzi et al.
(13) have suggested that apoptosis of infected cells may
represent a mechanism of host defense, although the interpretation of
this observation remains controversial.
The reason for restricted growth of M. avium in DC (Table 1)
remains to be determined. It is plausible that the intravacuolar environment in DC provided less favorable growth conditions than those
provided in M. Alternatively, in this study the slow bacterial replication in DC may have resulted from the exposure of these cells to
low concentrations of rhGM-CSF during the initial in vitro incubation.
A previous study from our laboratory demonstrated that GM-CSF enhances
the anti-M. avium activity of human monocyte-derived M in
a dose-dependent manner (3). Schaible et al. (29)
have also observed that cytokine activation of M leads to fusion of the bacillus-containing compartments with lysosomes, culminating in the
death of intracellular bacteria.
Electron microscopy studies, showing that in DC M. avium is
found inside vacuoles, correspond with the recent finding for M. tuberculosis (16). Our observation that some
(approximately 10%) vacuoles had breaks in a small percentage of cells
is intriguing and will require further investigation. It has been
suggested that mycobacterial antigens undergo exchange with the
cytoplasm. This assertion is supported by (i) immunoelectron microscopy
studies of M. avium- and M. tuberculosis-infected
M by Xu et al. (39), which demonstrated the presence of
vesicles containing mycobacterial constituents (discrete from the
bacterium-containing vacuoles), and (ii) the observation by Mazzaccaro
et al. (22) and Teitelbaum et al. (37) that
M. tuberculosis and Mycobacterium bovis BCG facilitate bidirectional exchange of macromolecules between cytoplasmic compartments and bacterium-containing vacuoles. Our view is further corroborated by the finding that CD8+ T cells responsive to
M. avium antigens are present in mice infected with these
bacilli (18).
Additional studies are required to determine if M. avium-containing vacuoles in DC are ruptured and if M. avium-infected DC are able to expand antigen-specific CD8+ cytotoxic T cells in vitro, which may have important implications for immunotherapy in conjunction with chemotherapy for management of opportunistic infection.
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ACKNOWLEDGMENTS |
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We thank Karen Allen for preparing the manuscript.
This work was supported by NIH Contract #NO1-A1-25140, the Arthritis Fund of the Kuzell Institute, and the Adelaid and Edward Williams Research Funds.
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FOOTNOTES |
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* Corresponding author. Mailing address: Kuzell Institute, 2200 Webster St., Suite 305, San Francisco, CA 94115. Phone: (415) 561-1624. Fax: (415) 441-8548. E-mail: luizb{at}cooper.cpmc.org.
Present address: Department of Pathology, Palo Alto VA Hospital,
Palo Alto, CA 94304.
Editor: R. N. Moore
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Discussion
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