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Antimicrobial Agents and Chemotherapy, March 1998, p. 550-554, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Rifampin Increases Cytokine-Induced Expression of
the CD1b Molecule in Human Peripheral Blood Monocytes
L.
Tentori,1
G.
Graziani,1,*
S. A.
Porcelli,2
M.
Sugita,2
M. B.
Brenner,2
R.
Madaio,1
E.
Bonmassar,3,4
A.
Giuliani,1,3 and
A.
Aquino1
Lymphocyte Biology Section, Department of Rheumatology, Immunology,
and Allergy, Brigham and Women's Hospital and Harvard Medical School,
Boston, Massachusetts 02115,2 and
Department of Experimental Medicine and Biochemical
Sciences, University of Rome Tor Vergata,1
Institute of Experimental Medicine, National Council of
Research,3 and
Istituto Dermopatico
dell'Immacolata, Istituto di Ricovero e Cura a Carattere
Scientifico,4 Rome, Italy
Received 8 September 1997/Returned for modification 21 October
1997/Accepted 24 December 1997
 |
ABSTRACT |
In recent years, it has been shown that a nonclassical, major
histocompatibility complex-independent system (i.e., CD1-restricted T-cell responses) is involved in T-cell immunity against nonpeptide antigens. The CD1 system appears to function by
presenting microbial lipid antigens to specific T cells, and the
antigens so far identified include several
known constituents of mycobacterial cell walls. Among the four known
human CD1 isoforms, the CD1b protein is the best characterized
with regard to its antigen-presenting function. Expression of CD1b is
upregulated on human blood monocytes upon exposure to
granulocyte/macrophage-colony stimulating factor, alone or in
combination with interleukin-4 (IL-4) (S. A. Porcelli, Adv.
Immunol. 59:1-98, 1995). Rifampin (RFP) and its derivatives are widely
used for chemoprophylaxis or chemotherapy against Mycobacterium tuberculosis. However, this agent was found to reduce the mitogen responsiveness of human B and T lymphocytes, chemotaxis, and
delayed-type hypersensitivity. The present study extends the
immunopharmacological profile of RFP by examining its effects on
CD1b expression by human peripheral blood monocytes exposed to
GM-CSF plus IL-4. The results showed that clinically attainable
concentrations (i.e., 2 or 10 µg/ml for 24 h) of the agent
produced a marked increase in CD1b expression on the plasma membrane,
as evaluated by fluorescence-activated cell sorter analysis, whereas it
had no effect on cytosolic fractions, as indicated by Western blot
analysis. This was found to be the result of increased CD1b gene
expression, as shown by Northern blot analysis of CD1b mRNA.
These results suggest that RFP could be of potential value in
augmenting the CD1b-restricted antigen recognition system, thereby
enhancing protective cellular immunity to M. tuberculosis.
| |
INTRODUCTION |
The incidence of mycobacterial
infections has rapidly increased in recent years. One of the principal
causes of this phenomenon appears to be the high susceptibility
of human immunodeficiency virus-positive persons to mycobacterial
pathogens (3, 11, 17).
A large amount of experimental and clinical evidence showing that
T-cell-mediated immune responses play a significant role in resistance
against mycobacteria is now available (18, 28). Subpopulations of T cells that are involved in antimycobacterial immunity include CD3+ lymphocytes bearing the 
T-cell
receptor (TCR), predominantly of the CD4+ phenotype
(18), and 
TCR T lymphocytes (28). Effector
CD4+ T cells are sensitized with mycobacterium-derived
peptides presented by antigen-presenting cells in association with the
class II major histocompatibility complex (MHC, 25). Immune lymphocytes
show a Th1-like response pattern, being cytotoxic for mycobacterial targets and capable of secreting gamma interferon upon challenge with
the relevant antigen (18, 28).
In recent years, growing interest has been elicited by a nonclassical,
MHC-independent system that appears to be additionally involved in
T-cell responses against mycobacteria. In this case, the human
antigen-presenting molecule is the group I, nonpolymorphic CD1b protein
(1, 2, 15, 19) expressed by cytokine-activated macrophages (20). The antigens presented by
the CD1b molecule belong to a variety of nonpeptide macromolecules
(20). Among them, mycolic acids, lipoarabinomannan, and
other lipid structures associated with the mycobacterial cell wall are
believed to be involved in CD1-dependent host resistance against
tuberculosis. Lipoarabinomannan is taken up by a macrophage mannose
receptor that carries the antigen to macrophage endosomes, where it is loaded onto CD1b molecules (21).
In this system, many of the responder cells come from the
CD4
8 phenotypic subset of
CD3+, TCR T cells. These cells, referred to as
double-negative T lymphocytes (20), proliferate and
generate cytotoxic clones following interaction with mycobacterial
glycolipids presented by CD1b+ monocytes preactivated with
granulocyte/macrophage-colony stimulating factor (GM-CSF), alone or in
combination with interleukin-4 (IL-4) (20). More recently,
CD8+, TCR T-cell clones with similar properties have
also been demonstrated (26).
Rifampin (RFP) and a number of its derivatives (e.g., rifabutin) are
widely used for therapy against Mycobacterium tuberculosis in immunocompromised patients (16) or to treat various types of mycobacterial infections provoked by atypical strains (i.e., M. avium; 4). However, previous studies
showed that RFP reduces humoral and cell-mediated immunity (9, 10,
14, 29). These observations suggested the possibility that
antitubercular chemotherapy with RFP would attenuate the functional
activity of the immune system, with possible negative effects on
resistance against mycobacterial infections. To study the possible
effects of this antibiotic on macrophage function relative to antigen
presentation by CD1b molecules, CD1b molecule expression has been
studied in vitro in human peripheral blood monocytes exposed to GM-CSF
plus IL-4, alone or in the presence of RFP. The results showed that
clinically attainable concentrations of the agent increased CD1b
expression, thus suggesting that the antibiotic could be of
potential value in improving the CD1b-restricted antigen recognition
system.
| |
MATERIALS AND METHODS |
Reagents and antibodies.
Recombinant human GM-CSF and IL-4
were obtained from Sandoz (Milan, Italy) and Genzyme (Cambridge,
Mass.), respectively. Phenylmethylsulfonyl fluoride, EGTA, Triton
X-100, leupeptin, aprotinin, soybean trypsin inhibitor, and RFP were
obtained from Sigma Chemical Co. (St. Louis, Mo.).
A purified, fluorescein isothiocyanate (FITC)-conjugated monoclonal
antibody (MAb) recognizing CD1b (SN13, immunoglobulin G1k [IgG1k],
K5-1B8 clone) and an FITC-conjugated MAb recognizing CD14 (IgG2a, UCHM1
clone) were obtained from Ancell (Bayport, Minn.). FITC-conjugated
mouse IgG1 or IgG2a was used as a negative control (Becton Dickinson,
Oxnard, Calif.). Rabbit polyclonal antiserum recognizing the denatured
CD1b protein for Western blot analysis was obtained in our laboratory
as previously described (8).
Preparation of human AMNC.
Peripheral blood mononuclear
cells were separated from heparinized whole blood, obtained from
healthy donors, on a Ficoll-Hypaque (Pharmacia, Uppsala, Sweden)
gradient, washed twice in RPMI 1640 medium (HyClone Europe Ltd.,
Cramlington, United Kingdom), and resuspended in RPMI 1640 medium
supplemented with 10% fetal calf serum (HyClone), 10 mM HEPES (Flow
Laboratories, McLean, Va.), 2 mM L-glutamine (Flow), 0.8 mM
nonessential amino acids (GIBCO, Paisley, Scotland), 0.4 mM essential
amino acids, and 50 µM 2-mercaptoethanol (Sigma) (hereafter referred
to as complete medium). Adherent mononuclear cells (AMNC) were removed
from samples by plastic adherence at 37°C for 2 h, followed by
extensive washing with warm RPMI 1640.
Immunofluorescence staining and cytofluorimetric analysis.
Cultured cells were washed twice in phosphate-buffered saline
supplemented with 0.1% bovine serum albumin and 0.02% sodium azide
(PBS-A; Sigma). Cells (106) were then suspended in 50 µl
of PBS-A containing the appropriate MAb. For a negative control, cells
were incubated with FITC-conjugated IgG1 or IgG2a. Samples were
incubated at 4°C for 30 min and then washed twice in PBS-A. The
labeled samples were analyzed with a FACScan. Data on 104
viable cells were collected as forward and side-angle light scatter. Data analysis was performed by using Lysis II software (Becton Dickinson).
Preparation of cell extracts.
Cells were washed extensively
with phosphate-buffered saline. The cell pellet was suspended in 5 volumes of lysis buffer (25 mM HEPES [pH 7.5], 2.5 mM
MgCl2, 2.5 mM EGTA, 50 mM 2-mercaptoethanol, 200-µg/ml leupeptin, 5-µg/ml aprotinin, 1 mM
phenylmethylsulfonyl fluoride, 400-µg/ml soybean trypsin
inhibitor), sonicated at 4°C for 5 s, and centrifuged at
100,000 × g and 4°C for 1 h. The supernatant was collected and designated as the cytosol fraction. The pellet was resuspended in lysis buffer containing 1% Triton
X-100, sonicated for 5 s, and centrifuged at
15,000 × g and 4°C in a microcentrifuge for 10 min. The supernatant was collected and defined as the membrane fraction.
Immunoblotting.
Membrane and cytosol fractions were
separated in sodium dodecyl sulfate (SDS)-10% (wt/vol)
polyacrylamide gels as described by Laemmli (13)
and transferred to nitrocellulose filters as described by Towbin et al.
(27), with a Bio-Rad electrophoretic miniblotting apparatus
(Bio-Rad, Hercules, Calif.). Transfer was carried out at 25 V and 4°C
for 14 h. After transfer, membranes were incubated with 3%
(wt/vol) nonfat dry milk (Bio-Rad) in TBS (20 mM Tris-HCl [pH 7.5],
0.9% NaCl) with gentle agitation for 1 h. The membranes were then
incubated at room temperature with rabbit anti-CD1b serum diluted
1:2,000 in TBS containing 0.05% Tween 20 (TBST) for 30 min.
Thereafter, the membranes were washed twice with TBST and incubated
with an alkaline phosphatase-coupled secondary antibody diluted 1:7,500
in TBST for 1 h. The bands were visualized by using the Protoblot
(Promega Biotec, Madison, Wis.) reagents in accordance with the
procedures provided by the manufacturer.
Northern blot analysis.
Total RNA was extracted by the
guanidinium thiocyanate method described by Chomczynski and Sacchi
(5). Fifteen micrograms of total RNA was denatured in 2.2 M
formaldehyde-50% formamide at 65°C and fractionated in a 1.2%
agarose gel containing 2.2 M formaldehyde. RNA was then transferred to
a GeneScreen Plus nylon membrane (Dupont, NEN Research products,
Boston, Mass.) in 10× SSC (1× SSC is 0.1 M NaCl plus 0.015 M sodium
citrate). Prehybridization and hybridization were performed in
accordance with the manufacturer's instructions. Briefly, filters were
prehybridized at 42°C in 50% formamide-10% dextran sulfate-1 M
NaCl-1% SDS for 2 h. Hybridization was then performed at the
same temperature in the prehybridization solution following addition of
denatured salmon sperm DNA (100 µg/ml) and of the probe labeled with
[-32P]dCTP (3,000 Ci/mmol; Dupont), using a random
primed labeling kit (Boehringer Mannheim, Indianapolis, Ind.). Filters
were washed with 2× SSC at room temperature for 5 min, with 2× SSC
containing 1% SDS at 60°C for 30 min, and then with 0.1× SSC at
room temperature for 30 min. Autoradiography was performed at 
80°C
with XAR-5 film (Kodak, Rochester, N.Y.).
Detection of the CD1b-specific transcript was done with a 266-bp cDNA
probe corresponding to the second exon of CD1b, which encodes the
extracellular domain of mature CD1b, designated 1 (15).
This probe was obtained by PCR amplification of 1 µg of genomic DNA
extracted from human monocytes by standard procedures (24).
The PCR was performed by adding a DNA template to a solution (total
volume, 100 µl) containing 1× PCR buffer (10 mM Tris-HCl [pH 8.3],
50 mM KCl, 1.5 mM MgCl2, 0.01% gelatin) and 200 µM
(each) dCTP, dATP, dGTP, and dTTP. Twenty picomoles each of two
synthetic oligonucleotides with the sequences
5'-CCTTCCAGGGGCCGACCTCCTTT-3' and
5'-TTCATCTGGAAATCACCGGCA-3' were added to the mixture.
Taq DNA polymerase (2 U; Boehringer Mannheim) was added to
the PCR mixture, and DNA amplification was performed for 30 cycles in a
DNA thermal cycler (Perkin Elmer Cetus, Norwalk, Conn.). Each cycle
consisted of denaturation at 95°C for 1 min, annealing at 58°C for
1 min, and extension at 72°C for 2 min.
A glyceraldehyde phosphate dehydrogenase (GAPDH) probe, corresponding
to a 0.9-kb
EcoRI fragment of the GAPDH gene, was used
as a
control for Northern blot analysis. This probe was kindly
provided by
R. Dalla Favera (Department of Pathology, Columbia
University, New
York, N.Y.).
| |
RESULTS |
Effect of RFP on CD1b expression at the AMNC membrane level.
Freshly prepared AMNC were tested for CD14 expression to evaluate the
amount of monocytic cells present at the beginning of each experiment.
In most cases, the percentage of CD14+ cells ranged from 70 to 85%.
Washed AMNC, seeded in 25-cm
2 tissue culture flasks
(50 × 10
6 cells/flask), were incubated with
GM-CSF (10 IU/ml) alone, IL-4
(200 IU/ml) alone, or GM-CSF and
IL-4 together. Additional groups,
untreated or treated with the
cytokines, were exposed to RFP at
2 to 10 µg/ml. On day 3 of culture,
the total number of viable
AMNC (i.e., cells excluding trypan blue) in
each group was determined.
Thereafter, the cells were washed, counted
again, and tested for
CD1b expression by fluorescence-activated cell
sorter analysis.
The results indicate that treatment with RFP (2 or 10 µg/ml) was
not toxic for AMNC, since no difference in cell number or
viability
was detected between groups not treated with the antibiotic
and
the corresponding groups subjected to RFP treatment (data not
shown). The results of fluorescence-activated cell sorter analysis
performed with a MAb recognizing the native form of the CD1b molecule,
illustrated in Fig.
1 and described in
the legend, show that (i)
marginal levels of the CD1b molecule were
present on the membranes
of untreated AMNC, whereas treatment with IL-4
alone resulted
in a slight increase of the percentage of CD1b-positive
cells;
(ii) marked expression of the CD1b epitope was detectable on the
membranes of AMNC treated with GM-CSF alone or in combination
with
IL-4; (iii) the percentages of cells expressing CD1b molecules
in AMNC
exposed to GM-CSF plus IL-4 and RFP (2 or 10 µg/ml) were
higher than
those of cells treated with the combination of cytokines
without the
antibiotic (Similarly, treatment with RFP increased
by 20% the
percentage of CD1b-positive cells in the group exposed
to GM-CSF
alone.); and (iv) exposure of AMNC to RFP (2 or 10 µg/ml)
did not
modify the low percentages of CD1b-positive cells in the
groups not
treated with the cytokines or treated with IL-4 alone.
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FIG. 1.
Flow cytometry analysis of CD1b expression in AMNC
pretreated with GM-CSF (10 IU/ml) plus IL-4 (200 IU/ml) alone (A) or
with RFP at 2 (B) or 10 (C) µg/ml. Analysis was performed after 3 days of culture. Isotype-matched control MAb results are shown as a
faint profile, and CD1b results are shown as a solid profile. Percent
values relative to cells positive for CD1b molecules (range of four
separate experiments; data not shown) were as follows: untreated AMNC,
1 to 3%; AMNC treated with IL-4 alone, 13 to 15%; AMNC treated with
GM-CSF alone, 50 to 53%; AMNC treated with GM-CSF plus RFP (2 or 10 µg/ml), 60 to 70%. Exposure of AMNC to RFP (2 or 10 µg/ml) did not
modify the limited percentage of CD1b-positive cells in the untreated
or IL-4-treated groups.
|
|
Influence of RFP on induction of the CD1b protein in cytosolic and
membrane fractions of AMNC.
Western blot analysis of cytosol and
cell membrane preparations obtained from nonstimulated or stimulated
AMNC, with or without RFP treatment, was performed by using the rabbit
polyclonal antiserum obtained in our laboratory. It should be noted
that the commercially available antibody against CD1b was unable to
react with the CD1b protein in a Western blot analysis (data not
shown). The polyclonal antibody used in the present study recognizes
the denatured form of the CD1b protein and is suitable for Western blot
assays. The specificity of the antibody was preliminarily examined by
immunoblotting with a human B-lymphoblastoid cell line (C1R)
permanently transfected with the expression vector pSR-Neo
containing the CD1b cDNA (C1R/CD1b cells). Control C1R cells were
obtained following transfection with a mock plasmid (C1R/MOCK cells). A
polyclonal antibody revealed a specific band of about 50 kDa only in
the membrane fraction of C1R/CD1b cells and AMNC activated with GM-CSF
plus IL-4 (Fig. 2). Control or stimulated
AMNC contained a cytosolic immunoreactive 45-kDa protein which was also
present in C1R/MOCK cells. Figure 3 shows
that RFP markedly increased the level of membrane CD1b in
cytokine-activated AMNC but had no effect on cytosolic fractions.
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FIG. 2.
Specificity of the polyclonal CD1b antibody. Shown is an
immunoblot of membrane (lanes 3, 4, 7, and 8) and cytosol (lanes 1, 2, 5, and 6) CD1b expressed in AMNC (lanes 1 to 4) and in human
B-lymphoblastoid cell line C1R after transfection with the expression
vector pSR-Neo containing CD1b cDNA (lanes 5 and 7) or with a mock
vector (lanes 6 and 8). Lanes: 1 and 3, unstimulated AMNC; 2 and 4 AMNC
treated with GM-CSF plus IL-4. The values on the left represent
molecular size standards in kilodaltons.
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|
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FIG. 3.
Effect of RFP treatment on CD1b in membrane and cytosol
fractions. Cells were treated with GM-CSF plus IL-4 (lanes 1 to 3 and 5 to 7) in the presence of RFP at 2 (lanes 2 and 6) or 10 (lanes 3 and 7)
µg/ml. Cell homogenates were separated into membrane and cytosol
fractions. Each fraction (20 µg) was separated by SDS-polyacrylamide
gel electrophoresis and visualized by immunoblotting with the
polyclonal antibody against CD1b. Lanes 1 to 4, cytosol fractions from
AMNC (lanes 1 to 3) and C1R/CD1b cells (lane 4); 5 to 8, membrane
fractions from AMNC (lanes 5 to 7) and C1R/CD1b cells (lane 8). The
values on the left are molecular size standards (in kilodaltons).
|
|
Influence of RFP on CD1b mRNA levels.
Northern blot analysis
of total RNA hybridized with a CD1b cDNA probe showed the presence of a
transcript of approximately 2.0 kb in AMNC stimulated with GM-CSF plus
IL-4 (Fig. 4A, lane 2). Additional
treatment of AMNC with RFP (10 [lane 3] or 2 [lane 4] µg/ml)
increased the level of CD1b mRNA as evidenced by the results of a
representative experiment illustrated in Fig. 4A (lanes 3 and 4 versus
lane 2) and by the densitometric analysis performed on bands obtained
in the Northern blot analysis (Fig. 4B). Hybridization of a similar
blot containing the same samples with a GAPDH probe resulted in
comparable hybridization signals in these lanes (Fig. 4). In addition,
exposure of AMNC to a high concentration of RFP (i.e., 50 µg/ml)
along with GM-CSF and IL-4, resulted in a marked (i.e.,
more-than-threefold) increase in the amount of the specific CD1b
transcript (data not shown). The integrity of RNA samples was confirmed
by ethidium bromide staining of the gel before blotting (data not
shown).
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FIG. 4.
Analysis of CD1b transcripts in cytokine-activated AMNC
exposed to RFP. (A) Northern blot analysis of a human CD1b transcript.
Lanes: 1, unstimulated AMNC; 2, GM-CSF-IL-4-treated AMNC; 3, GM-CSF-IL-4-treated AMNC in the presence of RFP at 10 µg/ml; 4, GM-CSF-IL-4-treated AMNC in the presence of RFP at 2 µg/ml. The
results shown are from a representative experiment of three with
comparable results. (B) Results of blot scanning by densitometer.
Optical densities (O.D.) are expressed in arbitrary units.
|
|
| |
DISCUSSION |
The results of the present study indicate that RFP, at
concentrations of clinical relevance, increases CD1b expression of cytokine-activated AMNC, as assessed by cytofluorimetry analysis. This
observation was further confirmed by Western and Northern blot
analyses.
No data are available that explain the mechanisms underlying this
phenomenon. The observation that an RFP-mediated increase in CD1b
expression occurs in AMNC activated by GM-CSF or by GM-CSF plus IL-4
without evidence of drug-induced cytotoxicity seems to rule out any
selection mechanism favoring the survival of CD1b-positive cells. It is
known that the antibiotic impairs the functional RNA polymerase
activity of bacteria by blocking transfer of the nascent RNA to the
RNA-binding site of the unit of the enzyme (30).
Therefore, it is reasonable to suggest the hypothesis that RFP would
impair the transcription of a DNA binding factor acting as a
negative regulator of CD1b gene transcription in AMNC during
cytokine-mediated induction of the antigen-presenting molecule.
The Northern blot analysis data show that the CD1b gene transcript is
detectable only in AMNC following treatment with GM-CSF (data not
shown) or GM-CSF plus IL-4 (Fig. 4). Additional treatment with RFP
increased the level of CD1b mRNA. Cytokine-induced appearance of the
CD1b protein on AMNC is due mainly to induction of CD1b gene
transcription, rather than to protein translocation from the cytoplasm
to the cell membrane. In this context, it should be noted that the
RFP-mediated increase in CD1b in cytokine-activated AMNC is also not
the result of augmented translocation of the antigen to the plasma
membrane but the consequence of an actual increase in CD1b protein
synthesis. This is further supported by Western blot analysis showing
that the CD1b protein is almost undetectable in the cytoplasm
of nonactivated AMNC or of cytokine-activated AMNC not treated or
exposed to RFP (Fig. 3).
It remains to be established whether the RFP-mediated increase in CD1b
protein is the result of an actual increase in gene transcription or of
augmented mRNA stability.
Reports from the literature on the immunotoxicological profile of RFP
suggest that this drug possesses modest but significant depressive effects on immune responses (9, 10, 14, 22, 29).
One of the molecular mechanisms underlying the presumed immunotoxic effects of RFP appears to be related to inhibition of
protein synthesis in immunocompetent cells induced by the
antitubercular agent (12). In addition, mycobacteria are
known to downregulate helper T-cell activity and B7 expression in
infected macrophages, thus reducing costimulatory signals required for
T-cell responses to mycobacterial peptides (23). It must be
pointed out that the efficacy of RFP and its analogs is conditioned by
efficient immune responses against the infectious agent (6,
7). Therefore, immunodepression induced by mycobacteria and by
the antibiotic itself should limit the therapeutic effectiveness of
RFP. However, a number of studies seem to confirm that
non-MHC-restricted CD1b molecules would play a pivotal role in
host resistance against M. tuberculosis. The results of the
present investigation suggest that RFP could amplify cytokine-mediated
induction of the CD1b molecule on monocyte membranes, thus contributing
positively to mycobacterial antigen presentation and, presumably, to
T-cell responses against the infectious agent.
In conclusion, the present report illustrates, for the first
time, a possible role that could be played by RFP in the
CD1-dependent system. Actually, a rather complex
immunopharmacological profile of the antibiotic appears to originate
from the available data concerning its interaction with the
immune system. The modest depression of classical MHC-dependent,
cell-mediated T-cell immunity induced by RFP could be balanced by its
favorable effects on lipid and glycolipid antigen presentation mediated
by CD1b molecules on peripheral blood monocytes. It should be added
that RFP does not show any detrimental effect on the functional
activity of double-negative T cells (data not shown), which are
involved in CD1b-restricted glycolipid antigen recognition and killing
of target cells carrying the relevant antigen. In any case, since no
data are available to establish the relative importance of classical
MHC-restricted and nonclassical CD1-restricted T-cell responses in
antitubercular immunity, further studies are required to identify the
overall effects of RFP on host resistance against mycobacteria in
vivo.
| |
ACKNOWLEDGMENTS |
This work was supported by the National Tuberculosis Project
(Istituto Superiore di Sanità, Ministero della Sanità,
Rome, Italy, [mandato 740, obtained by Grazia Graziani]).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Via di Tor Vergata 135, 00133 Rome, Italy. Phone:
39-6-72596335. Fax: 39-6-72596323. E-mail:
Graziani{at}utovrm.it.
| |
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Antimicrobial Agents and Chemotherapy, March 1998, p. 550-554, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
