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-Inducing Factors but Enhances NK Cell Production of IFN-1
,
Departments of
*
Medicine and
Physiology, East Carolina University School of Medicine, Greenville, NC 27858;
Department of Biology, Southern College of SDA, Collegedale, TN 37315;
§
Laboratory of Host Defense, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan;
¶
Hayashibara Biochemical Laboratories, Okayama, Japan;
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Japan BCG Laboratory, Tokyo, Japan; and
#
Myrvik Enterprises, Southport, NC 28461
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Abs. The results
established that chitin treatment of KO mice increased superoxide anion
release from alveolar macrophages (M
) to a level much higher than
that in wild-type (WT) mice. The results also suggested that the NK
cell is the source of IFN- that is primarily responsible for this
alveolar M priming. To further study the roles of IL-10-inhibiting
chitin-induced IFN- production, we used spleen cell cultures. The
experiments showed that IL-12, IL-18, and TNF-
, which were produced
by chitin-stimulated M, contributed to the IFN--inducing activity
of chitin. Our results established that exogenous IL-10 inhibited
chitin-induced IFN- production in spleen cell cultures from both KO
and WT mice. Exogenous IL-10 also inhibited IL-12 and TNF-
production by chitin-stimulated M. Exogenous IL-10 decreased IL-12-
or IL-18-induced IFN- levels in KO but not in WT NK cell cultures.
However, exogenous IL-10 enhanced IFN- levels when NK cells were
stimulated simultaneously with both IL-12 and IL-18 in KO and WT
cultures. Our in vitro data indicate that IL-10 has differential
effects on chitin-induced IFN- production. However, the inhibitory
effects of endogenous IL-10 appear to be dominant in the chitin-induced
alveolar M priming response in vivo. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/IL-18 production by
M,3 all of which are
extracellular signaling cytokines for IFN- production (1, 2, 3, 4). IL-18,
an 18-kDa IFN--inducing factor, acts synergistically with IL-12 to
induce IFN- production by Th1 cells (4).
We recently found that phagocytosable chitin
(N-acetyl-D-glucosamine polymer) is another
inducer of innate immunity (5, 6). Our studies (5, 6) showed that: 1)
splenic M phagocytose chitin through mannose receptors to produce
IL-12/TNF-; 2) unlike LPS-induced cytokine production, the mechanism
of this phagocytosis-induced cytokine production involves cytochalasin
D-sensitive actin polymerization; 3) the M-derived cytokines
stimulate NK cells to produce IFN-; and 4) this IFN- production
is negatively regulated by IL-4, TGF-ß, PGE2, and IL-10.
When C57BL/6 and SCID mice received chitin i.v., alveolar M were
activated within 3 days to become bactericidal. We further demonstrated
that endogenous IFN- produced by NK cells is responsible for this
alveolar M priming (6).
IL-10 is an important negative regulator of cell-mediated immunity/Th1
functions (7). IL-10 is secreted by several different cell populations
including T helper cells (Th1/Th2/Th0), monocytes, M, B cells, and
keratinocytes (7). IL-10 has been characterized as a factor that
inhibits IFN- secretion from activated Th1 lymphocytes and NK cells
(8, 9). In vitro studies have shown that IL-10 suppresses production of
cytokines (IL-1, IL-6, TNF-, GM-CSF, IL-12), generation of a
reactive oxygen intermediate, and expression of surface MHC class II
and costimulatory molecules such as B7 (10, 11, 12, 13). The immunoregulatory
roles of IL-10 in vivo, however, appear to be complex. Dai et al. (14)
have recently demonstrated that IL-10-deficient mice are resistant to
Listeria monocytogenes infections due to high levels of
endogenous IFN- production during the infection. Murray et al. (15)
have shown that IL-10-transgenic mice are unable to clear mycobacterial
infection. Surprisingly, excess IL-10 does not inhibit T cell responses
to mycobacteria and IFN- production in these mice (15).
This study in which IL-10-deficient (KO) mice are used was to define
the regulatory role of IL-10 with respect to: 1) the priming of
alveolar M by chitin in vivo; 2) the production of IFN--inducing
factors (IL-12, IL-18, TNF-) by chitin-stimulated splenic M in
vitro; and 3) the production of IFN- by NK cells stimulated by these
M-derived cytokine(s) in vitro.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Breeding pairs of IL-10-deficient mice (C57BL/6-Il10tm1Cgn) (16) were obtained from The Jackson Laboratory (Bar Harbor, ME). Offspring were raised under pathogen-free conditions. Nonpregnant females, 8 to 14 wk old, were used for experiments. Age-matched female C57BL/6 mice were obtained from The Jackson Laboratory and used as wild-type control (WT) mice. Both IL-10-deficient (KO) and WT mice were maintained in barrier-filtered cages and fed Purina laboratory chow and tap water ad libitum.
Preparations of CMI inducers (M activators)
Chitin particles (1–10 µm in diameter) were prepared from chitin powders (Sigma Chemical, St. Louis, MO) as described previously (5), suspended in saline (1 mg/ml), autoclaved, and kept at 4°C until use. Chitin preparations contained undetectable levels of endotoxin (<0.03 EU/ml). Cultured bacteria of Mycobacterium bovis Calmette-Guérin bacillus (BCG) Tokyo 172 strain were washed, autoclaved, and lyophilized. The powder of heat-killed (HK)-BCG was suspended in saline immediately before use. The suspensions of both chitin and HK-BCG were dispersed by brief sonication (10 s) when used. LPS (Escherichia coli 0111:B4, phenol) was obtained from Sigma.
Protocol for in vivo priming of mice
To prime alveolar M in vivo, mice were injected i.v. with 0.2
mg of chitin suspended in 0.2 ml of endotoxin-free saline. The alveolar
M were harvested 1 to 7 days after injection (5).
In vivo neutralization of IFN-
Endogenously produced IFN- was neutralized by injecting mice
i.p. with 2 x 105 neutralizing units of
anti-IFN- mAb (R4-6A2; specific activity, 2 x
105 neutralizing units per mg of IgG) 1 day before the
chitin injection (5). An equivalent amount of normal rat IgG (Sigma)
was used to control for the nonspecific effects of injecting foreign
Ig.
In vivo NK1.1+ cell depletion
As described previously (5), mice received i.p. 5 mg of purified anti-NK1.1 (IgG2a; clone PK136 from the American Type Culture Collection (ATCC), Manassas, VA) 1 day before chitin administration.
Alveolar M and spleen cells
Alveolar M were obtained by five repetitions of
bronchopulmonary lavage with 1 ml of sterile HBSS, pH 7.2. M
enrichment was performed by the plastic adherence method (37°C,
1 h) in the presence of 10% heat-inactivated FBS. To prepare
spleen cells, at least four spleens were pooled for each in vitro
experiment. Plastic-adherent spleen M were prepared as described
previously (17). In indicated experiments, NK cell-enriched spleen cell
populations were prepared as follows: CD4+ cells,
CD8+ cells, Ly-6G (Gr-1)+ cells, B220
(CD45R)+ cells in the spleen cells were eliminated with a
mixture of mAbs against CD4 (clone GK1.5 from ATCC), CD8 (clone 2.43;
purified mAb was a gift from M. Evans, East Carolina University School
of Medicine, Greenville, NC); Ly-6G (clone RB6-8C5 was a gift from
R. L. Coffman, DNAX), and B220 (clone RA3-6B2; purified mAb was a
gift from M. Evans), followed by treatment with rabbit serum (1:10,
Sigma) as a source of complement. Adherent M and damaged
cells were removed by passage through a Sephadex G-10 column (18). The
expression of surface antigens (Mac-1, NK1.1) on the M and NK cell
preparations, respectively, was determined by indirect
immunofluorescence in the presence of 5% heat-inactivated newborn calf
serum (Life Technologies, Grand Island, NY), pH 7.2, as described
previously (5). Nucleated cell numbers, cell viability, and
differential cell counts in freshly isolated cells and cultured cells
were performed as described previously (5).
Superoxide anion release assay
Superoxide dismutase (SOD)-inhibitable superoxide anion levels
released by alveolar M were measured by a cytochrome c
reduction assay as described previously (5). Briefly, alveolar lavage
cells were placed in a 24-well plate (Corning, Corning, NY) with
HEPES-bicarbonate buffer containing 50 µM ferricytochrome
c (Sigma). The adherent cells (>95% M, determined by
morphology) were incubated at 37°C for 1 h in the presence of
PMA (1 µM). SOD (700 U/ml; Sigma) was also added as a negative
control. The amount of reduced ferricytochrome c was
measured by using a molecular extinction coefficient of 21.1
mM-1 cm-1 from the change in absorbance at
550 nm against a cell-free blank. Superoxide formation was expressed as
nanomols per 106 cells.
Production of IFN- by spleen cell cultures stimulated with
chitin
Spleen cells (4 x 106 cells/ml) or
plastic-adherent M (106 cells/ml) in RPMI 1640 plus 10%
heat-inactivated FBS were incubated with chitin at 100 µg/ml, HK-BCG
at 100 µg/ml, or LPS at 100 ng/ml at 37°C. After 24 h of
incubation, the culture supernatants were harvested, filtered through a
0.22-µm pore size Zetapore filter (Cuno, Meriden, CT) which removes
particles and endotoxin, and stored at -80°C for later assays for
cytokines. In some experiments, chitin particle-stimulated spleen cell
cultures were further treated with recombinant mouse IL-10 (Pepro Tech,
Rocky Hill, NJ) or Abs (rat anti-mouse IL-12 (clone 17.8; Genzyme,
Cambridge, MA), polyclonal rabbit anti-mouse TNF- (Genzyme), or
polyclonal rabbit anti-mouse IL-18 (4). IFN- production was also
performed using NK cell-enriched spleen cells (106
cells/ml) which were incubated with exogenous IL-12 (Genzyme) and/or
IL-18 (4) at various doses or with the chitin-stimulated M culture
filtrates described above. After 24 h of incubation at 37°C, the
supernatants were collected, and IFN- levels in the supernatants
were measured by ELISA (5). The levels of IL-12p70 and IL-10 were also
determined by specific ELISA (6). TNF- bioactivity was measured by
its cytotoxicity for L929 fibroblasts as described previously (6).
Statistics
Differences between mean values were analyzed by Student’s t test. p values of <0.05 were considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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priming by i.v. administration of chitin in KO mice
Chitin particle suspensions were given i.v. to KO and WT mice (1
mg/ml, 0.2 ml/injection). After selected periods, superoxide anion
release by PMA-elicited alveolar M was detected as described in
Materials and Methods. PMA-elicited alveolar M in WT mice
generated <0.2 nmol/106 cells/h superoxide anion.
Superoxide anion release was greatly enhanced 1 to 3 days after the
injection of chitin and returned to normal (baseline) by day 7, which
was consistent with previous reports (5). The kinetics of
chitin-induced superoxide anion release in KO mice was similar to that
of WT mice, peaking at day 3 and returning to normal by day 7. However,
the magnitude of superoxide anion release was significantly increased
compared with that of WT mice throughout the entire 7 days (Fig. 1
). SOD at 700 U/ml completely inhibited
superoxide anion release by alveolar M (data not shown).
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and NK cells were responsible
for the chitin-induced alveolar M priming, we treated KO mice with
rat anti-IFN- mAb or mouse anti-NK1.1 mAb 1 day before
inoculating them with chitin. As shown previously (5), both treatments
significantly decreased alveolar M priming in KO mice as well as in
WT mice (Fig. 2).
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production in spleen
cell cultures
Previously, we demonstrated that chitin induced production of
IL-12p70 (bioactive IL-12), TNF-, and IFN- in spleen cell
cultures prepared from C57BL/6 mice (6). To define the role of IL-10,
spleen cells isolated from KO mice were incubated with chitin
particles. As shown in Table I, the
levels of IL-12, TNF-, and IFN- were markedly higher than those
from WT mice. To determine whether these endogenous cytokines
contributed IFN- production, spleen cell cultures were treated with
neutralizing Abs against IL-12 and TNF- before the stimulation of
chitin. Abs against IL-12 and TNF- inhibited the IFN--inducing
activities (Fig. 3). Anti-IL-18 also
inhibited the IFN--inducing activity (Fig. 3). When exogenous IL-10
was added to the spleen cell cultures, the levels of IFN- were
dramatically reduced (Fig. 4). Treatments
with IL-10 at 1 and 10 ng/ml resulted in >95% inhibition of the
cytokine production.
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, and
IFN- production (Table I
). Exogenous IL-10 added to the cultures
markedly inhibited IFN- production (Fig. 4).
These results indicate that IL-10 down-regulates not only
chitin-induced IFN- production but also BCG- or LPS-induced IFN-
production. However, it is still unclear which step(s) of innate
immunity induced by chitin is inhibited by IL-10.
IL-10 inhibits IL-12/TNF- production by splenic M
Spleen cells isolated from IL-10-deficient mice and controls
contained 6 and 7% of Mac-1+ cells, respectively (mean,
n = 3, data not shown). Plastic-adherent M
preparations from KO and WT mice contained 70 and 74%
Mac-1+ cells, respectively (data not shown). Splenic M
were stimulated with chitin in the presence or absence of exogenous
IL-10. The levels of IL-12 and TNF- produced in the M cultures
are shown in Table II. These results
showed that when stimulated by chitin, KO M produced six- and
threefold more IL-12 and TNF-, respectively, than WT M. Treatment
with exogenous IL-10 at 1 and 10 ng/ml resulted in >90% inhibition of
the production of IL-12 and TNF- (Table II).
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Splenic NK (NK1.1+) cells, but not CD4+
cells, are the major producers of IFN- in chitin-induced innate
immunity (5). NK1.1+ cells accounted for 7% of the spleen
cells in both KO and WT mice (data not shown). Following negative
selection as described in Materials and Methods,
NK1.1+ cells accounted for 67 and 71% from KO and WT mice,
respectively (data not shown). To assess the effect of IL-10, NK cells
were cultured with IL-12 and/or IL-18 for 24 h at 37°C. NK cells
were also cultured with the chitin-stimulated KO M culture filtrates
prepared above.
WT NK cells responded to either IL-12 or IL-18 (both at 0.01–10 ng/ml)
and released IFN- in a small but notable dose-dependent manner.
Typical results at 1 ng/ml of the cytokines are shown in Table III. The combination of IL-12 and IL-18
showed synergistic effects on IFN- production (Table III).
Similarly, the culture filtrates from chitin-, BCG-, and LPS-stimulated
KO M cultures (Table II; Fig. 3) induced IFN- production. The
amounts of IFN- were significantly higher than those induced by
IL-12 alone or IL-18 alone (Table III). When KO NK cells were
stimulated with IL-12 alone or IL-18 alone, they released more IFN-
than WT NK cells (Table III). In addition, neither synergistic nor
additive effects of these two cytokines were observed. The levels of
IFN- production induced by the mixtures of two cytokines were
comparable to, but slightly lower than, those shown by WT NK cells
(Table III).
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production,
exogenous IL-10 was added to NK cell cultures described above. In KO NK
cells, the levels of IL-12- or IL-18-induced IFN- production were
decreased by exogenous IL-10 in a dose-dependent manner (Table III).
Surprisingly, IFN- levels induced by the mixtures of IL-12/IL-18 or
the chitin-stimulated KO M culture filtrates were slightly but
significantly increased (Table III). In contrast, the levels of IFN-
production in WT mice, when stimulated by IL-12 alone or IL-18 alone,
were unchanged by the exogenous IL-10 treatments (Table III). Exogenous
IL-10 at 1 and 10 ng/ml, however, enhanced IFN- production at 20 to
40% when induced by the mixtures of IL-12/IL-18 or by the
chitin-stimulated KO M culture filtrates (Table III).
IL-10 production by chitin-stimulated M and by
IL-12/IL-18-stimulated NK cells
We measured the levels of IL-10 in the cultures of splenic M
and NK cells isolated from WT mice. As shown in Table IV, when M were stimulated with
chitin, 317 pg/ml IL-10 were detected. Comparable levels of IL-10 were
also detected by stimulation with HK-BCG and LPS. Although neither
IL-12 nor IL-18 induced detectable IL-10, the combination of these
cytokines or the chitin-induced KO M culture filtrates induced
significant amounts of IL-10 production in NK cell cultures (Table IV).
These results suggest that endogenous IL-10 produced in the
chitin-induced innate immunity is derived, at least in part, from M
and NK cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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as
compared with WT mice (Fig. 1); 2) the mechanisms of NK cell-produced
IFN-, which is primarily responsible for this alveolar M priming,
appear to be down-regulated by endogenous IL-10 (Fig. 2); 3) exogenous
IL-10 inhibits chitin/BCG/LPS-induced IFN- production in both KO and
WT spleen cell cultures (Fig. 4); 4) IL-12, TNF-, and IL-18, which
are produced by chitin-stimulated splenic M (inhibition by IL-10),
contribute to the IFN--inducing activity of chitin (Fig. 3; Tables I
and II); 5) exogenous IL-10 decreases IL-12- or IL-18-induced IFN-
production by KO NK cells but not WT NK cells (Table III); and 6)
exogenous IL-10, however, enhances IFN- levels when NK cells are
stimulated simultaneously with both IL-12 and IL-18 in KO and WT
cultures (Table III).
We have previously demonstrated that the mechanism of IL-12 and TNF-
production induced by chitin and HK-BCG involves mannose
receptor-mediated phagocytosis that depends on cytochalasin D-sensitive
actin polymerization events (6). In contrast, LPS-induced IL-12
production is independent of these cellular events (6). Based on the
present study, however, it is clear that IL-10 modifies the M
responses not only to chitin and HK-BCG but also to LPS for the
production of IL-12, TNF-, and IL-18. We also found in this study
that splenic M produce IL-10 when stimulated with chitin/BCG/LPS
(Table IV). Our results clearly indicate that consistent with earlier
observations (10, 11, 12), IL-10 down-regulates the initial stages of
innate immunity mediated by M in an "autocrine" fashion.
IFN- production by NK cells is induced not only by IL-12 and TNF-
as previously described (3, 5) but also by IL-18 as described in this
study. IL-18 produced by M was originally identified and
characterized as IFN--inducing factor by Okamura et al. (4). Since
then, synergistic effects between IL-12 and IL-18 on IFN- production
by T-helper clones and CD40-stimulated B cell activation have been
documented in other models (19, 20, 21). In the present study, IL-12 and
IL-18 synergistically induce splenic NK cells to produce IFN- in WT
mice. Such synergistic enhancement of IFN- production was initially
observed by TNF- and IL-12, although TNF- alone does not induce
IFN- production (9, 22). This mechanism can explain that the initial
induction of IFN- by NK cells does not require detectable levels of
IL-12 in chitin-induced innate immunity. This possibility is supported
by our preliminary study where IL-12 at 1 pg/ml, undetectable by ELISA,
does not induce IFN- production (>5 U/ml) by WT NK cells unless
costimulated with IL-18 at 10 pg/ml (data not shown). In addition,
previous studies including ours (1, 5, 22) indicate that endogenous
IFN- has a stimulatory effect on M and makes them more responsive
to chitin.
A unique immunostimulatory effect of IL-10 on IFN- production is
demonstrated in this study. IL-10 enhances IFN- levels when NK cells
(KO or WT) are stimulated with chitin-stimulated KO M culture
filtrates containing both IL-12 and IL-18. Our additional results
(Table III), however, suggest an exception that in some cases where
M produce either IL-12 or IL-18, IL-10 decreases IFN- production.
Overall, our in vitro study indicates that IL-10 has differential
effects on the chitin-induced innate immune responses: 1) inhibitory
effect on M cytokine production; and 2) stimulatory effect of
IFN- production by NK cells. In the chitin-induced alveolar M
priming in vivo, the inhibitory effects of endogenous IL-10 appear to
be dominant.
Murray et al. (15) found that overexpression of IL-10 does not inhibit
but rather enhances IFN- secretion by purified protein
derivative-stimulated spleen cells isolated from the
BCG-immunized IL-10-transgenic mouse model. Although further
confirmation of whether these observations are made particularly in the
transgenic mice is required, this study strongly suggests that IL-10
directly enhances IFN- production by Ag-specific Th1 cells and/or
nonspecifically by NK cells under chronic immunologic conditions.
Furthermore, there are several studies indicating IL-10 as an
immmunostimulator (23, 24, 25). For example, IL-10 injection in mice (200
µg/mouse/day) with expecting immunosuppressive roles in graft-vs-host
diseases failed because IL-10 may have been an immunostimulant, which
probably enhanced IFN- production (23).
Peritt et al. (26) documented that IL-12-induced NK cells produce
IL-10. In this connection, it has been proposed that although both T
cells and NK cells express IL-10 receptors, the effects of IL-10 on
these two cells would differ (27, 28). Carson et al. (28), using human
NK cells, found that: 1) IL-10 receptors are constitutively expressed
on human NK cells; 2) unlike IL-2-activated T cells, the proliferation
of IL-2-activated NK cells is further enhanced by IL-10; 3) the
production of IFN-, TNF-, and GM-CSF by IL-2-activated NK cells
is significantly enhanced by IL-10; 4) IL-10 induces NK cell cytotoxic
activity against tumor cells; and 5) IL-10 does not enhance IFN-
production when human NK cells are stimulated by IL-12 alone. These
observations and our results suggest that IL-10 inhibits or enhances NK
cell functions in an "autocrine" fashion, depending on the cytokine
milieu.
In addition to the inhibitory effects of IL-10 on IFN- production as
described above, the following two additional mechanisms would be
involved for the enhancement of chitin-induced alveolar M priming in
KO mice. First, it is well established that IL-10 inhibits the
generation of a reactive oxygen intermediate and a reactive nitrogen
intermediate by IFN--induced effector M (12, 29). This
mechanism was further supported by our unpublished studies using an in
vitro IFN--induced alveolar M priming assay (100 U/ml IFN-,
24 h) (5). We found that the capacities of PMA-elicited superoxide
anion release are higher in IFN--primed M from KO mice than those
from WT mice (5.6 and 3.8 nmol/106 cells/h, respectively,
data not shown). Exogenous IL-10 at 1 to 100 ng/ml during the IFN-
treatment inhibited superoxide anion release in a dose-dependent manner
(up to 30% inhibition) in both KO and WT mice (data not shown). Unlike
IL-4 (30), however, the inhibitory effect of IL-10 was not observed
when exogenous IL-10 was added to alveolar M, which had been
primed previously either in vitro with IFN- or in vivo by chitin
injection (data not shown). Secondly, the generation of the M
effector functions is induced by not only IFN- but also M-derived
cytokines including TNF- (31), which is produced at higher levels by
KO M (Tables I and II).
The present study indicates major endogenous cytokines regulating innate immunity. The unique contribution of our series of studies (5, 6) is that nonantigenic and biodegradable chitin represents an effective tool to study immunoregulatory mechanisms of IL-10.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Yoshimi Shibata, Department of Medicine, East Carolina University School of Medicine, Greenville, NC 27858. E-mail address:
3 Abbreviations used in this paper: M, macrophages; HK, heat killed; SOD, superoxide dismutase; WT mice, wild-type control mice; KO mice, IL-10-deficient (knockout) mice; BCG, Calmette-Guérin bacillus.
Received for publication October 17, 1997. Accepted for publication June 8, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production by stimulation of interleukin-12 and tumor necrosis factor-. Cell. Immunol. 167:72.[Medline]
production by T cells. Nature 378:88.[Medline]
are costimulators of interferon production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist. Proc. Natl. Acad. Sci. USA 90:3725.-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J. Exp. Med. 178:1041. production from activated B cells. Proc. Natl. Acad. Sci. USA 94:3948.-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12. J. Immunol. 158:1550.
-inducing factor in enhanced production of IFN-. J. Immunol. 159:2125. and tumor necrosis factor . J. Exp. Med. 181:1615.-activated macrophages. J. Immunol. 148:1792.[Abstract]
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S. Ahmed, M. Colmenares, L. Soong, K. Goldsmith-Pestana, L. Munstermann, R. Molina, and D. McMahon-Pratt Intradermal Infection Model for Pathogenesis and Vaccine Studies of Murine Visceral Leishmaniasis Infect. Immun., January 1, 2003; 71(1): 401 - 410. [Abstract] [Full Text] [PDF]
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G. S. Deepe, Jr., and R. S. Gibbons Cellular and Molecular Regulation of Vaccination with Heat Shock Protein 60 from Histoplasma capsulatum Infect. Immun., July 1, 2002; 70(7): 3759 - 3767. [Abstract] [Full Text] [PDF]
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 H Tilg, C van Montfrans, A van den Ende, A Kaser, S J H van Deventer, S Schreiber, M Gregor, O Ludwiczek, P Rutgeerts, C Gasche, et al. Treatment of Crohn's disease with recombinant human interleukin 10 induces the proinflammatory cytokine interferon {gamma} Gut, February 1, 2002; 50(2): 191 - 195. [Abstract] [Full Text] [PDF]
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M. M. L. Pompeu, C. Brodskyn, M. J. Teixeira, J. Clarencio, J. Van Weyenberg, I. C. B. Coelho, S. A. Cardoso, A. Barral, and M. Barral-Netto Differences in Gamma Interferon Production In Vitro Predict the Pace of the In Vivo Response to Leishmania amazonensis in Healthy Volunteers Infect. Immun., December 1, 2001; 69(12): 7453 - 7460. [Abstract] [Full Text] [PDF]
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Y. Shibata, I. Honda, J. P. Justice, M. R. Van Scott, R. M. Nakamura, and Q. N. Myrvik Th1 Adjuvant N-Acetyl-D-Glucosamine Polymer Up-Regulates Th1 Immunity but Down-Regulates Th2 Immunity against a Mycobacterial Protein (MPB-59) in Interleukin-10-Knockout and Wild-Type Mice Infect. Immun., October 1, 2001; 69(10): 6123 - 6130. [Abstract] [Full Text] [PDF]
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K. Emmanuilidis, H. Weighardt, S. Maier, K. Gerauer, T. Fleischmann, X. X. Zheng, W. W. Hancock, B. Holzmann, and C.-D. Heidecke Critical Role of Kupffer Cell-Derived IL-10 for Host Defense in Septic Peritonitis J. Immunol., October 1, 2001; 167(7): 3919 - 3927. [Abstract] [Full Text] [PDF]
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S.-i. Fujii, K. Shimizu, T. Shimizu, and M. T. Lotze Interleukin-10 promotes the maintenance of antitumor CD8+ T-cell effector function in situ Blood, October 1, 2001; 98(7): 2143 - 2151. [Abstract] [Full Text] [PDF]
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 T. Goldmann, G. Zissel, R. S. Gupta, M. Schlaak, E. Vollmer, and J. Muller-Quernheim Formation of Granulomas in the Lungs of Severe Combined Immunodeficient Mice after Infection with Bacillus Calmette-Guerin Am. J. Pathol., May 1, 2001; 158(5): 1890 - 1891. [Full Text] [PDF]
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F. N. Lauw, D. Pajkrt, C. E. Hack, M. Kurimoto, S. J. H. van Deventer, and T. van der Poll Proinflammatory Effects of IL-10 During Human Endotoxemia J. Immunol., September 1, 2000; 165(5): 2783 - 2789. [Abstract] [Full Text] [PDF]
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P. Lauzurica, D. Sancho, M. Torres, B. Albella, M. Marazuela, T. Merino, J. A. Bueren, C. Martinez-A, and F. Sanchez-Madrid Phenotypic and functional characteristics of hematopoietic cell lineages in CD69-deficient mice Blood, April 1, 2000; 95(7): 2312 - 2320. [Abstract] [Full Text] [PDF]
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Y. Shibata, L. A. Foster, J. F. Bradfield, and Q. N. Myrvik Oral Administration of Chitin Down-Regulates Serum IgE Levels and Lung Eosinophilia in the Allergic Mouse J. Immunol., February 1, 2000; 164(3): 1314 - 1321. [Abstract] [Full Text] [PDF]
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) and WT (
) mice received 0.2 mg of chitin i.v.
(3 mice/group). After the numbers of days indicated, alveolar M
