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*
Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and the
Veterans Affairs Medical Center and Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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. Injection of CpG ODN into murine
dermis also led to enhanced expression of MHC class II and CD86 Ag by
LC in overlying epidermis and intracytoplasmic IL-12 accumulation in a
subpopulation of activated LC. We conclude that immunostimulatory CpG
ODN stimulate DC in vitro and in vivo. Bacterial DNA-based vaccines may
preferentially elicit Th1-predominant immune responses because they
activate and mobilize DC and induce them to produce large amounts of
IL-12. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recent studies demonstrated that the adjuvant properties of bacterial
DNA are related to the high frequency of unmethylated CpG dinucleotides
in bacterial compared with eukaryotic DNA (reviewed in 12 .
Synthetic phosphorothioate oligodeoxynucleotides (ODN) containing a
consensus immunostimulatory motif
(5'-purine-purine-CpG-pyrimidine-pyrimidine-3'; CpG ODN) can also act
as adjuvants (9). We became interested in the adjuvant properties of
bacterial DNA and CpG ODN while studying the efficacy of genetic
vaccines in a murine model of leishmaniasis. We determined that a
plasmid encoding gp63, a Leishmania major cell surface
protein, induced a gp63-specific Th1 response and protected some BALB/c
mice from infection (
30%), while gp63 protein-based vaccines were
ineffective (13). Gurunathan et al.
recently demonstrated that plasmids encoding another L.
major protein, the LACK Ag, induce considerably more protection
(14). In a subsequent study, we observed that an ODN containing two CpG
immunostimulatory motifs in a tandem array (CpG ODN 1826) converted an
ineffective parasite lysate vaccine into one with considerable efficacy
(i.e., one that afforded 40%
protection).5
Coadministration of CpG ODN 1826 and live parasites to susceptible mice
also abrogated infection in most animals (65% of those inoculated;
see Footnote 5). Similar results have recently been reported by Lipford
et al. (15).
Because DC are thought to be essential for the initiation of primary
immune responses in T cells in vivo (16), we hypothesized that CpG ODN
might be potent activators of DC. We focused on immature (nonlymphoid)
DC because they are more likely to be involved in the acquisition of Ag
(including Leishmania Ag) in peripheral tissues than mature
interdigitating DC in lymphoid organs (17, 18), and made use of an in
vitro model of murine epidermal Langerhans cells (LC), i.e. fetal
skin-derived DC (FSDDC), that has recently been developed in
our laboratory (19). FSDDC are expanded in primary cultures of C57BL/6
fetal skin and are isolated as tight aggregates comprised of cells
(immature FSDDC (FSDDC-I)) with an LC-like phenotype. Like LC,
FSDDC-I spontaneously give rise to cells that resemble mature
interdigitating DC (mature FSDDC (FSDDC-M)) during a several-day
subculture period (19) and can be triggered to differentiate into
FSDDC-M by inflammatory mediators (IL-1, TNF-, and LPS) (20).
Because FSDDC model the transition of LC into interdigitating DC with
considerable fidelity, we assessed the responses of these cells to
various ODN, including CpG ODN 1826. We also assayed ODN for
LC-activating activity in vivo. Our results indicate that CpG ODN that
function as adjuvants in vivo (21, 22, 23) are potent activators of
immature cutaneous DC in vitro and in vivo. In addition, the ability of
CpG ODN 1826 to induce the production of large amounts of IL-12 by DC
may explain its propensity to augment the development of Th1 immune
responses in vivo (22, 23).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Eight- to twelve-week-old female C57BL/6, timed pregnant C57BL/6, and female BALB/c mice were obtained from the National Cancer Institute Animal Production Program (Frederick, MD) and were housed and used in accordance with institutional guidelines. Gestational day 0 represents the day of conception.
Propagation and stimulation of FSDDC
FSDDC were propagated from day 16 C57BL/6 fetal skin in FCS-containing medium supplemented with murine recombinant GM-CSF (10 ng/ml; R&D Systems, Minneapolis, MN) and CSF-1 (10 ng/ml; PeproTech, Rocky Hill, NJ) and were isolated as aggregates as recently described (19). When necessary, FSDDC-I were dissociated with trypsin in EDTA (0.025% trypsin in calcium- and magnesium-free HBSS containing 1 mM EDTA for 30 min at 37°C) to allow enumeration of cells. FSDDC aggregates were subcultured in cytokine-supplemented complete medium at 5 x 105 cells/ml in T-25 flasks or 24-well plates in the presence or the absence of ODN and LPS as indicated.
Oligodeoxynucleotides and LPS
ODN with a nuclease-resistant phophorothioate backbone and ODN
with a phosphodiester backbone (see Table I
) were synthesized by Oligos, Etc.
(Wilsonville, OR), a GMP facility. Sodium salts of ODN were ethanol
precipitated, stored at -20°C, and diluted in PBS immediately before
use. Escherichia coli and calf thymus DNA were purchased
from Sigma (St. Louis, MO) and prepared for use as previously described
(24). LPS levels in phosphorothioate ODN were undetectable (<1 pg/mg)
by Limulus amebocyte lysate assay (Whittaker Bioproducts,
Walkersville, MD). Amounts of LPS in phosphodiester ODN, calf thymus
DNA, and E. coli DNA were detectable, but were <10% of the
threshold amounts required to activate FSDDC in vitro (
10 pg/ml final
concentration) (20) (T.J. and M.C.U., unpublished observations).
LPS (E. coli K235-derived LPS; <0.008% protein) was
provided by Dr. Stephanie Vogel (Uniformed Services University of the
Health Services, Bethesda, MD).
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Anti-I-Ab (Y3P, mouse IgG2a)-, anti-I-Ad (MKD6, mouse IgG2a)-, and anti-I-Ab/d, I-Ed (M5/114, rat IgG2b)-producing hybridomas were obtained from American Type Culture Collection (Manassas, VA), and an anti-E-cadherin mAb-producing hybridoma (ECCD-2, rat IgG2a) was provided by Dr. Masatoshi Takeichi (Kyoto University, Kyoto, Japan). Mouse mAb were purified from hybridoma supernatants using immobilized protein A (Pierce, Rockford, IL), and rat mAb were prepared using immobilized protein G (Pierce). Y3P, MKD6, and M5/114 were conjugated with FITC (Sigma) as previously described (19). Anti-CD40 (HM40–3, hamster IgM), anti-CD45 (30F11.1, rat IgG2b), anti-CD80 (1G10, rat IgG2a), anti-CD86 (GL-1, rat IgG2a), anti-mIL-12 p40 (C15.6, rat IgG1), and isotype controls were purchased as purified biotin-, PE-, or FITC-modified mAb from PharMingen (San Diego, CA). PE-streptavidin was obtained from Tago (Burlingame, CA).
FSDDC aggregates were subcultured in GM-CSF- and CSF-1-supplemented
media for 18 h in 24-well plates (5 x 105 cell
equivalents/1 ml/well) in the presence or the absence of LPS or ODN.
Before staining, FSDDC aggregates were dissociated in HBSS containing 1
mM EDTA (30 min at 37°C) in 10% Chelex-100 treated FCS 10 (Sigma,
St. Louis, MO) (25). For multicolor flow cytometry, cells were
suspended in cold PBS containing 5% FCS and 0.02% NaN3,
preincubated with saturating concentrations of anti-FcR
II/III
(2.4G2, supplied by Julie Titus, National Cancer Institute), and then
serially incubated with saturating concentrations of FITC-mAb,
biotin-mAb, and PE-streptavidin. Stained cells were analyzed using a
FACScan flow cytometer equipped with CellQuest software (Becton
Dickinson, Mountain View, CA). Propidium iodide-permeable (nonviable)
cells were excluded from analyses.
Flow cytometric assessment of DC-associated IL-12 in FSDDC-I incubated
with LPS or ODN was conducted as described above, except that brefeldin
A (1 µg/ml; PharMingen) was added for the last 4 h of the 18-h
incubation period (26). FSDDC were subsequently harvested, dissociated
with EDTA, preincubated with anti-FcRII/III mAb, stained with
FITC I-Ab or control mAb, fixed and permeabilized (4%
paraformaldehyde and 0.1% saponin) for 20 min at 4°C, washed, and
then stained with PE-conjugated anti-IL-12 p40 (C15.6) or isotype
control. Propidium iodide was omitted from the staining protocol.
FSDDC cytokine production
Aggregates of FSDDC were suspended (0.5 x 105
cell equivalents/ml) in GM-CSF- and CSF-1-containing DC media and
incubated for 18 h in the presence or the absence of LPS or ODN.
At the end of the incubation, supernatants were decanted, nonadherent
cells were removed by centrifugation, and the cell-free supernatants
were stored at -70°C. Concentrations of IL-1ß (19), IFN- and
TNF- (27), and IL-6 and IL-12 p40 (11) in culture supernatants were
determined as recently described.
Mixed leukocyte reactions
EDTA-dissociated FSDDC were exposed to 20 Gy, suspended in RPMI 1640 supplemented with 10% FCS, and added to 2 x 105 accessory cell-depleted BALB/c lymph node T cells in 96-well, flat-bottom microtiter plates as previously described (27). After 72 h, [3H]TdR (New England Nuclear, Cambridge, MA) was added (1 µCi/well), and the incubation was continued for an additional 18 h. Cell-associated radioactivity was determined by direct beta counting.
Assessment of LC activation in vivo
Mice were anesthetized via i.p. injection of ketamine (2.5 mg/animal) and xylazine (0.05 mg/animal). The dorsum of each ear was injected with recombinant mouse IL-1ß (50 ng in 50 µl; Genzyme Diagnostics, Cambridge, MA) or ODN (50 µg) in PBS (four mice per group). After 12 h, epidermal cell suspensions were obtained from the skin overlying the injection site by limited trypsinization as previously described (28), and the surface phenotype of LC was characterized using flow cytometry. Intracellular IL-12 p40 accumulation in LC activated by in vivo administration of LPS (200 ng) or CpG ODN 1826 (50 µg) was evaluated in epidermal cell suspensions obtained 12 h after injection and an additional 5-h culture in complete medium (1 x 106 cells/ml) (28) supplemented with brefeldin A (1 µg/ml) using a procedure analogous to that used to quantitate intracellular IL-12 in FSDDC (see above).
Statistical analysis
The statistical significance of differences in cytokine production of FSDDC and LC surface Ag expression was calculated using the paired Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We previously demonstrated that immature DC expanded in primary
cultures of murine fetal skin cells (FSDDC-I) and isolated as
trypsin-resistant aggregates resemble epidermal LC (19). Adhesion
within aggregates is E-cadherin mediated (19) and serves as an in vitro
correlate of E-cadherin-mediated adhesion of LC and keratinocytes in
the epidermis (29). We have also determined that the ability of
inflammatory mediators to induce loss of adhesion in FSDDC aggregates
and initiate maturation correlates with their ability to activate and
mobilize LC in vivo (20). Thus, we initially screened phosphorothioate
ODN for FSDDC-activating activity using a simple disaggregation assay.
The sequences of the ODN used are presented in Table I
. Each ODN,
except ODN 1911 and 2067, contained two immunostimulatory CpG motifs in
overlapping (CpG ODN 1758 and 1835) or tandem repeats (CpG ODN 1826 and
2061). FSDDC-I were incubated in ODN or LPS for 18 h and
observed at various times. CpG ODN 1826 (6 µg/ml) and LPS (100 ng/ml)
caused almost complete loss of E-cadherin-mediated adhesion in FSDDC
aggregates within 18 h, whereas the base composition-matched ODN
1911 (6 µg/ml) and CpG ODN 1758 or 1836 were without effect (see Fig. 1). Loss of homotypic cell adhesion was
accompanied by a reduction in E-cadherin surface expression (data not
shown) (20). The disaggregation observed with CpG ODN 1826 was dose
dependent, with no effects observed at concentrations <1.5 µg/ml,
and, like that due to LPS, began after a lag period of approximately
6 h (data not shown).
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).
Cell surface levels of CD80 were also somewhat increased. Identical
concentrations (6 µg/ml) of CpG ODN 1758 and 1835 and control ODN
1911 did not result in significant changes in cell surface phenotype
(Fig. 2). To determine whether the failure of ODN other than 1826 to
activate FSDDC-I was relative or absolute, we conducted dose-response
studies. FSDDC-I were exposed to concentrations of ODN ranging from 0.6
to 200 µg/ml for 18 h, and MHC class II Ag levels were
evaluated. Concentrations of CpG ODN 1826 that were >2 µg/ml
resulted in FSDDC activation (see Fig. 3). In the experiment depicted, CpG ODN
1758 (20 µg/ml) also induced almost complete FSDDC-I activation, and
CpG ODN 1835 had similar effects at 60 µg/ml. Indeed, even ODN 1911,
an ODN with the same base content as CpG ODN 1826 but lacking the
immunostimulatory CpG motifs (see Table I), activated FSDDC-I to some
extent at high concentrations (
60 µg/ml).
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The accessory cell activity of APC and the type of response that
ensues after interactions of T cells with APC and Ag depend on the
cytokines produced by APC as well as the costimulator molecules that
they express on their cell surfaces. To characterize the cytokines
produced by FSDDC following CpG ODN stimulation, FSDDC
aggregates were cultured for 18 h in control medium (supplemented
with GM-CSF and CSF-1) or in medium also containing LPS (100 ng/ml) or
ODN (6 µg/ml), and immunoreactive IL-1ß, IFN-, TNF-, IL-6,
and IL-12 p40 were assayed in cell-free supernatants by ELISA. IL-1ß
and IFN- were not detected in FSDDC supernatants under any of these
conditions (data not shown). As expected, LPS-treated FSDDC released
significant amounts of TNF-, IL-6, and IL-12 into the medium (see
Table II). Addition of CpG ODN 1826 also
stimulated cytokine production by FSDDC. In comparison to LPS, CpG ODN
1826 induced about fivefold less TNF-, about sevenfold less IL-6,
and about 10 times more IL-12 production. Interestingly, ODN 1911 (6
µg/ml) induced the release of as much IL-12 as LPS, and considerably
more than identical amounts of CpG ODN 1758 and 1835.
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) and accumulation of
intracellular IL-12 p40 in a minor population (3%) of FSDDC.
Although the effects of CpG ODN 1826 on FSDDC MHC class II expression
were similar to those of LPS, this immunostimulatory ODN resulted in a
dose-dependent dramatic up-regulation of IL-12 p40 in a major
subpopulation (14–32%) of cells (see Fig. 4). In comparison,
treatment with ODN 1911 at a concentration of 6 or 20 µg/ml resulted
in intracellular IL-12 p40 accumulation in only a minor subpopulation
(1–2%) of FSDDC. At a high concentration (60 µg/ml), ODN 1911 also
up-regulated MHC class II Ag and intracellular IL-12 p40 accumulation
somewhat (Fig. 4). These results conclusively demonstrate that the
IL-12 produced in response to CpG ODN 1826 was synthesized by DC. In
addition, these data indicate that both CpG ODN 1826 and ODN 1911
preferentially induced IL-12 p40 accumulation in FSDDC that expressed
the highest levels of MHC class II Ag (i.e., the most mature DC in the
preparations).
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). Augmentation of FSDDC accessory cell activity by CpG ODN
To determine whether increases in cell surface MHC Ag and
costimulator expression and cytokine production were accompanied by an
increase in the ability of FSDDC to stimulate unprimed T cells, C57BL/6
FSDDC-I were incubated for 18 h in LPS (10 ng/ml) or ODN (6
µg/ml), washed, and then tested for allostimulatory activity in a
mixed leukocyte reaction using accessory cell-depleted BALB/c T cells
as responders. Treatment of FSDDC with CpG ODN 1826 resulted in a
severalfold increase in the potency of FSDDC as an allostimulator (see
Fig. 5). This was considerably less than
the approximately 10-fold increase in accessory cell activity induced
by LPS, but was clearly increased relative to that due to other ODN.
ODN 1911, CpG ODN 1758, and CpG ODN 1835 had no accessory
cell-augmenting activity at 6 µg/ml.
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Although FSDDC accurately model various aspects of LC biology, we
sought to determine whether immunostimulatory ODN also had the capacity
to activate immature nonlymphoid DC in vivo. Subpopulations of LC
become activated by exposure to contact allergens, IL-1, TNF-, and
LPS and are subsequently induced to emigrate from epidermis (30, 31, 32, 33).
Before they exit the epidermis, activated LC express increased levels
of cell surface MHC class II and CD86 Ag and can be differentiated from
unstimulated LC using multicolor flow cytometry. To test the ability of
CpG ODN 1826 and ODN 1911 to stimulate LC in situ, we injected IL-1ß
(50 ng in 50 µl of PBS), CpG ODN 1826 (50 µg/50 µl), ODN 1911 (50
µg/50 µl), or PBS into the dorsal ear skin of BALB/c mice, prepared
epidermal cell suspensions from the overlying epidermis 12 h
later, and stained cells for simultaneous expression of MHC class II
and CD86 Ag. Introduction of IL-1ß and CpG ODN 1826 into murine skin
led to increased expression of MHC class II and CD86 Ag by significant
subpopulations of LC in three experiments (see Fig. 6 and Table III). The proportion of LC activated by
CpG ODN 1826 in vivo was always less than that activated by IL-1ß,
but was significantly greater than that due to injection of control ODN
1911 or PBS. Similar results were obtained in an identical experiment
conducted with C57BL/6 mice.
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) and could be
clearly resolved from MHC class II-negative epidermal cells. Therefore,
we compared intracellular levels of IL-12 in LC activated by LPS with
those in LC stimulated with CpG ODN 1826. We found that in three
experiments a small subpopulation of LC activated by CpG ODN 1826 in
vivo (4.3 ± 1.6%) contained detectable levels of intracellular
IL-12, whereas LPS-activated LC did not (Fig. 7). Thus, CpG ODN 1826 selectively
induced IL-12 production by cutaneous DC in vivo as well as in vitro.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Exposure of LC-like FSDDC-I to low concentrations of CpG ODN (especially CpG ODN 1826) in vitro resulted in loss of E-cadherin-mediated adhesion within DC aggregates, pronounced up-regulation of MHC class II Ag and costimulator molecule (CD40, CD80, and CD86) expression, and acquisition of enhanced accessory cell activity. In addition, CpG ODN resulted in a large increase in IL-12 production by FSDDC. Significantly, intradermal injection of CpG ODN also led to increased expression of MHC class II Ag and costimulator molecules as well as induction of IL-12 synthesis by LC in overlying epidermis. CpG ODN had no effect on cytokine production or cell surface Ag expression by primary murine keratinocytes (data not shown), suggesting that, at least in murine skin, immunostimulatory DNA acts primarily on DC.
The CpG ODN-induced enhancement of accessory cell activity that we observed was less marked than the changes in cell surface phenotype or cytokine (especially IL-12) production that were detected. We attribute this difference to the characteristics of the cells that we studied and the assays that we used. We have previously shown that FSDDC-I differentiate into cells that resemble mature interdigitating dendritic cells over a several-day period in isolation without additional stimulation (19). Presumably FSDDC also mature at a similar (or faster) rate when cocultured for several days with allogenic T cells. Thus, we are detecting enhanced function in an in vitro assay in which accessory cell activity is already being rapidly up-regulated. Assays of the effects of CpG ODN on cell surface Ag expression and cytokine production involve incubations of hours rather than days, such that backgrounds attributable to spontaneous maturation are considerably lower.
A variety of CpG ODN have immunostimulatory activity in vivo (10, 15, 21, 22, 23, 38), and it has been suggested that different CpG ODN may act
preferentially on different leukocyte subpopulations and/or induce
different kinds of responses in distinct subpopulation of cells. The
immature DC used in the present study (FSDDC and LC) preferentially
responded to CpG ODN 1826, an ODN with tandem nonoverlapping
immunostimulatory motifs, compared with other CpG ODN (1758 and 1835).
Interestingly, an ODN that is base composition matched to CpG ODN 1826
but lacks CpG sequences (ODN 1911) also activated FSDDC at high
concentrations. It is difficult to explain this observation because we
do not fully understand how CpG ODN activate immune cells.
Nonsequence-specific effects of ODN have been attributed to
phosphorothioate modification of the backbone (39, 40, 41, 42, 43). In the present
study, however, phosphodiester ODN and sequence-matched phosphorothiate
ODN had comparable DC-activating potentials (Fig. 4). Inasmuch as
immunostimulatory properties of other anionic polymers, including
single- and double-stranded polynucleotides (34), dextran sulfate (44),
and heparan sulfate (45), are well known, additional physicochemical
properties of ODN may also be relevant.
The propensity of bacterial plasmid-based vaccines to induce
Th1-predominant responses has been previously ascribed to their ability
to induce IL-12 production by macrophages in a CpG
dinucleotide-dependent fashion (15, 35, 36, 37). This interpretation is
difficult to reconcile with data indicating that DC, rather than
macrophages, are primarily responsible for T cell priming in vivo (16).
Reis e Sousa and co-workers have recently demonstrated that
Toxoplasma gondii extracts that activate innate immunity
selectively induce rapid and dramatic IFN--independent up-regulation
of IL-12 production in splenic DC in vivo and also cause DC
redistribution within central lymphoid tissue (46). These authors have
also implicated IL-12-producing DC as important regulators of the
initial phases of Th1 differentiation/expansion. Our results indicate
that CpG ODN have similar dramatic effects on DC IL-12 production, and
that they can also activate immature nonlymphoid DC. To our knowledge,
these results represent the first direct demonstration that LC can be
stimulated to produce IL-12.
We suggest that intracutaneous genetic vaccines induce Th1 responses because CpG dinucleotide sequences in bacterial DNA activate DC in skin and induce them to produce large amounts of IL-12. Similar scenarios may occur in the setting of chronic infections that probably result in the release of immunostimulatory DNA into skin or in instances where CpG-containing DNA is coadministered with simple (22, 23, 38) or complex Ag, or even live organisms (see Footnote 5) (14). We propose that introduction (or accumulation) of immunostimulatory CpG-containing DNA in skin leads to LC activation manifested by attenuation of E-cadherin-mediated adhesion of LC to keratinocytes (29, 47) and enhanced expression of MHC Ag and costimulator molecules. LC MHC Ag could be loaded with antigenic peptides synthesized endogenously (e.g., during the course of immunization with naked DNA) (4, 6), peptides synthesized by other skin cells (e.g., keratinocytes or fibroblasts) (3), or nominal Ag derived from infectious organisms themselves. Ultimately, epidermal LC (and perhaps DC in the dermis) are mobilized, such that DC bearing Ag acquired in skin migrate from skin to regional lymph nodes, where they localize in T cell-dependent areas as mature interdigitating DC (4, 6, 31) capable of initiating Th1 responses in naive T cells.
Other immunostimulatory activities of CpG ODN may also be important.
The ability of CpG ODN to induce regional lymphadenopathy after s.c.
injection (A. M. Krieg, unpublished observation) suggests that CpG
ODN distribute to the lymph node and could activate DC in
lymphoid tissues. In addition, CpG ODN are known to act directly on B
cells (inducing decreased apoptosis (48), proliferation, enhanced Ig
synthesis, and IL-6 release (11)) and on macrophages (resulting in
increased IL-12 production) (15, 34, 35, 36, 37). Indirect actions of CpG ODN
on NK cells (IL-12-dependent IFN- production) (37) may also be
relevant, especially in chronic infections. Although the relative
importance of the effects of CpG ODN on immature DC vis-a-vis effects
on immune responses in vivo remains to be conclusively demonstrated, we
propose that the effects of CpG ODN as well as immunostimulatory DNA
derived from pathogens on T cell priming are probably mediated via DC.
Thus, results of in vitro and in vivo studies of the DC-activating
potential of CpG ODN such as we have reported here may allow rapid
screening of ODN for possible Th1 response-promoting activity and may
facilitate identification of CpG ODN that show promise as preventive or
therapeutic agents for infectious and inflammatory diseases or cancer.
Note added in proof. In subsequent studies, small amounts of immunoreactive IL-12 p70 (10 pg/106 cells) have been detected in supernatants of FSDDC incubated with CpG ODN 1826 for 72 h. IL-12 p70 was not released by FSDDC treated with the control ODN 1911. A similar report, coauthored by T. Sparwasser et al., appeared while this manuscript was in press (Sparwasser, T., E. S. Koch, R. M. Vabulas, K. Heeg, G. B. Lipford, J. W. Ellwart, and H. Wagner. 1998. Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur. J. Immunol. 28:2045).
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Acknowledgments |
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Footnotes |
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2 These authors contributed equally to the work described in this report and are listed in alphabetical order.
3 Address correspondence and reprint requests to Dr. Jonathan C. Vogel, Dermatology Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 12N238, 9000 Rockville Pike; Bethesda, MD 20892-1908. E-mail address:
4 Abbreviations used in this paper: DC, dendritic cell; CpG ODN, oligodeoxynucleotide containing the CpG motif; LC, Langerhans cell; FSDDC-I (-M), fetal skin-derived dendritic cells-immature (-mature); GM-CSF, granulocyte-macrophage CSF; PE, phycoerythrin.
5 P. S. Walker, T. Scharton-Kersten, A. M. Krieg, L. Love-Homan, E. D. Rowton, M. C. Udey, and J. C. Vogel. Immunostimulatory oligonucleotides promote protective immunity and provide systemic therapy for leishmaniasis. Submitted for publication.
Received for publication February 17, 1998. Accepted for publication May 19, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in vivo and increases the toxicity of lipopolysaccharides. J. Immunol. 156:4570.[Abstract]
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production is dependent on macrophage secretion of IL-12. Clin. Immunol. Immunopathol. 84:185.[Medline]
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V. Flacher, M. Bouschbacher, E. Verronese, C. Massacrier, V. Sisirak, O. Berthier-Vergnes, B. de Saint-Vis, C. Caux, C. Dezutter-Dambuyant, S. Lebecque, et al. Human Langerhans Cells Express a Specific TLR Profile and Differentially Respond to Viruses and Gram-Positive Bacteria J. Immunol., December 1, 2006; 177(11): 7959 - 7967. [Abstract] [Full Text] [PDF]
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R. Liang, J. V. van den Hurk, L. A. Babiuk, and S. van Drunen Littel-van den Hurk Priming with DNA encoding E2 and boosting with E2 protein formulated with CpG oligodeoxynucleotides induces strong immune responses and protection from Bovine viral diarrhea virus in cattle. J. Gen. Virol., October 1, 2006; 87(Pt 10): 2971 - 2982. [Abstract] [Full Text] [PDF]
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P. J. Tacken, I. J. M. de Vries, K. Gijzen, B. Joosten, D. Wu, R. P. Rother, S. J. Faas, C. J. A. Punt, R. Torensma, G. J. Adema, et al. Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti-DC-SIGN antibody Blood, August 15, 2005; 106(4): 1278 - 1285. [Abstract] [Full Text] [PDF]
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Y.-L. Lin, Y.-C. Liang, S.-S. Lee, and B.-L. Chiang Polysaccharide purified from Ganoderma lucidum induced activation and maturation of human monocyte-derived dendritic cells by the NF-{kappa}B and p38 mitogen-activated protein kinase pathways J. Leukoc. Biol., August 1, 2005; 78(2): 533 - 543. [Abstract] [Full Text] [PDF]
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C. De Trez, B. Pajak, M. Brait, N. Glaichenhaus, J. Urbain, M. Moser, G. Lauvau, and E. Muraille TLR4 and Toll-IL-1 Receptor Domain-Containing Adapter-Inducing IFN-{beta}, but Not MyD88, Regulate Escherichia coli-Induced Dendritic Cell Maturation and Apoptosis In Vivo J. Immunol., July 15, 2005; 175(2): 839 - 846. [Abstract] [Full Text] [PDF]
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D. Alignani, B. Maletto, M. Liscovsky, A. Ropolo, G. Moron, and M. C. Pistoresi-Palencia Orally administered OVA/CpG-ODN induces specific mucosal and systemic immune response in young and aged mice J. Leukoc. Biol., June 1, 2005; 77(6): 898 - 905. [Abstract] [Full Text] [PDF]
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C. Traidl-Hoffmann, V. Mariani, H. Hochrein, K. Karg, H. Wagner, J. Ring, M. J. Mueller, T. Jakob, and H. Behrendt Pollen-associated phytoprostanes inhibit dendritic cell interleukin-12 production and augment T helper type 2 cell polarization J. Exp. Med., February 22, 2005; 201(4): 627 - 636. [Abstract] [Full Text] [PDF]
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D. S. Pouniotis, O. Proudfoot, V. Bogdanoska, V. Apostolopoulos, T. Fifis, and M. Plebanski Dendritic Cells Induce Immunity and Long-Lasting Protection against Blood-Stage Malaria despite an In Vitro Parasite-Induced Maturation Defect Infect. Immun., September 1, 2004; 72(9): 5331 - 5339. [Abstract] [Full Text] [PDF]
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J. R. Ramirez-Pineda, A. Frohlich, C. Berberich, and H. Moll Dendritic Cells (DC) Activated by CpG DNA Ex Vivo Are Potent Inducers of Host Resistance to an Intracellular Pathogen That Is Independent of IL-12 Derived from the Immunizing DC J. Immunol., May 15, 2004; 172(10): 6281 - 6289. [Abstract] [Full Text] [PDF]
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C. De Trez, M. Brait, O. Leo, T. Aebischer, F. A. Torrentera, Y. Carlier, and E. Muraille Myd88-Dependent In Vivo Maturation of Splenic Dendritic Cells Induced by Leishmania donovani and Other Leishmania Species Infect. Immun., February 1, 2004; 72(2): 824 - 832. [Abstract] [Full Text] [PDF]
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L. J. Berry, D. K. Hickey, K. A. Skelding, S. Bao, A. M. Rendina, P. M. Hansbro, C. M. Gockel, and K. W. Beagley Transcutaneous Immunization with Combined Cholera Toxin and CpG Adjuvant Protects against Chlamydia muridarum Genital Tract Infection Infect. Immun., February 1, 2004; 72(2): 1019 - 1028. [Abstract] [Full Text] [PDF]
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M. P. Gould, J. A. Greene, V. Bhoj, J. L. DeVecchio, and F. P. Heinzel Distinct Modulatory Effects of LPS and CpG on IL-18-Dependent IFN-{gamma} Synthesis J. Immunol., February 1, 2004; 172(3): 1754 - 1762. [Abstract] [Full Text] [PDF]
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K. Abeyama, K.-i. Kawahara, S. Iino, T. Hamada, S.-i. Arimura, K. Matsushita, T. Nakajima, and I. Maruyama Antibiotic cyclic AMP signaling by "primed" leukocytes confers anti-inflammatory cytoprotection J. Leukoc. Biol., November 1, 2003; 74(5): 908 - 915. [Abstract] [Full Text] [PDF]
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S.-J. Yeo, J.-G. Yoon, and A.-K. Yi Myeloid Differentiation Factor 88-dependent Post-transcriptional Regulation of Cyclooxygenase-2 Expression by CpG DNA: TUMOR NECROSIS FACTOR-{alpha} RECEPTOR-ASSOCIATED FACTOR 6, A DIVERGING POINT IN THE Toll-LIKE RECEPTOR 9-SIGNALING J. Biol. Chem., October 17, 2003; 278(42): 40590 - 40600. [Abstract] [Full Text] [PDF]
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P. Lundberg, P. Welander, X. Han, and E. Cantin Herpes Simplex Virus Type 1 DNA Is Immunostimulatory In Vitro and In Vivo J. Virol., October 15, 2003; 77(20): 11158 - 11169. [Abstract] [Full Text] [PDF]
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A. S. Lonsdorf, H. Kuekrek, B. V. Stern, B. O. Boehm, P. V. Lehmann, and M. Tary-Lehmann Intratumor CpG-Oligodeoxynucleotide Injection Induces Protective Antitumor T Cell Immunity J. Immunol., October 15, 2003; 171(8): 3941 - 3946. [Abstract] [Full Text] [PDF]
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L. Beloeil, M. Tomkowiak, G. Angelov, T. Walzer, P. Dubois, and J. Marvel In Vivo Impact of CpG1826 Oligodeoxynucleotide on CD8 T Cell Primary Responses and Survival J. Immunol., September 15, 2003; 171(6): 2995 - 3002. [Abstract] [Full Text] [PDF]
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J. Kuchtey, M. Pennini, R. K. Pai, and C. V. Harding CpG DNA Induces a Class II Transactivator-Independent Increase in Class II MHC by Stabilizing Class II MHC mRNA in B Lymphocytes J. Immunol., September 1, 2003; 171(5): 2320 - 2325. [Abstract] [Full Text] [PDF]
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N. B. Ray and A. M. Krieg Oral Pretreatment of Mice with CpG DNA Reduces Susceptibility to Oral or Intraperitoneal Challenge with Virulent Listeria monocytogenes Infect. Immun., August 1, 2003; 71(8): 4398 - 4404. [Abstract] [Full Text] [PDF]
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J. Kochling, S. A. Konig-Merediz, R. Stripecke, D. Buchwald, A. Korte, H. G. von Einsiedel, F. Sack, G. Henze, K. Seeger, B. Wittig, et al. Protection of Mice against Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia by Cell-based Vaccination Using Nonviral, Minimalistic Expression Vectors and Immunomodulatory Oligonucleotides Clin. Cancer Res., August 1, 2003; 9(8): 3142 - 3149. [Abstract] [Full Text] [PDF]
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S.-J. Yeo, D. Gravis, J.-G. Yoon, and A.-K. Yi Myeloid Differentiation Factor 88-dependent Transcriptional Regulation of Cyclooxygenase-2 Expression by CpG DNA: ROLE OF NF-{kappa}B AND p38 J. Biol. Chem., June 13, 2003; 278(25): 22563 - 22573. [Abstract] [Full Text] [PDF]
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U. Kumaraguru, C. D. Pack, and B. T. Rouse Toll-like receptor ligand links innate and adaptive immune responses by the production of heat-shock proteins J. Leukoc. Biol., May 1, 2003; 73(5): 574 - 583. [Abstract] [Full Text] [PDF]
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A.-K. Yi, J.-G. Yoon, and A. M. Krieg Convergence of CpG DNA- and BCR-mediated signals at the c-Jun N-terminal kinase and NF-{kappa}B activation pathways: regulation by mitogen-activated protein kinases Int. Immunol., May 1, 2003; 15(5): 577 - 591. [Abstract] [Full Text] [PDF]
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D. Skokos, H. G. Botros, C. Demeure, J. Morin, R. Peronet, G. Birkenmeier, S. Boudaly, and S. Mecheri Mast Cell-Derived Exosomes Induce Phenotypic and Functional Maturation of Dendritic Cells and Elicit Specific Immune Responses In Vivo J. Immunol., March 15, 2003; 170(6): 3037 - 3045. [Abstract] [Full Text] [PDF]
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K. Sano, H. Shirota, T. Terui, T. Hattori, and G. Tamura Oligodeoxynucleotides Without CpG Motifs Work as Adjuvant for the Induction of Th2 Differentiation in a Sequence-Independent Manner J. Immunol., March 1, 2003; 170(5): 2367 - 2373. [Abstract] [Full Text] [PDF]
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D. Stober, I. Jomantaite, R. Schirmbeck, and J. Reimann NKT Cells Provide Help for Dendritic Cell-Dependent Priming of MHC Class I-Restricted CD8+ T Cells In Vivo J. Immunol., March 1, 2003; 170(5): 2540 - 2548. [Abstract] [Full Text] [PDF]
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S. Radhakrishnan, L. T. Nguyen, B. Ciric, D. R. Ure, B. Zhou, K. Tamada, H. Dong, S.-Y. Tseng, T. Shin, D. M. Pardoll, et al. Naturally Occurring Human IgM Antibody That Binds B7-DC and Potentiates T Cell Stimulation by Dendritic Cells J. Immunol., February 15, 2003; 170(4): 1830 - 1838. [Abstract] [Full Text] [PDF]
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S. Gomis, L. Babiuk, D. L. Godson, B. Allan, T. Thrush, H. Townsend, P. Willson, E. Waters, R. Hecker, and A. Potter Protection of Chickens against Escherichia coli Infections by DNA Containing CpG Motifs Infect. Immun., February 1, 2003; 71(2): 857 - 863. [Abstract] [Full Text] [PDF]
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A. D. Sandler, H. Chihara, G. Kobayashi, X. Zhu, M. A. Miller, D. L. Scott, and A. M. Krieg CpG Oligonucleotides Enhance the Tumor Antigen-specific Immune Response of a Granulocyte Macrophage Colony-stimulating Factor-based Vaccine Strategy in Neuroblastoma Cancer Res., January 15, 2003; 63(2): 394 - 399. [Abstract] [Full Text] [PDF]
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S.-J. Yeo, J.-G. Yoon, S.-C. Hong, and A.-K. Yi CpG DNA Induces Self and Cross-Hyporesponsiveness of RAW264.7 Cells in Response to CpG DNA and Lipopolysaccharide: Alterations in IL-1 Receptor-Associated Kinase Expression J. Immunol., January 15, 2003; 170(2): 1052 - 1061. [Abstract] [Full Text] [PDF]
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W. Jiang, H. J. Baker, and B. F. Smith Mucosal Immunization with Helicobacter, CpG DNA, and Cholera Toxin Is Protective Infect. Immun., January 1, 2003; 71(1): 40 - 46. [Abstract] [Full Text] [PDF]
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H. Sashinami, A. Nakane, Y. Iwakura, and M. Sasaki Effective Induction of Acquired Resistance to Listeria monocytogenes by Immunizing Mice with In Vivo-Infected Dendritic Cells Infect. Immun., January 1, 2003; 71(1): 117 - 125. [Abstract] [Full Text] [PDF]
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T.-Y. Kim, H.-J. Myoung, J.-H. Kim, I.-S. Moon, T.-G. Kim, W.-S. Ahn, and J.-I. Sin Both E7 and CpG-Oligodeoxynucleotide Are Required for Protective Immunity against Challenge with Human Papillomavirus 16 (E6/E7) Immortalized Tumor Cells: Involvement of CD4+ and CD8+ T Cells in Protection Cancer Res., December 15, 2002; 62(24): 7234 - 7240. [Abstract] [Full Text] [PDF]
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B. J. Weigel, N. Nath, P. A. Taylor, A. Panoskaltsis-Mortari, W. Chen, A. M. Krieg, K. Brasel, and B. R. Blazar Comparative analysis of murine marrow-derived dendritic cells generated by Flt3L or GM-CSF/IL-4 and matured with immune stimulatory agents on the in vivo induction of antileukemia responses Blood, December 1, 2002; 100(12): 4169 - 4176. [Abstract] [Full Text] [PDF]
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K. Heckelsmiller, K. Rall, S. Beck, A. Schlamp, J. Seiderer, B. Jahrsdorfer, A. Krug, S. Rothenfusser, S. Endres, and G. Hartmann Peritumoral CpG DNA Elicits a Coordinated Response of CD8 T Cells and Innate Effectors to Cure Established Tumors in a Murine Colon Carcinoma Model J. Immunol., October 1, 2002; 169(7): 3892 - 3899. [Abstract] [Full Text] [PDF]
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E. Davila, M. G. Velez, C. J. Heppelmann, and E. Celis Creating space: an antigen-independent, CpG-induced peripheral expansion of naive and memory T lymphocytes in a full T-cell compartment Blood, September 18, 2002; 100(7): 2537 - 2545. [Abstract] [Full Text] [PDF]
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M. Kakimoto, A. Hasegawa, S. Fujita, and M. Yasukawa Phenotypic and Functional Alterations of Dendritic Cells Induced by Human Herpesvirus 6 Infection J. Virol., September 11, 2002; 76(20): 10338 - 10345. [Abstract] [Full Text] [PDF]
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B. Maletto, A. Ropolo, V. Moron, and M. C. Pistoresi-Palencia CpG-DNA stimulates cellular and humoral immunity and promotes Th1 differentiation in aged BALB/c mice J. Leukoc. Biol., September 1, 2002; 72(3): 447 - 454. [Abstract] [Full Text] [PDF]
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X. P. Ioannou, P. Griebel, R. Hecker, L. A. Babiuk, and S. van Drunen Littel-van den Hurk The Immunogenicity and Protective Efficacy of Bovine Herpesvirus 1 Glycoprotein D plus Emulsigen Are Increased by Formulation with CpG Oligodeoxynucleotides J. Virol., August 12, 2002; 76(18): 9002 - 9010. [Abstract] [Full Text] [PDF]
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R. K. Pai, D. Askew, W. H. Boom, and C. V. Harding Regulation of Class II MHC Expression in APCs: Roles of Types I, III, and IV Class II Transactivator J. Immunol., August 1, 2002; 169(3): 1326 - 1333. [Abstract] [Full Text] [PDF]
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H. Shirota, K. Sano, N. Hirasawa, T. Terui, K. Ohuchi, T. Hattori, and G. Tamura B Cells Capturing Antigen Conjugated with CpG Oligodeoxynucleotides Induce Th1 Cells by Elaborating IL-12 J. Immunol., July 15, 2002; 169(2): 787 - 794. [Abstract] [Full Text] [PDF]
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M. Gierynska, U. Kumaraguru, S.-K. Eo, S. Lee, A. Krieg, and B. T. Rouse Induction of CD8 T-Cell-Specific Systemic and Mucosal Immunity against Herpes Simplex Virus with CpG-Peptide Complexes J. Virol., June 5, 2002; 76(13): 6568 - 6576. [Abstract] [Full Text] [PDF]
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H. J. Cho, T. Hayashi, S. K. Datta, K. Takabayashi, J. H. Van Uden, A. Horner, M. Corr, and E. Raz IFN-{alpha}{beta} Promote Priming of Antigen-Specific CD8+ and CD4+ T Lymphocytes by Immunostimulatory DNA-Based Vaccines J. Immunol., May 15, 2002; 168(10): 4907 - 4913. [Abstract] [Full Text] [PDF]
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P. Riedl, D. Stober, C. Oehninger, K. Melber, J. Reimann, and R. Schirmbeck Priming Th1 Immunity to Viral Core Particles Is Facilitated by Trace Amounts of RNA Bound to Its Arginine-Rich Domain J. Immunol., May 15, 2002; 168(10): 4951 - 4959. [Abstract] [Full Text] [PDF]
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T.-H. Chuang, J. Lee, L. Kline, J. C. Mathison, and R. J. Ulevitch Toll-like receptor 9 mediates CpG-DNA signaling J. Leukoc. Biol., March 1, 2002; 71(3): 538 - 544. [Abstract] [Full Text] [PDF]
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I. Miconnet, S. Koenig, D. Speiser, A. Krieg, P. Guillaume, J.-C. Cerottini, and P. Romero CpG Are Efficient Adjuvants for Specific CTL Induction Against Tumor Antigen-Derived Peptide J. Immunol., February 1, 2002; 168(3): 1212 - 1218. [Abstract] [Full Text] [PDF]
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T. Luft, M. Jefford, P. Luetjens, H. Hochrein, K.-A. Masterman, C. Maliszewski, K. Shortman, J. Cebon, and E. Maraskovsky IL-1{beta} Enhances CD40 Ligand-Mediated Cytokine Secretion by Human Dendritic Cells (DC): A Mechanism for T Cell-Independent DC Activation J. Immunol., January 15, 2002; 168(2): 713 - 722. [Abstract] [Full Text] [PDF]
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Y. Park, S. W. Lee, and Y. C. Sung Cutting Edge: CpG DNA Inhibits Dendritic Cell Apoptosis by Up-Regulating Cellular Inhibitor of Apoptosis Proteins Through the Phosphatidylinositide-3'-OH Kinase Pathway J. Immunol., January 1, 2002; 168(1): 5 - 8. [Abstract] [Full Text] [PDF]
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Z. K. Ballas, A. M. Krieg, T. Warren, W. Rasmussen, H. L. Davis, M. Waldschmidt, and G. J. Weiner Divergent Therapeutic and Immunologic Effects of Oligodeoxynucleotides with Distinct CpG Motifs J. Immunol., November 1, 2001; 167(9): 4878 - 4886. [Abstract] [Full Text] [PDF]
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Y. Kawarada, R. Ganss, N. Garbi, T. Sacher, B. Arnold, and G. J. Hammerling NK- and CD8+ T Cell-Mediated Eradication of Established Tumors by Peritumoral Injection of CpG-Containing Oligodeoxynucleotides J. Immunol., November 1, 2001; 167(9): 5247 - 5253. [Abstract] [Full Text] [PDF]
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T. Luft, M. Rizkalla, T. Y. Tai, Q. Chen, R. I. MacFarlan, I. D. Davis, E. Maraskovsky, and J. Cebon Exogenous Peptides Presented by Transporter Associated with Antigen Processing (TAP)-Deficient and TAP-Competent Cells: Intracellular Loading and Kinetics of Presentation J. Immunol., September 1, 2001; 167(5): 2529 - 2537. [Abstract] [Full Text] [PDF]
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B. R. Blazar, A. M. Krieg, and P. A. Taylor Synthetic unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides are potent stimulators of antileukemia responses in naive and bone marrow transplant recipients Blood, August 15, 2001; 98(4): 1217 - 1225. [Abstract] [Full Text] [PDF]
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C. W. Cutler, R. Jotwani, and B. Pulendran Dendritic Cells: Immune Saviors or Achilles' Heel? Infect. Immun., August 1, 2001; 69(8): 4703 - 4708. [Full Text] [PDF]
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A. Al-Mariri, A. Tibor, P. Mertens, X. De Bolle, P. Michel, J. Godefroid, K. Walravens, and J.-J. Letesson Protection of BALB/c Mice against Brucella abortus 544 Challenge by Vaccination with Bacterioferritin or P39 Recombinant Proteins with CpG Oligodeoxynucleotides as Adjuvant Infect. Immun., August 1, 2001; 69(8): 4816 - 4822. [Abstract] [Full Text] [PDF]
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H. Shirota, K. Sano, N. Hirasawa, T. Terui, K. Ohuchi, T. Hattori, K. Shirato, and G. Tamura Novel Roles of CpG Oligodeoxynucleotides as a Leader for the Sampling and Presentation of CpG-Tagged Antigen by Dendritic Cells J. Immunol., July 1, 2001; 167(1): 66 - 74. [Abstract] [Full Text] [PDF]
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N. Etchart, P.-O. Desmoulins, K. Chemin, C. Maliszewski, B. Dubois, F. Wild, and D. Kaiserlian Dendritic Cells Recruitment and In Vivo Priming of CD8+ CTL Induced by a Single Topical or Transepithelial Immunization Via the Buccal Mucosa with Measles Virus Nucleoprotein J. Immunol., July 1, 2001; 167(1): 384 - 391. [Abstract] [Full Text] [PDF]
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T. De Smedt, E. Butz, J. Smith, R. Maldonado-Lopez, B. Pajak, M. Moser, and C. Maliszewski CD8{alpha}- and CD8{alpha}+ subclasses of dendritic cells undergo phenotypic and functional maturation in vitro and in vivo J. Leukoc. Biol., June 1, 2001; 69(6): 951 - 958. [Abstract] [Full Text] [PDF]
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M. Bauer, V. Redecke, J. W. Ellwart, B. Scherer, J.-P. Kremer, H. Wagner, and G. B. Lipford Bacterial CpG-DNA Triggers Activation and Maturation of Human CD11c-, CD123+ Dendritic Cells J. Immunol., April 15, 2001; 166(8): 5000 - 5007. [Abstract] [Full Text] [PDF]
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S. Jilek, C. Barbey, F. Spertini, and B. Corthesy Antigen-Independent Suppression of the Allergic Immune Response to Bee Venom Phospholipase A2 by DNA Vaccination in CBA/J Mice J. Immunol., March 1, 2001; 166(5): 3612 - 3621. [Abstract] [Full Text] [PDF]
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F.-G. Zhu and J. S. Marshall CpG-containing oligodeoxynucleotides induce TNF-{alpha} and IL-6 production but not degranulation from murine bone marrow-derived mast cells J. Leukoc. Biol., February 1, 2001; 69(2): 253 - 262. [Abstract] [Full Text]
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P. Harle, S. Noisakran, and D. J. J. Carr The Application of a Plasmid DNA Encoding IFN-{{alpha}}1 Postinfection Enhances Cumulative Survival of Herpes Simplex Virus Type 2 Vaginally Infected Mice J. Immunol., February 1, 2001; 166(3): 1803 - 1812. [Abstract] [Full Text] [PDF]
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D. Askew, R. S. Chu, A. M. Krieg, and C. V. Harding CpG DNA Induces Maturation of Dendritic Cells with Distinct Effects on Nascent and Recycling MHC-II Antigen-Processing Mechanisms J. Immunol., December 15, 2000; 165(12): 6889 - 6895. [Abstract] [Full Text] [PDF]
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D. J. Shedlock and D. B. Weiner DNA vaccination: antigen presentation and the induction of immunity J. Leukoc. Biol., December 1, 2000; 68(6): 793 - 806. [Abstract] [Full Text]
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T. L. Warren, S. K. Bhatia, A. M. Acosta, C. E. Dahle, T. L. Ratliff, A. M. Krieg, and G. J. Weiner APC Stimulated by CpG Oligodeoxynucleotide Enhance Activation of MHC Class I-Restricted T Cells J. Immunol., December 1, 2000; 165(11): 6244 - 6251. [Abstract] [Full Text] [PDF]
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C. Brunner, J. Seiderer, A. Schlamp, M. Bidlingmaier, A. Eigler, W. Haimerl, H.-A. Lehr, A. M. Krieg, G. Hartmann, and S. Endres Enhanced Dendritic Cell Maturation by TNF-{alpha} or Cytidine-Phosphate-Guanosine DNA Drives T Cell Activation In Vitro and Therapeutic Anti-Tumor Immune Responses In Vivo J. Immunol., December 1, 2000; 165(11): 6278 - 6286. [Abstract] [Full Text] [PDF]
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F. Meyer, K. T. Wilson, and S. P. James Modulation of Innate Cytokine Responses by Products of Helicobacter pylori Infect. Immun., November 1, 2000; 68(11): 6265 - 6272. [Abstract] [Full Text] [PDF]
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G. J. Weiner The immunobiology and clinical potential of immunostimulatory CpG oligodeoxynucleotides J. Leukoc. Biol., October 1, 2000; 68(4): 455 - 463. [Abstract] [Full Text]
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S. W. Lee, M. K. Song, K. H. Baek, Y. Park, J. K. Kim, C. H. Lee, H.-K. Cheong, C. Cheong, and Y. C. Sung Effects of a Hexameric Deoxyriboguanosine Run Conjugation into CpG Oligodeoxynucleotides on Their Immunostimulatory Potentials J. Immunol., October 1, 2000; 165(7): 3631 - 3639. [Abstract] [Full Text] [PDF]
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J. J. DONNELLY, M. A. LIU, and J. B. ULMER Antigen Presentation and DNA Vaccines Am. J. Respir. Crit. Care Med., October 1, 2000; 162(4): S190 - 193. [Abstract] [Full Text] [PDF]
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W. Olszewska, C. D. Partidos, and M. W. Steward Antipeptide Antibody Responses following Intranasal Immunization: Effectiveness of Mucosal Adjuvants Infect. Immun., September 1, 2000; 68(9): 4923 - 4929. [Abstract] [Full Text] [PDF]
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G. B. Lipford, T. Sparwasser, S. Zimmermann, K. Heeg, and H. Wagner CpG-DNA-Mediated Transient Lymphadenopathy Is Associated with a State of Th1 Predisposition to Antigen-Driven Responses J. Immunol., August 1, 2000; 165(3): 1228 - 1235. [Abstract] [Full Text] [PDF]
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A. Kolb-Maurer, I. Gentschev, H.-W. Fries, F. Fiedler, E.-B. Brocker, E. Kampgen, and W. Goebel Listeria monocytogenes-Infected Human Dendritic Cells: Uptake and Host Cell Response Infect. Immun., June 1, 2000; 68(6): 3680 - 3688. [Abstract] [Full Text] [PDF]
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E. Ban, L. Dupre, E. Hermann, W. Rohn, C. Vendeville, B. Quatannens, P. Ricciardi-Castagnoli, A. Capron, and G. Riveau CpG motifs induce Langerhans cell migration in vivo Int. Immunol., June 1, 2000; 12(6): 737 - 745. [Abstract] [Full Text] [PDF]
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 J. S. Waters, A. Webb, D. Cunningham, P. A. Clarke, F. Raynaud, F. di Stefano, and F. E. Cotter Phase I Clinical and Pharmacokinetic Study of Bcl-2 Antisense Oligonucleotide Therapy in Patients With Non-Hodgkin's Lymphoma J. Clin. Oncol., May 9, 2000; 18(9): 1812 - 1823. [Abstract] [Full Text] [PDF]
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R. S. Chu, T. McCool, N. S. Greenspan, J. R. Schreiber, and C. V. Harding CpG Oligodeoxynucleotides Act as Adjuvants for Pneumococcal Polysaccharide-Protein Conjugate Vaccines and Enhance Antipolysaccharide Immunoglobulin G2a (IgG2a) and IgG3 Antibodies Infect. Immun., March 1, 2000; 68(3): 1450 - 1456. [Abstract] [Full Text] [PDF]
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R. M. Vabulas, H. Pircher, G. B. Lipford, H. Hacker, and H. Wagner CpG-DNA Activates In Vivo T Cell Epitope Presenting Dendritic Cells to Trigger Protective Antiviral Cytotoxic T Cell Responses J. Immunol., March 1, 2000; 164(5): 2372 - 2378. [Abstract] [Full Text] [PDF]
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 H. Shirota, K. Sano, T. Kikuchi, G. Tamura, and K. Shirato Regulation of T-helper Type 2 Cell and Airway Eosinophilia by Transmucosal Coadministration of Antigen and Oligodeoxynucleotides Containing CpG Motifs Am. J. Respir. Cell Mol. Biol., February 1, 2000; 22(2): 176 - 182. [Abstract] [Full Text]
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G. Hartmann, R. D. Weeratna, Z. K. Ballas, P. Payette, S. Blackwell, I. Suparto, W. L. Rasmussen, M. Waldschmidt, D. Sajuthi, R. H. Purcell, et al. Delineation of a CpG Phosphorothioate Oligodeoxynucleotide for Activating Primate Immune Responses In Vitro and In Vivo J. Immunol., February 1, 2000; 164(3): 1617 - 1624. [Abstract] [Full Text] [PDF]
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G. Hartmann and A. M. Krieg Mechanism and Function of a Newly Identified CpG DNA Motif in Human Primary B Cells J. Immunol., January 15, 2000; 164(2): 944 - 953. [Abstract] [Full Text] [PDF]
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M. G. Chiaramonte, M. Hesse, A. W. Cheever, and T. A. Wynn CpG Oligonucleotides Can Prophylactically Immunize Against Th2-Mediated Schistosome Egg-Induced Pathology by an IL-12-Independent Mechanism J. Immunol., January 15, 2000; 164(2): 973 - 985. [Abstract] [Full Text] [PDF]
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D. P. Sester, S. J. Beasley, M. J. Sweet, L. F. Fowles, S. L. Cronau, K. J. Stacey, and D. A. Hume Bacterial/CpG DNA Down-Modulates Colony Stimulating Factor-1 Receptor Surface Expression on Murine Bone Marrow-Derived Macrophages with Concomitant Growth Arrest and Factor-Independent Survival J. Immunol., December 15, 1999; 163(12): 6541 - 6550. [Abstract] [Full Text] [PDF]
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