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Baylor Institute for Immunology Research, Dallas, TX 75204; and
Immunex Corporation, Seattle, WA 98101
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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, in response to influenza virus. CD11c+ and
CD11c- cells can mature in vitro with GM-CSF + TNF- or
with IL-3 + CD40 ligand, respectively. These two subsets up-regulate
MHC class II costimulatory molecules as well as the DC maturation
marker DC-lysosome-associated membrane protein, and they stimulate
naive, allogeneic CD4+ T cells efficiently. These two DC
subsets elicit distinct cytokine profiles in CD4+ T cells,
with the CD11c- subset inducing higher levels of the Th2
cytokine IL-10. The differential mobilization of distinct DC subsets or
DC precursors by in vivo administration of FL and G-CSF offers a novel
strategy to manipulate immune responses in humans. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Although it is known that DCs are critical in initiating T cell immunity, emerging evidence suggests that DCs also play roles in the regulation of such responses. For example, distinct DC subsets can differentially regulate the Th1/Th2 balance in vivo (3, 4) and in vitro (5). Much information about DCs has accrued from the study of DCs grown in vitro under the influence of cytokines such as GM-CSF (6, 7, 8, 9). However the study of DCs in vivo has been difficult because of their rarity in the blood and in other tissues. In mice, the identification of cytokines such as Flt3-ligand (FL) that mobilize DCs in vivo has offered an attractive means of expanding various DC subsets in vivo (3, 10, 11, 12). FL has been shown to expand distinct DC subsets in mice and to greatly augment Ag-specific T and B cell responses against soluble Ags and tumors (3, 13, 14).
In humans, cytokines such as GM-CSF and FL play crucial roles in the expansion and maturation of DCs in vitro. Therefore, investigating the effects of such cytokines on DC function in vivo is of paramount importance, especially from a clinical perspective. In particular, it is essential to determine whether distinct cytokines might elicit the expansion of functionally different DC subsets in humans, as is seen in mice (3). If indeed they do, this may open up new possibilities for immunomodulation and may offer more mechanistic and rational approaches to the use of such cytokines in enhancing anti-infectious or antitumor immunity. In this context, the immunomodulatory effects of cytokines such as GM-CSF and G-CSF are well-known. For example, GM-CSF has been used as an effective vaccine adjuvant for protein- and peptide-based vaccines (15, 16). G-CSF, despite mobilizing large numbers of mononuclear cells, does not increase the severity of acute graft-versus-host disease after allogeneic bone marrow transplantion compared with historical control bone marrow grafts (17, 18, 19). In addition, G-CSF suppresses T cell proliferation (20, 21, 22) and the generation of cytolytic effectors (22). However, the immunological mechanisms underlying such potent effects are unknown. Because DCs play vital roles in the regulation of immune responses (1, 2, 3, 4, 5), it is possible that these cytokines may act through the generation of functionally distinct DC populations in vivo. To this end, we are investigating the effects of cytokines on in vivo DC mobilization in healthy volunteers.
We report in this paper that FL and G-CSF dramatically enhance the numbers of distinct DC subsets in the peripheral blood of healthy human volunteers. In particular, FL expands two subsets of precursor or immature DCs that circulate in human blood and that can be identified by the differential expression of CD11c, the immature CD11c+ DC subset, and the precursor CD11c- DC subset (1, 5, 23, 24, 25, 26, 27, 28). In contrast, G-CSF results in a preferential expansion of the CD11c- subset.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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In this clinical study, a total of 12 healthy volunteers received either FL (Immunex, Seattle, WA) s.c. at 10 µg/kg/day for 10 days (six volunteers; institutional review board no. 098-024) or G-CSF s.c. at 10 µg/kg/day for 5 days (six volunteers; institutional review board no. 097-053). The volunteers had HLA-A2 phenotype and normal blood counts and chemistries, and they were >21 years of age. Informed written consent was obtained from each of the volunteers. FL-treated volunteers underwent apheresis at baseline and after 10 days of FL administration to collect large numbers of cells for immunological studies. G-CSF-treated volunteers underwent apheresis after 5 days of G-CSF administration (i.e., at day 6). Both FL and G-CSF were well-tolerated by the volunteers.
Abs and reagents
Purified mAbs used in this study were: CD11b, CD11c, CD14, CD2,
CD5, CD8, CD80, CD69, CD16, CD123, HLA-DR (BD-PharMingen, San Diego);
CD13, CD33, CD86, CD95, CD116, CD55, CD59 (PharMingen, San Diego, CA);
CD4, CD1a, CD83, CD40, CD40 ligand (CD40L), CD54, CD135, CD12
(Coulter/Immunotech, Palo Alto, CA); and CD32 (Caltag, South San
Francisco, CA). Recombinant human cytokines used in this study were:
rhGM-CSF (Immunex; final concentration of 100 ng/ml); TNF-
(Boehringer Ingelheim, Ridgefield, CT; final concentration of 10
ng/ml); IL-3 (Immunex; final concentration of 10 ng/ml); and CD40L
(Immunex; final concentration of 200 ng/ml). RPMI complete (RPMIc)
medium consisted of RPMI 1640, 1% L-glutamine, 1%
penicillin/streptomycin, 50 mM 2-ME, 1% sodium pyruvate, 1% essential
amino acids, and heat-inactivated 10% FCS (all from Life Technologies,
Grand Island, NY).
Flow cytometric identification and purification of CD11c+ and CD11c- DCs
CD11c+ and CD11c- blood DCs were isolated from mononuclear fraction according to the study protocol. The mononuclear cell fractions from the apheresed samples were run over a CD34 column (Cell Pro, Seattle, WA) to deplete CD34+ cells. Briefly, DC precursors were enriched from mononuclear cells by magnetic bead depletion (goat anti-mouse IgG Dynabeads from Dynal, Lake Success, NY) after incubation with a cocktail of mAbs to lineage markers including CD3, CD14, CD16, CD19, CD56, and glycophorin A (Coulter, Palo Alto, CA). The recovery after depletion ranged from 6 to 19% at day 0 and from 11 to 46% after FL treatment (day 10). The recovered DC fraction was labeled using FITC-lineage cocktail, APC-CD11c, peridinin chlorophyl protein-HLA-DR, and PE-CD123 and was sorted as LINneg, HLA-DR+CD11c+ and HLA-DR+CD11c-CD123+ populations. Sorting was accomplished on a FACSVantage flow cytometer (Becton Dickinson) equipped with an Enterprise II laser (Coherent Radiatin, Palo Alto, CA).
Cell culture of sorted CD11c+ and CD11c- populations
Sorted CD11c+ and
CD11c- cells were cultured at 1 x
106 cells/ml in RPMIc + 5% FBS and were cultured
in the presence of GM-CSF + TNF- or IL-3 + CD40L, respectively, for
5 days.
T cell proliferation and cytokine assay
Freshly isolated CD11c+ and CD11c- cells, or in vitro-matured DCs, were cultured with freshly isolated CD4+, CD45RA+ allogeneic T cells from cord blood or from adult blood. Allogeneic T cells were purified by anti-CD8/CD16/CD19/CD56/CD14/HLA-DR/CD45RO-based immunomagnetic depletion of PBMCs from adult blood or cord blood. DC T cell cultures were set up for 5 days in RPMIc + 5% FBS. Cells were pulsed for the last 10 h with 1.0 µCi [3H]thymidine per well, and incorporation of the radionucleotide was measured by ß-scintillation spectroscopy. For cytokine analysis, supernatants were harvested 5 days after culture, and the cells were restimulated with PHA in fresh medium for 24 h. Cytokines released were assayed by ELISA kits from R&D Systems (Minneapolis, MN).
Confocal microscopy
Intracellular immunofluorescence staining was performed as previously described for suspension cells (29). Briefly, the cells were allowed to adhere on polylysin-coated coverslips for 1 h at room temperature, fixed for 15 min with 4% paraformaldehyde in PBS, permeabilized and labeled with anti-DC-lysosome-associated membrane protein (LAMP) (generous gift from Dr. S. Lebecque, Schering-Plough, Dardilly, France), revealed with donkey anti-mouse Abs coupled to Texas Red (Jackson Laboratories, West Grove, PA), and/or labeled with anti-HLA-DR, anti-CD1a coupled to FITC (Becton Dickinson). Coverslips were mounted onto glass slides with Fluoromount (Southern Biotechnology Associates, Birmingham, AL). Confocal microscopy was performed using a TCS SP microscope equipped with argon and krypton ion lasers and a x100 1.4 NA PLAPO objective (Leica Microsystem, Heidelberg, Germany).
IFN- assay
Freshly sorted CD11c+,
CD11c-, and
CD14+CD11c+ cells
(monocytes) were cultured in RPMIc + 5% FCS at 2 x
105 cells/ml with various doses of influenza
virus for 24 h. Supernatants were harvested and assayed for
IFN- using an ELISA assay kit from BioSource (Camarillo,
CA).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Six healthy adult volunteers were injected with FL s.c. at 10
µg/kg/day for 10 days. Previous studies in mice (10, 11)
and recent work in humans (26) suggest that optimal DC
expansion is seen after 10 days of FL injections. The volunteers were
apheresed at days 0 and 10 to collect mononuclear cells. The
mononuclear fractions from FL-treated volunteers were analyzed by flow
cytometry to assess the frequencies and absolute numbers of various
APCs in the blood. The mobilization of the CD11c+
and CD11c- populations at day 10 was evaluated.
The CD11c+ and CD11c-
subsets were defined by lack of lineage marker expression
(CD3-CD14-CD16-CD19-CD56-),
expression of HLA-DR, and differential expression of CD11c and CD123
(Fig. 1
). In absolute numbers per
milliliter of blood, the CD11c+ cells are
increased 48-fold, from 36,354 ± 6333 per ml (n =
5; range, 23,520–57,850) to 1,759,423 ± 547,215 per ml
(n = 5; range, 867,970–3,489,600) (Fig. 2A). In contrast, the number
of CD11c- DCs are increased 13-fold, from
28,880 ± 11,764 per ml (n = 5; range,
12,200–49,400) to 387,300 ± 93,112 per ml (n =
5; range, 232,100–681,600) (Fig. 2B). Thus, the numeric
ratio of CD11c+/CD11c- DCs
is considerably increased in FL-treated donors compared with baseline
controls (Fig. 2C).
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G-CSF treatment preferentially expands the CD11c- pre-DC subset in peripheral blood
Five healthy adult volunteers were treated with G-CSF s.c. at 10
µg/kg/day for 5 days and were apheresed at day 6. The mononuclear
cell fractions from these volunteers were analyzed by flow cytometry
after lineage depletion in the same manner as FL samples were. G-CSF
preferentially increases the CD11c- pre-DC
population (Figs. 1
and 2). This increase is reflected in an increase
in the absolute numbers of CD11c- pre-DCs (Fig. 2B) from 36,354 per ml at day 0 to 205,786 ± 67,876
per ml (n = 5; range, 44,928–500,610) at day 5.
In contrast, the CD11c+ DCs are unchanged in
their absolute numbers. Thus G-CSF, in contrast to FL, preferentially
mobilizes the CD11c- pre-DC subset (Fig. 2, B and C).
The morphology of CD11c+ and CD11c- cells from G-CSF-treated volunteers was similar to the equivalent cells from FL-treated individuals. The CD11c+ DCs had multilobulated nuclei and possessed very few dendrites, whereas the CD11c- pre-DCs had large eccentric nuclei with a granular cytoplasm (data not shown).
CD11c+ and CD11c- cells from FL- and G-CSF-treated donors are similar to the corresponding cells in nontreated donors
An extensive phenotypic analysis of the
CD11c+ and CD11c- subsets
from FL and G-CSF volunteers was performed. DC-enriched fractions from
FL- or G-CSF-treated donors were stained with a series of Abs (Table I). The CD11c+ and
the CD11c- subsets expanded by FL treatment were
very similar to the corresponding subsets in G-CSF-treated volunteers.
CD11c- subsets from both FL and G-CSF donors
expressed high levels of IL-3R (CD123; Table I), confirming the
identity of this subset as the plasmacytoid T cell-related DC
precursors reported earlier (23). As previously
described (23, 24, 25), the CD11c+ and
CD11c- subsets differed phenotypically with
respect to several markers. The CD11c- pre-DC
subset expresses low levels of the myeloid markers CD11b, CD13, and
CD33. CD2, CD5, and CD4, which are expressed on T cells, are also
expressed by this subset. Cells in this subset do not express CD80 and
express low levels of CD40 and negligible levels of CD86. Overall,
based on their morphology and on the low expression of costimulatory
molecules, the CD11c- cells do not appear to be
mature DCs.
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Allostimulatory capacities of freshly isolated CD11c+ and CD11c- cells
CD11c+ and CD11c-
cells from FL donors were sorted and assessed for their capacity to
stimulate naive CD4+ T cells in an allogeneic MLR
reaction. The CD11c+ cells could efficiently
stimulate naive CD4+ T cells, but the
CD11c- cells were unable to stimulate naive
CD4+ T cells (Fig. 3). Based on their higher allostimulatory
capacity and on their higher level of expression of surface HLA-DR, the
CD11c+ cells appear to be more mature than the
CD11c- cells. Therefore, the
CD11c+ cells display some characteristics of
immature DCs, whereas the CD11c- subset likely
represents precursors of DCs. However, it is important to stress that
the CD11c+ population has the potential to
develop into several different types of APCs under the appropriate
stimuli. For example, the CD11c+ population can
be induced to differentiate into macrophages by M-CSF (27)
(K. Palucka, B. Pulendran, A. Rolland, N. Taquet, E. Neidhart-Berard,
P. Blanco, S. Burkeholder, E. Kraus, J. Daroust, C. Chalouui, J. Fay,
C. Maliszewski, and J. Baucherean, manuscript in preparation), into
Langerhans cells by TGF-ß (28) (K. Palucka et al.,
manuscript in preparation), or into myeloid DCs by GM-CSF + TNF-
(24, 25, 27). This suggests that the
CD11c+ population contains precursor cells that
can develop into the various types of mature cells under different
stimuli. Whether these various mature cell types develop from the very
same precursor cells or from distinct cells is presently under
investigation (K. Palucka et al., manuscript in preparation).
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production by freshly isolated CD11c+ and
CD11c- cells
Two recent reports suggest that CD11c-
pre-DCs, freshly isolated (24) or cultured in vitro for 2
days with IL-3 (31), secrete large amounts of IFN- in
response to viruses. In this study, we wished to determine whether
CD11c+ and CD11c-
mobilized in vivo by cytokines would behave similarly.
CD11c+ and CD11c- cells
were sorted by flow cytomtery and cultured in vitro with various doses
of influenza virus for 24 h. Sorted
CD14+CD11c+ monocytes were
also cultured with influenza virus as a control. As shown in Fig. 4, the CD11c-
cells secrete much higher levels of IFN- than
CD14+CD11c+ monocytes do.
The CD11c+ cells did not secrete IFN- at any
of the doses tested. The reduction in IFN- levels observed at 1000
U/ml may reflect the lysis of cells by excessive infection. These data
are consistent with previous reports that CD11c-
cells secrete IFN- in response to viruses.
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We wished to determine whether the DC subsets mobilized by
FL and G-CSF treatment could be induced to undergo maturation in vitro.
Previous reports have demonstrated that CD11c+
and CD11c- DCs can be matured in vitro with GM +
TNF- and IL-3 + CD40L, respectively (5, 24, 25). In
this study, we sorted the CD11c+ and
CD11c- DC subsets from FL and G-CSF donors and
cultured them in vitro with the respective cytokines. After 5 days, we
assessed the phenotype, morphology, and allostimulatory capacity of the
mature DCs. CD11c+ DCs cultured in vitro with GM
+ TNF- up-regulated HLA-DR (Fig. 5),
CD86, and CD40, but down-regulated CD1a (data not shown), suggesting
maturation. Confocal microscopy of the cultured
CD11c+ DCs revealed a classical DC morphology,
with many dendrites, abundant veils, and bright HLA-DR surface
staining, suggesting translocation of HLA-DR from the internal
compartments revealed in freshly isolated cells (Fig. 5).
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and
data not shown). Confocal staining of these cells revealed numerous
dendrites and up-regulation of surface HLA-DR (Fig. 5).
Thus, IL-3 + CD40L appears to induce a maturation of the
CD11c- DCs. DC-LAMP, which is specifically
induced in maturing DCs derived from monocytes and cord blood
(29), was also up-regulated on the
CD11c+ and the CD11c-
subsets after in vitro maturation (Fig. 6). Expression of DC-LAMP was confined to
intracellular compartments, which is consistent with its localization
in lysosomes (29).
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A). The
CD11c- precursors from both FL and G-CSF donors
gave the same yield of DCs when cultured in vitro. These
CD11c- DCs from both FL- and G-CSF-treated
individuals appear to be very similar with respect to their
allostimulatory capacities.
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It has been reported that CD11c+ and CD11c- DCs differ in the cytokine profiles they induce in T cells. One recent report suggests that monocyte-derived DCs elicit a polarized Th1 response, whereas CD11c- DCs elicit a Th2 response (5). A second report examined CD11c+ and CD11c- DCs from the peripheral blood for Th1/Th2 skewing but failed to detect strongly polarized Th1 and Th2 responses (24). The discrepancy between these studies may reflect the fact that monocyte-derived DCs were used in the study by Rissoan et al. (5), whereas DCs derived from CD11c+ cells were used in the later study (24). Alternatively, the discrepancy could be because of differences in the maturation stages of the CD11c+ DCs used or because of differences in the cytokines used to mature them in vitro.
Therefore, we assessed whether the CD11c+ and
CD11c- DCs mobilized by FL could differentially
skew cytokine production in T cells. CD11c+ and
CD11c- cells were sorted and cultured for 5 days
with GM-CSF + TNF- and with IL-3 + CD40L, respectively. Then the
CD11c+ and CD11c- DCs were
cultured with CD45RA+ naive allogeneic
CD4+ T cells isolated from either adult blood or
cord blood. After 5 days of culture, the cells were restimulated with
PHA overnight, and the secondary supernatants were harvested and
assayed for cytokines. As shown in Fig. 5, both
CD11c+ and CD11c- DCs
could induce the production of IFN-
, IL-4, and IL-10. However, the
CD11c- DCs consistently elicited greater levels
of IL-10 than the CD11c+ DCs (Fig. 7b). In
addition, the levels of IFN- induced by the
CD11c+ DCs were significantly higher than those
induced by the CD11c- DCs. Thus, the
CD11c+ and CD11c- DC
subsets appear to elicit distinct Th cytokine profiles, although the
CD11c+ DCs do not induce a strong Th1 response,
as observed with monocyte-derived DCs (5).
It is conceivable that the induction of IL-10 production by the CD11c- DCs exerts a regulatory effect on T cell proliferation, ultimately resulting in T cell anergy (30). In G-CSF-treated donors, where this CD11c- subset is preferentially expanded, this may result in a dampening of T cell responses. This is consistent with the well-known anti-inflammatory effects of G-CSF in suppressing T cell proliferation in vitro (17, 18, 19, 20, 21, 22). This is also consistent with data from murine allogeneic transplantation models, which suggest that G-CSF treatment may also have direct effects on donor T cell function by polarizing toward a Th2-cytokine phenotype (17).
In summary, our data demonstrate that FL and G-CSF are potent mobilization factors of distinct DC subsets in vivo. FL mobilizes both the CD11c+ and the CD11c- DC subsets, whereas G-CSF preferentially mobilizes the latter. The effects of G-CSF on mobilizing the CD11c- subset are consistent with a recent report (32). These two DC subsets elicit distinct profiles of cytokines in T cells. In mice, cytokines such as FL and GM-CSF can act as potent adjuvants that differentially skew the Th1/Th2 balance in vivo (3). It is now important to consider whether such cytokines can also enhance T and B cell responses in humans. In particular, it is of great importance to investigate whether FL and G-CSF can elicit distinct types of immune responses in healthy humans.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Bali Pulendran, Baylor Institute for Immunology Research, 3434 Live Oak, Dallas, TX 75204.
3 Abbreviations used in this paper: DC, dendritic cell; FL, Flt3-ligand; CD40L, CD40 ligand; LAMP, lysosome-associated membrane protein.
Received for publication December 28, 1999. Accepted for publication April 17, 2000.
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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 M. Stasiolek, A. Bayas, N. Kruse, A. Wieczarkowiecz, K. V. Toyka, R. Gold, and K. Selmaj Impaired maturation and altered regulatory function of plasmacytoid dendritic cells in multiple sclerosis Brain, May 1, 2006; 129(5): 1293 - 1305. [Abstract] [Full Text] [PDF]
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 J.A. Levy HIV Pathogenesis: Knowledge Gained after Two Decades of Research Advances in Dental Research, April 1, 2006; 19(1): 10 - 16. [Abstract] [Full Text] [PDF]
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S. Rutella, F. Zavala, S. Danese, H. Kared, and G. Leone Granulocyte Colony-Stimulating Factor: A Novel Mediator of T Cell Tolerance J. Immunol., December 1, 2005; 175(11): 7085 - 7091. [Abstract] [Full Text] [PDF]
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R. Tussiwand, N. Onai, L. Mazzucchelli, and M. G. Manz Inhibition of Natural Type I IFN-Producing and Dendritic Cell Development by a Small Molecule Receptor Tyrosine Kinase Inhibitor with Flt3 Affinity J. Immunol., September 15, 2005; 175(6): 3674 - 3680. [Abstract] [Full Text] [PDF]
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M. Rossi and J. W. Young Human Dendritic Cells: Potent Antigen-Presenting Cells at the Crossroads of Innate and Adaptive Immunity J. Immunol., August 1, 2005; 175(3): 1373 - 1381. [Abstract] [Full Text] [PDF]
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M. Wysocka, L. J. Montaner, and C. L. Karp Flt3 Ligand Treatment Reverses Endotoxin Tolerance-Related Immunoparalysis J. Immunol., June 1, 2005; 174(11): 7398 - 7402. [Abstract] [Full Text] [PDF]
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H. Gur, R. Krauthgamer, E. Bachar-Lustig, H. Katchman, R. Arbel-Goren, A. Berrebi, T. Klein, A. Nagler, A. Tabilio, M. F. Martelli, et al. Immune regulatory activity of CD34+ progenitor cells: evidence for a deletion-based mechanism mediated by TNF-{alpha} Blood, March 15, 2005; 105(6): 2585 - 2593. [Abstract] [Full Text] [PDF]
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A. Rolland, L. Guyon, M. Gill, Y.-H. Cai, J. Banchereau, K. McClain, and A. K. Palucka Increased Blood Myeloid Dendritic Cells and Dendritic Cell-Poietins in Langerhans Cell Histiocytosis J. Immunol., March 1, 2005; 174(5): 3067 - 3071. [Abstract] [Full Text] [PDF]
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K. McKenna, A.-S. Beignon, and N. Bhardwaj Plasmacytoid Dendritic Cells: Linking Innate and Adaptive Immunity J. Virol., January 1, 2005; 79(1): 17 - 27. [Full Text] [PDF]
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 H. Kared, A. Masson, H. Adle-Biassette, J.-F. Bach, L. Chatenoud, and F. Zavala Treatment With Granulocyte Colony-Stimulating Factor Prevents Diabetes in NOD Mice by Recruiting Plasmacytoid Dendritic Cells and Functional CD4+CD25+ Regulatory T-Cells Diabetes, January 1, 2005; 54(1): 78 - 84. [Abstract] [Full Text] [PDF]
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K. A. Swanson, Y. Zheng, K. M. Heidler, Z.-D. Zhang, T. J. Webb, and D. S. Wilkes Flt3-Ligand, IL-4, GM-CSF, and Adherence-Mediated Isolation of Murine Lung Dendritic Cells: Assessment of Isolation Technique on Phenotype and Function J. Immunol., October 15, 2004; 173(8): 4875 - 4881. [Abstract] [Full Text] [PDF]
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M. Mohty, E. Jourdan, N. B. Mami, N. Vey, G. Damaj, D. Blaise, D. Isnardon, D. Olive, and B. Gaugler Imatinib and plasmacytoid dendritic cell function in patients with chronic myeloid leukemia Blood, June 15, 2004; 103(12): 4666 - 4668. [Abstract] [Full Text] [PDF]
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N. Teleshova, J. Jones, J. Kenney, J. Purcell, R. Bohm, A. Gettie, and M. Pope Short-term Flt3L treatment effectively mobilizes functional macaque dendritic cells J. Leukoc. Biol., June 1, 2004; 75(6): 1102 - 1110. [Abstract] [Full Text] [PDF]
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E. Chklovskaia, P. Nowbakht, C. Nissen, A. Gratwohl, M. Bargetzi, and A. Wodnar-Filipowicz Reconstitution of dendritic and natural killer-cell subsets after allogeneic stem cell transplantation: effects of endogenous flt3 ligand Blood, May 15, 2004; 103(10): 3860 - 3868. [Abstract] [Full Text] [PDF]
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J. H. Edwan, G. Perry, J. E. Talmadge, and D. K. Agrawal Flt-3 Ligand Reverses Late Allergic Response and Airway Hyper-Responsiveness in a Mouse Model of Allergic Inflammation J. Immunol., April 15, 2004; 172(8): 5016 - 5023. [Abstract] [Full Text] [PDF]
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W. Chen, S. Antonenko, J. M. Sederstrom, X. Liang, A. S. H. Chan, H. Kanzler, B. Blom, B. R. Blazar, and Y.-J. Liu Thrombopoietin cooperates with FLT3-ligand in the generation of plasmacytoid dendritic cell precursors from human hematopoietic progenitors Blood, April 1, 2004; 103(7): 2547 - 2553. [Abstract] [Full Text] [PDF]
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 R. S. Freedman, S. Vadhan-Raj, C. Butts, C. Savary, B. Melichar, C. Verschraegen, J. J. Kavanagh, M. E. Hicks, L. B. Levy, J. K. Folloder, et al. Pilot Study of Flt3 Ligand Comparing Intraperitoneal with Subcutaneous Routes on Hematologic and Immunologic Responses in Patients with Peritoneal Carcinomatosis and Mesotheliomas Clin. Cancer Res., November 1, 2003; 9(14): 5228 - 5237. [Abstract] [Full Text] [PDF]
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A. K. Palucka, J. Gatlin, J. P. Blanck, M. W. Melkus, S. Clayton, H. Ueno, E. T. Kraus, P. Cravens, L. Bennett, A. Padgett-Thomas, et al. Human dendritic cell subsets in NOD/SCID mice engrafted with CD34+ hematopoietic progenitors Blood, November 1, 2003; 102(9): 3302 - 3310. [Abstract] [Full Text] [PDF]
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P. T. H. Coates, S. M. Barratt-Boyes, L. Zhang, V. S. Donnenberg, P. J. O'Connell, A. J. Logar, F. J. Duncan, M. Murphey-Corb, A. D. Donnenberg, A. E. Morelli, et al. Dendritic cell subsets in blood and lymphoid tissue of rhesus monkeys and their mobilization with Flt3 ligand Blood, October 1, 2003; 102(7): 2513 - 2521. [Abstract] [Full Text] [PDF]
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M. Jefford, M. Schnurr, T. Toy, K.-A. Masterman, A. Shin, T. Beecroft, T. Y. Tai, K. Shortman, M. Shackleton, I. D. Davis, et al. Functional comparison of DCs generated in vivo with Flt3 ligand or in vitro from blood monocytes: differential regulation of function by specific classes of physiologic stimuli Blood, September 1, 2003; 102(5): 1753 - 1763. [Abstract] [Full Text] [PDF]
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M. Dauer, B. Obermaier, J. Herten, C. Haerle, K. Pohl, S. Rothenfusser, M. Schnurr, S. Endres, and A. Eigler Mature Dendritic Cells Derived from Human Monocytes Within 48 Hours: A Novel Strategy for Dendritic Cell Differentiation from Blood Precursors J. Immunol., April 15, 2003; 170(8): 4069 - 4076. [Abstract] [Full Text] [PDF]
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V. Pullarkat, P. P. Lee, R. Scotland, V. Rubio, S. Groshen, C. Gee, R. Lau, J. Snively, S. Sian, S. L. Woulfe, et al. A Phase I Trial of SD-9427 (Progenipoietin) with a Multipeptide Vaccine for Resected Metastatic Melanoma Clin. Cancer Res., April 1, 2003; 9(4): 1301 - 1312. [Abstract] [Full Text] [PDF]
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S. Vuckovic, M. Kim, D. Khalil, C. J. Turtle, G. V. Crosbie, N. Williams, L. Brown, K. Williams, C. Kelly, P. Stravos, et al. Granulocyte-colony stimulating factor increases CD123hi blood dendritic cells with altered CD62L and CCR7 expression Blood, March 15, 2003; 101(6): 2314 - 2317. [Abstract] [Full Text] [PDF]
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G. Sailaja, S. Husain, B. P. Nayak, and A. M. Jabbar Long-Term Maintenance of gp120-Specific Immune Responses by Genetic Vaccination with the HIV-1 Envelope Genes Linked to the Gene Encoding Flt-3 Ligand J. Immunol., March 1, 2003; 170(5): 2496 - 2507. [Abstract] [Full Text] [PDF]
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K. P. A. MacDonald, V. Rowe, C. Filippich, R. Thomas, A. D. Clouston, J. K. Welply, D. N. J. Hart, J. L. M. Ferrara, and G. R. Hill Donor pretreatment with progenipoietin-1 is superior to granulocyte colony-stimulating factor in preventing graft-versus-host disease after allogeneic stem cell transplantation Blood, March 1, 2003; 101(5): 2033 - 2042. [Abstract] [Full Text] [PDF]
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R.-N. E. Dogan, C. Vasu, M. J. Holterman, and B. S. Prabhakar Absence of IL-4, and Not Suppression of the Th2 Response, Prevents Development of Experimental Autoimmune Graves' Disease J. Immunol., February 15, 2003; 170(4): 2195 - 2204. [Abstract] [Full Text] [PDF]
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 Y. Sawa, Y. Horie, Y. Yamaoka, N. Ebata, T. Kim, and S. Yoshida Production of Colony-stimulating Factor in Human Dental Pulp Fibroblasts Journal of Dental Research, February 1, 2003; 82(2): 96 - 100. [Abstract] [Full Text] [PDF]
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I. D. Davis, M. Jefford, P. Parente, and J. Cebon Rational approaches to human cancer immunotherapy J. Leukoc. Biol., January 1, 2003; 73(1): 3 - 29. [Abstract] [Full Text] [PDF]
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P. Brawand, D. R. Fitzpatrick, B. W. Greenfield, K. Brasel, C. R. Maliszewski, and T. De Smedt Murine Plasmacytoid Pre-Dendritic Cells Generated from Flt3 Ligand-Supplemented Bone Marrow Cultures Are Immature APCs J. Immunol., December 15, 2002; 169(12): 6711 - 6719. [Abstract] [Full Text] [PDF]
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M. Wysocka, M. H. Zaki, L. E. French, J. Chehimi, M. Shapiro, S. E. Everetts, K. S. McGinnis, L. Montaner, and A. H. Rook Sezary syndrome patients demonstrate a defect in dendritic cell populations: effects of CD40 ligand and treatment with GM-CSF on dendritic cell numbers and the production of cytokines Blood, October 16, 2002; 100(9): 3287 - 3294. [Abstract] [Full Text] [PDF]
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 H. Matsuda, T. Suda, H. Hashizume, K. Yokomura, K. Asada, K. Suzuki, K. Chida, and H. Nakamura Alteration of Balance between Myeloid Dendritic Cells and Plasmacytoid Dendritic Cells in Peripheral Blood of Patients with Asthma Am. J. Respir. Crit. Care Med., October 15, 2002; 166(8): 1050 - 1054. [Abstract] [Full Text] [PDF]
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M. R. Comeau, A.-R. Van der Vuurst de Vries, C. R. Maliszewski, and L. Galibert CD123bright Plasmacytoid Predendritic Cells: Progenitors Undergoing Cell Fate Conversion? J. Immunol., July 1, 2002; 169(1): 75 - 83. [Abstract] [Full Text] [PDF]
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R. J. Steptoe, J. M. Ritchie, and L. C. Harrison Increased Generation of Dendritic Cells from Myeloid Progenitors in Autoimmune-Prone Nonobese Diabetic Mice J. Immunol., May 15, 2002; 168(10): 5032 - 5041. [Abstract] [Full Text] [PDF]
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M. O'Keeffe, H. Hochrein, D. Vremec, J. Pooley, R. Evans, S. Woulfe, and K. Shortman Effects of administration of progenipoietin 1, Flt-3 ligand, granulocyte colony-stimulating factor, and pegylated granulocyte-macrophage colony-stimulating factor on dendritic cell subsets in mice Blood, March 15, 2002; 99(6): 2122 - 2130. [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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 M. F. Lipscomb and B. J. Masten Dendritic Cells: Immune Regulators in Health and Disease Physiol Rev, January 1, 2002; 82(1): 97 - 130. [Abstract] [Full Text] [PDF]
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P. J. O'Connell, W. Li, Z. Wang, S. M. Specht, A. J. Logar, and A. W. Thomson Immature and Mature CD8{alpha}+ Dendritic Cells Prolong the Survival of Vascularized Heart Allografts J. Immunol., January 1, 2002; 168(1): 143 - 154. [Abstract] [Full Text] [PDF]
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M. Mohty, D. Jarrossay, M. Lafage-Pochitaloff, C. Zandotti, F. Briere, X.-N. de Lamballeri, D. Isnardon, D. Sainty, D. Olive, and B. Gaugler Circulating blood dendritic cells from myeloid leukemia patients display quantitative and cytogenetic abnormalities as well as functional impairment Blood, December 15, 2001; 98(13): 3750 - 3756. [Abstract] [Full Text] [PDF]
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M. Korbling and P. Anderlini Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter? Blood, November 15, 2001; 98(10): 2900 - 2908. [Abstract] [Full Text] [PDF]
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R. Jotwani, A. K. Palucka, M. Al-Quotub, M. Nouri-Shirazi, J. Kim, D. Bell, J. Banchereau, and C. W. Cutler Mature Dendritic Cells Infiltrate the T Cell-Rich Region of Oral Mucosa in Chronic Periodontitis: In Situ, In Vivo, and In Vitro Studies J. Immunol., October 15, 2001; 167(8): 4693 - 4700. [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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 G.B. Toews Cytokines and the lung Eur. Respir. J., July 2, 2001; 18(34_suppl): 3S - 17s. [Abstract] [Full Text] [PDF]
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T. J. Sellati, S. L. Waldrop, J. C. Salazar, P. R. Bergstresser, L. J. Picker, and J. D. Radolf The Cutaneous Response in Humans to Treponema pallidum Lipoprotein Analogues Involves Cellular Elements of Both Innate and Adaptive Immunity J. Immunol., March 15, 2001; 166(6): 4131 - 4140. [Abstract] [Full Text] [PDF]
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J. Banchereau, B. Pulendran, R. Steinman, and K. Palucka Will the Making of Plasmacytoid Dendritic Cells in Vitro Help Unravel Their Mysteries? J. Exp. Med., December 18, 2000; 192(12): f39 - f44. [Full Text] [PDF]
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B. Blom, S. Ho, S. Antonenko, and Y.-J. Liu Generation of Interferon {alpha}-Producing Predendritic Cell (Pre-Dc)2 from Human Cd34+ Hematopoietic Stem Cells J. Exp. Med., December 18, 2000; 192(12): 1785 - 1796. [Abstract] [Full Text] [PDF]
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 J. Baggers, G. Ratzinger, and J. W. Young Dendritic Cells as Immunologic Adjuvants for the Treatment of Cancer J. Clin. Oncol., December 1, 2000; 18(23): 3879 - 3882. [Full Text] [PDF]
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M. Gilliet, A. Boonstra, C. Paturel, S. Antonenko, X.-L. Xu, G. Trinchieri, A. O'Garra, and Y.-J. Liu The Development of Murine Plasmacytoid Dendritic Cell Precursors Is Differentially Regulated by FLT3-ligand and Granulocyte/Macrophage Colony-Stimulating Factor J. Exp. Med., April 1, 2002; 195(7): 953 - 958. [Abstract] [Full Text] [PDF]
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