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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Institut Fédératif de Recherche
Necker-Enfants Malades (Service d'Anatomie Pathologique EA 219, Unité Mixte de Recherche 8603 CNRS/Université Paris-V,
Service de Dermatologie, Unité d'Immunologie et
d'Hématologie Pédiatrique), Hôpital Necker-Enfants
Malades, Faculté Necker, Université Paris-V René
Descartes, Paris, France; and Schering-Plough Laboratory for
Immunological Research, Dardilly, France.
Langerhans cell histiocytosis (LCH) consists of lesions composed of
cells with a dendritic Langerhans cell (LC) phenotype. The clinical
course of LCH ranges from spontaneous resolution to a chronic and
sometimes lethal disease. We studied 25 patients with various clinical
forms of the disease. In bone and chronic lesions, LCH cells had
immature phenotype and function. They coexpressed LC antigens CD1a and
Langerin together with monocyte antigens CD68 and CD14. Class II
antigens were intracellular and LCH cells almost never expressed CD83
or CD86 or dendritic cell (DC)-Lamp, despite their CD40 expression.
Consistently, LCH cells sorted from bone lesions (eosinophilic
granuloma) poorly stimulated allogeneic T-cell proliferation in vitro.
Strikingly, however, in vitro treatment with CD40L induced the
expression of membrane class II and CD86 and strongly increased LCH
cell allostimulatory activity to a level similar to that of mature DCs.
Numerous interleukin-10-positive (IL-10+),
Langerin Langerhans cell histiocytosis (LCH) affects mainly
young children and features accumulation of CD1a+ Birbeck
granule+ cells within the epidermis and dermis, the bones,
and occasionally lymphoid organs, lungs, and digestive
tract.1-4 A frequent clinical feature is a skin eruption
in the first months or days after birth. It may spontaneously resolve
(Hashimoto-Pritzker syndrome) or be part of a widespread disease
(Letterer-Siwe syndrome).5-8 In the older child,
chronic/granulomatous forms are more frequent (eosinophilic
granuloma, Hand-Schuller-Christian disease).9 Eosinophilic
granuloma, found in 50% to 80% of all patients with LCH,9 consists of chronic lytic bone lesions that may be
unifocal or multifocal and may associate with the involvement of smooth tissue. It may be difficult, however, to distinguish between an active
and an inactive bone lesion without serial biopsies, which are not
performed in most cases for obvious ethical reasons. Treatment of
severe or chronic disease, relying on cytotoxic chemotherapy, continues
to be controversial and, in many cases, ineffectual. Although LCH has
been proposed to be a clonal disorder,10,11 its cause
remains unknown, despite an extensive search for evidence of consistent
cytogenetic abnormalities or gene rearrangements. Whether LCH is
reactive or neoplastic is even debated, and several features provide
seemingly contradictory evidence on this point (spontaneous resolution
of disease on the one hand and clonality of lesional LCH on the other).
Similarly, the pathogenesis of the disease is enigmatic, although the
altered expression of cytokines and cellular adhesion molecules,
important for migration and homing of the normal Langerhans cell (LC),
may play an important role.4,12-18 It has been suggested
that LCH cells may be in an arrested state of activation and/or
differentiation of LCs. Apparently, contrasting studies have reported
that LCH cells may be activated, based on phenotypic
data,17,19 whereas others have failed to detect alloantigen-presenting activity.20 Although no immune
defect has been identified in affected children, some T lymphocyte
phenotype abnormalities that suggest alterations in antigen-driven
activation processes have been reported.21
Recent progress in the field of dendritic cell (DC) biology has led us
to revisit the phenotype and function of LCH cells in an attempt to
better understand the pathophysiology of this disease and to explain
why an accumulation of antigen-presenting cells may develop in the
apparent absence of an efficient immune response. We first investigated
the differentiation stages of LCH cells in the distinct clinical forms
of the disease by combining phenotypic and functional studies. We
concluded that LCH cells are functionally immature DCs in the chronic
form of the disease. We then investigated whether immature LCH cells
may be induced to become mature DCs, and we found that CD40 triggering
induced their differentiation as efficiently as for normal DCs. To
investigate why LCH cells remain immature in vivo, we examined their
microenvironment. We found that non-Langerhans cells (macrophages)
within bone and chronic lesions produced interleukin-10 (IL-10) in
vivo. On the contrary, we have observed that LCH cells in isolated or
healing skin lesions have a more mature phenotype and that
IL-10-producing cells were absent from these lesions. The presence of
IL-10 may contribute to the immaturity of LCH cells in bone/chronic
lesions. The results of our study therefore indicate that LCH cells, in the bone/chronic form of the disease, are maintained immature in vivo,
most probably by extrinsic signals. These data shed some light on the
pathogenesis of LCH and may be useful for designing therapeutic
strategies in this disease.
Patients
Cells
LC-type dendritic cells were prepared as previously
described.22,23 Briefly, fresh CD14+ monocytes
were isolated from peripheral blood mononuclear cells (PBMCs) of
healthy volunteers obtained by the standard Ficoll-Hypaque method and
immediately separated by negative magnetic depletion by using
hapten-conjugated CD3, CD7, CD19, CD45RA, CD56, and anti-IgE antibodies
(MACS; Miltenyi Biotec) and a MACS according to the manufacturer's
instructions, routinely resulting in more than 95% purity of the
CD14+ cells. Cells were cultured in flasks or in 6- or
24-well tissue culture plates (Costar Corp, Cambridge, MA) for 5 to 7 days in complete medium supplemented with 100 ng/mL
granulocyte-macrophage colony-stimulating factor (GM-CSF), 10 ng/mL
IL-4, and 10 ng /mL transforming growth factor beta 1(TGF Murine fibroblast cell lines transfected with human CD40L (LcCD40L) or CD32 (LcCD32) were kindly provided by Dr J. Banchereau and Dr F. Briére (Schering-Plough, Dardilly, France).24 T cells were isolated from the PBMCs of healthy volunteers by the standard Ficoll-Hypaque method, followed by magnetic depletion of non-T cells (MACS; Miltenyi Biotec). Antibodies Uncoupled antibody to CD1a (clone BL6) used for cell separation and immunochemistry on tissue sections was purchased from Immunotech (Marseille, France). Fluoroscein isothiocyanate (FITC)-conjugated anti-CD1a (clone VVM-35) used for flow cytometry was purchased from TEBU (Le Perray en Yvelines, France). Unconjugated antibodies to HLA-DR (clone B8.12.2), CD80 (MAB 104) IgG1, CD83 (HB15A), DC-Lamp, and CD40 (mAb89) were obtained from Immunotech. Antibodies to CD86 (IT2.2) and CD14 (Leu-M3) were obtained from Becton Dickinson (Le Pont de Claix, France). Phycoerythrin (PE)-conjugated anti-CD1a, CD14, and CD86 and FITC-conjugated HLA-DR were obtained from the same company as the unconjugated counterparts. Biotinylated rat antihuman IL-10 (JES3-12G8) was purchased from Pharmingen (Becton Dickinson). Monoclonal antibody DCGM4 to Langerin has been described.25,26Immunohistochemistry Serial cryostat sections of biopsy specimens were stained with CD1a, Langerin, CD14, CD40, CD80, CD83, DC-Lamp, or CD86 mouse primary antibodies at the appropriate concentration as determined by titration, and then labeled with a goat antimouse alkaline phosphatase-conjugated antibody. Fast red (Sigma, St Louis, MO) was used as a substrate for alkaline phosphatase. Isotype-matched antibodies were used as negative control. Internal positive controls were always observed. Mounted slides were evaluated on serial sections for the expression of Langerin, CD14, CD40, CD80, CD83, or CD86 by CD1a+ LCH cells. The results were scored as follows: ++ staining of most (more than 75%) LCH cells ; + staining of numerous (25%-75%) LCH cells ; ± staining of few LCH cells (less than 25%); and absence of staining of LCH cells (less than 5%).
Flow cytometry For 2-color flow cytometry, 5 × 104 to 1 × 105 cells were incubated in 96-well plates (Becton Dickinson) for 15 minutes at 4°C in phosphate-buffered saline (PBS), 2% human AB serum, and 0.01 M NaN3, with FITC- and PE-conjugated monoclonal antibodies (mAbs) at the appropriate concentration, or with control isotype-matched irrelevant mAbs at the same concentration (Becton Dickinson). After washing, 104 events were analyzed with a FACScalibur (Becton Dickinson) using CellQuest software (Becton Dickinson).Confocal microscopy Cells were washed in Ca++/Mg++-free PBS and centrifuged onto glass slides by using Cytospins (Shandon, Pittsburgh, PA), dried for 1 hour at room temperature, fixed in acetone for 10 minutes, and stored at20°C. Frozen tissue
section (5 µM thick) were also fixed in acetone for 10 minutes and
stored at 20°C. For staining, slides were rehydrated for 5 minutes
in PBS with 2% pooled normal human serum AB (staining medium), and
then incubated for 1 hour at room temperature with mouse antihuman
Langerin, followed by goat antimouse Cy3 or FITC-conjugated mAb to
Langerin, FITC-conjugated mAb to HLA-DR, PE-conjugated mAb to CD1a,
CD14, CD86, and CD68, biotinylated rat antihuman IL-10 and streptavidin
Cy3 and Cy5 (Jackson Laboratories, Bar Harbor, ME). Slides were
mounted with Fluoprep (Biomerieux SA, Marcy l'Etoile, France) and
analyzed with a confocal laser microscope system attached to a microscope.
Allogeneic lymphocyte proliferation Patient CD1a+ cells and LC-type DCs were resuspended in 24-well tissue culture plates at a concentration of 5.105 cell/mL in complete medium supplemented with 100 ng/mL GM-CSF and 10 ng/mL IL-4 for stimulation. Fibroblastic L-cells transfected with either CD40L, or CD32 as control, were irradiated at 80 Gy and added to the culture wells at a proportion of 25%. Cells were collected after 40 hours of stimulation, washed 3 times in PBS, resuspended in RPMI with 10% human AB serum, and added in triplicate at various concentrations to 105 autologous T cells per well in 96-well tissue culture plates (Falcon, Amersham, Freiburg, Germany). [3H]Thymidine (Amersham Life Science, Buckinghamshire, United Kingdom) incorporation was measured in newly synthesized DNA over 18 hours, by using pulses initiated at day 5 of the culture with 0.037 MBq (1 µCi) per well of [3H]thymidine. Cells were then harvested with a 96-well Harvester (Pharmacia, St. Quentin, France), collected on glass-fiber filter (Pharmacia), and the incorporation of thymidine was measured with a beta-plate microscintillation counter (LKB, Pharmacia).
Patients As shown in Table 1, 12 patients presented with bone disease (eosinophilic granuloma), either unifocal or multifocal, 8 patients presented with LCH restricted to the skin, and among them 4 had self-healing cutaneous histiocytosis (Hashimoto-Pritzker syndrome) diagnosed. Five patients presented with multifocal LCH involving more than 2 organs. In patients with skin LCH, lesional cells constituted an homogenous dermoepidermal infiltrate of CD1a+ cells (Figure 1) also characterized by their round shape, admixed with various amounts of small lymphocytes. A few polymorphonuclear eosinophils were present in some patients' biopsy specimens, and CD1a macrophages were absent or very rare
in all cases. In the bone biopsy specimens (eosinophilic granuloma),
round-shaped CD1a+ LCH cells were admixed with relatively
numerous CD68+ CD1a macrophages (Figures 1,
4), occasional multinucleated giant cells, eosinophilic
polymorphonuclear cells, and scattered lymphocytes. Lymph node biopsy
specimens revealed the presence of CD1a+ cells within the
sinuses and the T-cell areas, and the presence of CD1a,
CD68+ macrophages. These features fitted with previously
described characteristics of cutaneous, bone, and lymph node lesions of LCH.1,6-8
Langerhans cell histiocytosis cells express Langerin, CD14, and CD68 In all 25 patients, more than 75% CD1a positive cells stained for Langerin in serial sections (Figure 1; Table 1). Confocal microscopy study on eosinophilic granuloma samples (n = 3) further demonstrated that antibodies against CD1a and Langerin labeled the same cells (Figure 2A). Langerin expression was a constant feature of CD1a+ LCH cells, whatever the site of the biopsy (skin, bone, or lymph node), or the stage or clinical form of the disease. We found that CD1a+ cells frequently coexpressed CD14 in situ on serial sections in all patients with extracutaneous disease (Figure 1A,B; Table 1). To exclude that the CD14 positive staining may be solely due to expression of CD14 by macrophages that are present in LCH lesions, flow cytometry analysis was performed in 3 patients and confirmed the expression of various levels of CD14 by up to 70% of the CD1a+ cells (Figure 3A). In addition, confocal microscopy (Figure 2B) showed that besides Langerin CD14+ macrophages, both
Langerin+ CD14 and Langerin+
CD14+ Langerhans cells were observed. CD14 expression
appeared to depend on the clinical form of the disease. Numerous
CD1a+ cells were stained in bone lesions (eosinophilic
granuloma, a chronic lesion) (11 patients) and numerous LCH cells were
also CD14+ on serial sections from involved lymph nodes
(n = 3, Figure 1B). However, many fewer cells were stained in skin
samples (Figure 1C), and CD14+ cells were numerous in only
3 of 7 tested patients with pure cutaneous disease (Table 1). In
addition, in all patients, most CD1a+ Langerin+
cells coexpressed CD68, although at a lower level than do macrophages (Table 1, Figure 1; also Figure 5B). This
is in accordance with previous studies.27,28 CD68 is a
lysosomal antigen expressed (at high levels) in monocyte/macrophages,
and (at low levels) in immature skin LCs, and down-regulated on
maturation. In skin lesions, CD68, CD1a, and Langerin staining patterns
were very similar on serial sections. In bone and lymph node lesions,
similarly to what was observed for CD14 staining, some
CD1a Langerin cells were CD68+,
indicating the presence of macrophages admixed with Langerhans cells
(Figure 5B). Altogether, these data suggested that LCH cells have
features of immature LCs, and we therefore investigated the expression
of costimulatory molecules and the cellular localization of major
histocompatibility complex (MHC) class II molecules in these
cells.
Major histocompatibility complex class II and costimulatory molecules Although CD80 was frequently detected (Table 1), CD86 (B7-2) expression was undetectable on most LCH cells in the majority of bone lesions (10 of 11), in 2 of 3 cases of lymphadenopathy, and in skin lesions from patients with multisystem disease (Table 1, Figure 1, Figure 3A). CD83, a marker of mature DCs, was expressed only by scattered cells in all these samples, except for one case of lymphadenopathy (Table 1, Figure 1). In accordance, DC-Lamp, another molecule selectively expressed by mature DCs,29 was only expressed by scattered cells (Figure 2C). Moreover, although it has been reported that LCH cells express MHC class II molecules,27,30 we showed by confocal microscopy on sorted LCH cells from bone lesions that most class II resides within intracellular vesicular compartments (Figure 3B), as observed in immature LCs. In contrast, among patients with pure cutaneous disease, including patients with Hashimoto-Pritzker syndrome, CD86 was expressed by the majority of LCH cells in skin lesions of all tested patients (6 of 6) (Table 1, Figure 1C) and CD83 was expressed by a majority of cells in 2 of 7. Moreover, DC-Lamp was also expressed by the majority of cells in 3 of 3 patients tested (Figure 2D). This confirms that the phenotype of LCH cells differs between cases of isolated skin involvement and bone/disseminated diseases, being more immature in the latter. This suggests that LCH cells, although most frequently immature, may become mature in some circumstances. This may possibly occur through CD40/CD40L interaction, because in all patients, LCH cells expressed CD40 at an even higher level than did normal epidermal Langerhans cells (Table 1, Figure 4A). We therefore investigated the functional properties of LCH cells.
LCH cells from bone lesions are functionally immature, but can mature after CD40 triggering Sorted CD1a+ cells from the bone lesion (eosinophilic granuloma) of 3 patients (7459, 10391, 3774) were studied for their ability to trigger allogeneic lymphocyte proliferation. In situ, cells from these patients were CD1a+, Langerin+, CD40+, CD14+, CD68+. CD80 cells were rare (10391) or numerous (3774, 7459), and CD86 and CD83 cells were rare in all patients. Sorted cells exhibited the same phenotype (Figure 4E; data not shown). In patient 7459 (Figure 4B), the CD1a+ and CD1a fractions were purified as
described in the "Materials and methods" section, and cocultured
with sorted allogenous T lymphocytes. As a control, immature DCs
(Langerhans cell type) and CD40L-treated mature DCs, generated as
described,23 were also cultured in the same experiment
with allogeneic T lymphocytes from the same donor. Patients'
CD1a+ cells and control cultured immature DCs had
comparable effects on T lymphocytes and failed to induce significant
thymidine incorporation at a 1% stimulator/effector ratio. This is
clearly different from the vigourous T-cell proliferation induced by
mature DCs (Figure 4B). In further experiments (Figure 4C,D, patients
10391 and 3774, respectively), sorted CD1a+ LCH cells and
control immature DCs were cultured either with CD40L or with CD32
transfected fibroblasts for 2 days before being added to allogeneic
lymphocytes. Strikingly, although both LCH cells and control immature
DCs cultured with CD32 transfected cells equally (poorly) stimulated
lymphocyte proliferation, both LCH cells and control immature DCs
stimulated via CD40 showed a strong increase in their capacity to
stimulate lymphocytes at low stimulator/effector ratio. Confocal
microcopy examination of patients' CD1a+ sorted cells
after the 2-day culture with transfected fibroblasts substantiated this
finding, showing that, although cells cocultured with control
fibroblasts still had an immature (intracellular MHC class II and
CD86) phenotype, cells cultured with CD40L-transfected
fibroblasts expressed high-membrane MHC class II and CD86 (Figure 4E).
It is, however, noticeable that, in these experiments, LCH cells remained round shaped (Figure 4E) and frequently did not acquire a
"dendritic" morphology. Therefore, LCH cells from eosinophilic granuloma displayed both an immature phenotype and function, but could
be induced to express CD86 and membrane class II and to become potent
stimulators of an allogeneic response in vitro.
Macrophages produce IL-10 in eosinophilic granuloma lesions and involved lymph nodes The above results suggested that the immature phenotype of LCH cells in bone lesions did not result from an intrinsic maturation blockade. We investigated whether inhibitory signals may be found in the vicinity of LCH cells within lesions. With the use of confocal microscopy examination of patients' tissue sections, no IL-10 was detected within LCH lesions from patients with localized cutaneous disease (Figure 5A, n = 3). In contrast, relatively numerous IL-10-expressing cells were detected within bone and lymph node lesions (Figure 5A, n = 4). Interestingly, the cells that expressed IL-10 were found to be very large sized, did not express CD1a or Langerin (Figure 5A,B), and were also CD3 negative (data not shown) but strongly expressed CD68 (Figure 5B), and therefore were identified as macrophages. These IL-10-expressing macrophages were found to be frequently in close contact with LCH Langerin+ cells (Figure 5A,B) and T lymphocytes (data not shown). Examination of control reactive lymph nodes did not reveal the presence of these IL-10-expressing cells (data not shown). These observations suggest that Langerin+ LCH cells and infiltrating T cells are exposed to IL-10, mainly produced by surrounding macrophages.
This study aimed to define phenotypic and functional characteristics of LCH cells that may account for the pathogenesis of the disease, and in particular, their ability to induce an immune response. We have studied the in situ phenotype of LCH cells in a large series of patients, relative to the low incidence, that represents the various clinical courses of the disease. However, flow cytometry analysis and functional studies could be performed only in a smaller number of patients, due to the difficulty to obtain fresh lesional tissue at the time of diagnosis. Despite the widely accepted use of CD1a antibodies to confirm the diagnosis of LCH,31-35 CD1a expression is not restricted to Langerhans cells, and accurate diagnosis of Langerhans cell histiocytosis, required in such a study, may be questionable in the absence of electron microscopy. The results presented here are reinforced by the 100% concordance observed between positivity of Langerin and of CD1a stainings in the 25 patients who had various clinical forms and stages of LCH diagnosed, at various biopsy sites. Assuming that Langerin is a specific LC marker25 associated with Birbeck granules at the ultrastructural level,26 this indicates that all studied patients indeed presented with "Langerhans cell" histiocytosis. Our findings also establish Langerin as a useful marker for diagnosis of LCH. It appears clearly from our results that LCH cells express CD14 at
least in bone and lymph node involvement. CD14 expression may depend on
the clinical form of the disease because fewer cells are stained in
skin lesions. Earlier studies have reported that LCH cells
may,30 or may not,27 express CD14. Such a
phenotype, CD1a+, Langerin+, CD14+,
is unusual because normal Langerhans cells do not, or very poorly, express CD14.36 It is, however, reminiscent of the
phenotype of recent immigrant Langerhans cells within the epidermis
after a bone marrow graft as described by Murphy et al.37
It is noteworthy that (i) during monocyte to DC differentiation in
vitro, CD14 and CD68 are down-regulated, whereas CD1a is induced, due
to the effect of IL-4 (or IL-13) and TGF The major finding in this study is that LCH cells are in an immature stage of differentiation in the bone/chronic forms of the disease, but are able to trigger an immune response if they receive a maturation signal such as CD40L in vitro. Although only 3 patients could be studied in functional assay, the results were clear and consistent with phenotypic studies. Both in situ and ex vivo results presented here argue against the hypothesis of an intrinsic maturation blockade of LCH cells, and indicate that LCH cells can be induced to elicit an immune response. Indeed, in the spontaneously regressive form of the disease, LCH cells do frequently exhibit CD86 and DC-Lamp expression in situ, suggesting that they represent more mature DCs. Functional studies in the latter form, however, could not be performed due to the lack of sufficient material, and in addition would have been difficult to interpret because of the probable contamination by normal epidermal LCs. In contrast, CD1a+ LCH cells sorted from bone lesions do not express membrane MHC class II or costimulatory CD86, and poorly stimulate T cells. In vivo, and even in vitro after a 2-day culture with fibroblasts, these cells remain in an immunologically immature stage. Strikingly, however, CD1a+ LCH cells differentiate toward mature DCs on CD40 triggering in vitro. This is somewhat surprising, because patients with LCH do not present
with CD40L deficiency, and because, in addition to the presence of T
cells within the lesions, LCH lesions, especially eosinophilic
granuloma, abundantly express inflammatory cytokines such as
TNF Altogether our findings in this functional study attempting to draw a picture of the pathogenesis of LCH may account for a maturation blockade of LCH cells due to extrinsic signals and reconcile contrasting studies on a few cases that either reported that LCH cells may be activated or mature on phenotypic data17,19 or failed to detect alloantigen-presenting activity by LCH cells.20 In our study, LCH cells from bone/chronic lesions are undoubtedly
immature Langerhans-type dendritic cells that express higher levels of
CD68 and CD14 than normal LCs, intracellular MHC class II, are
frequently negative for CD86 and DC-Lamp and have the same
allostimulatory activity as immature normal DCs. It is, however, clear
that LCH cells are not by themselves "frozen" in an arrested state
of activation/differentiation because we show that LCH cells may become
activated in vitro in response to CD40 triggering. Moreover, in some
cases in vivo, especially, and interestingly, in self-healing cutaneous
lesions, a more mature phenotype can be observed and LCH cells appear
to down-regulate CD14 and up-regulate CD86 and DC-Lamp. Although a
direct role of IL-10 cannot be demonstrated here, IL-10 produced by
CD1a LCH has been advocated to be a malignancy or a viral disease; however, both the search for a viral cause and for molecular abnormalities are still unsuccessful.10,40,41 Several viruses have been shown to interfere with DC functions, and it is conceivable that an inadequate response to a viral challenge may result in the LCH features described: local recruitment of immature LCs or their precursors, their abnormal homing, and their persistence in the absence of efficient maturation. Finally, our results may contribute to explain the paradox of an "antigen presenting-cell tumor" that does not induce its own rejection by the immune system. In bone/chronic forms, LCH cells are maintained in an immature stage by factors from their environment. This may open the way for new strategies in the treatment of LCH. Whether drugs that enhance in vivo the ability of LCH cells to become mature may lead to their killing by activated CTL and may be beneficial to some patients should be investigated. Alternatively, pharmacologically induced death of immature DCs may also be considered.
We are grateful to the French Histiocytosis Study Group and to Pr F. Jaubert for support, to Dr Aucouturier for critical reading of the manuscript, and to Mr Y. Goureau for help with confocal microscopy.
Submitted July 27, 2000; accepted November 7, 2000.
Supported by the Université Paris V and the CNRS, and by grants from the Histiocytosis Association of America and the Association pour la Recherche contre le Cancer. J.V. was supported by Fondation Merieux.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Frédéric Geissmann, Service d'Anatomie Pathologique and UMR 8603 CNRS-Université Paris V, Hopital Necker-Enfants Malades, 161 rue de Sevres, 75743 Paris Cedex 15, France; e-mail: geissman{at}necker.fr.
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© 2001 by The American Society of Hematology.
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Q.-G. Steiner, L. A. Otten, M. J. Hicks, G. Kaya, F. Grosjean, E. Saeuberli, C. Lavanchy, F. Beermann, K. L. McClain, and H. Acha-Orbea In vivo transformation of mouse conventional CD8{alpha}+ dendritic cells leads to progressive multisystem histiocytosis Blood, February 15, 2008; 111(4): 2073 - 2082. [Abstract] [Full Text] [PDF]
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A. Rivollier, M. Mazzorana, J. Tebib, M. Piperno, T. Aitsiselmi, C. Rabourdin-Combe, P. Jurdic, and C. Servet-Delprat Immature dendritic cell transdifferentiation into osteoclasts: a novel pathway sustained by the rheumatoid arthritis microenvironment Blood, December 15, 2004; 104(13): 4029 - 4037. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
1).
) and mature (
) (CD40L
treated) monocyte-derived DCs and CD1a+ (
) and
CD1a
) cells sorted from fresh eosinophilic granuloma
tissue from patient 7459 were cultured with 105 allogenous
lymphocytes at 1% or 4% stimulator to effector ratio. (C) sorted
CD1a+ cells from eosinophilic granuloma from patient 10391 (
, 
) and control monocyte-derived DC (
