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Blood, Vol. 94 No. 6 (September 15), 1999:
pp. 2065-2071
Hodgkin/Reed-Sternberg Cells Induce Fibroblasts to Secrete Eotaxin,
a Potent Chemoattractant for T Cells and Eosinophils
By
Franziska Jundt,
Ioannis Anagnostopoulos,
Kurt Bommert,
Florian Emmerich,
Gerd Müller,
Hans-Dieter Foss,
Hans-Dieter Royer,
Harald Stein, and
Bernd Dörken
From the Universitätsklinikum Charité,
Robert-Rössle-Klinik, Humboldt University of Berlin, Berlin,
Germany; the Max Delbrück Center for Molecular Medicine, Berlin,
Germany; and the Institute of Pathology, Klinikum Benjamin Franklin,
Free University of Berlin, Berlin, Germany.
 |
ABSTRACT |
Hodgkin's disease is histopathologically characterized by the
relative scarcity of neoplastic Hodgkin and Reed-Sternberg cells and
for yet unknown reasons by an abundant reactive background of T
lymphocytes and often eosinophils. Eotaxin is a CC-chemokine attracting
eosinophils and T helper 2 (Th2) cells in allergic inflammation. We now
report that eotaxin is strongly expressed in fibroblasts of Hodgkin's
disease tissues, whereas Hodgkin/Reed-Sternberg cells do not express
this chemokine. In tissue culture, Hodgkin's disease tumor cells
induce eotaxin expression in cocultured dermal fibroblasts in a
concentration leading to a specific chemotactic response of a Th2 cell
clone. Production of tumor necrosis factor- (TNF-) by
Hodgkin/Reed-Sternberg cells appears to be responsible for this
induction, because blocking of TNF- by neutralizing antibodies
prevented fibroblast eotaxin expression. Our data suggest that eotaxin
is involved in the pathobiology of Hodgkin's disease by contributing
to eosinophil and T-lymphocyte recruitment.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
CYTOKINES PLAY AN important role in the
pathogenesis of Hodgkin's disease (HD).1,2 Characteristic
clinical symptoms such as B symptoms (fever, night sweats, and weight
loss) and immunosuppression are mediated by neoplastic or reactive
cell-derived cytokines such as interleukin-1 (IL-1), IL-6, transforming
growth factor- (TGF-), and tumor necrosis factor-
(TNF-).3,4 Proliferation and differentiation of
neoplastic cells are affected by cytokines acting as autocrine or
paracrine growth factors.1 The typical histopathologic
feature of HD, that is, relative scarcity of Hodgkin/Reed-Sternberg
cells surrounded by massive infiltration of reactive cells, is assumed
to be caused by various cytokines such as IL-1, IL-5, IL-6, IL-7, IL-8,
lymphotoxin- (LT-), TNF-, TGF-, and granulocyte-macrophage
colony-stimulating factor (GM-CSF).1,5-7 Mechanisms that lead to increased recruitment of eosinophils and T
lymphocytes, which constitute the vast majority of cells in tumor
tissues, are largely unknown.
Tissue eosinophilia is mainly found in nodular sclerosis and mixed
cellularity subtypes, which represent greater than 80% of all HD
cases.8,9 Production of IL-5 and GM-CSF by
Hodgkin/Reed-Sternberg cells may account in part for the recruitment
and functional activation of eosinophils.10-13 The
pathobiologic significance of tissue eosinophilia became evident,
because eosinophils provide ligands for TNF superfamily receptors (CD30
and CD40) expressed on Hodgkin/Reed-Sternberg cells, thereby
functionally interacting with Hodgkin/Reed-Sternberg cells and
contributing to tumor cell proliferation.14-17 Furthermore, eosinophils may be involved in connective tissue remodeling and collagen formation in HD tissues, because they produce TGF- and stimulate fibroblast DNA synthesis.18,19 It is of interest that CD4+ T lymphocytes with a T helper 2 (Th2)-like
immunophenotype are the most abundant cell type in Hodgkin's lymphoma
tissues.20 Th2 cells produce IL-5, which primes and
activates eosinophils.21 Moreover, interaction of these T
cells with neoplastic cells and eosinophils also involves ligands of
TNF receptors (CD30L and CD40L).14 T lymphocytes as well as
eosinophils transmit via these ligands proliferative and antiapoptotic
signals to Hodgkin/Reed-Sternberg cells and thereby influence tumor
biology.14,15
Recently, the human CC-chemokine eotaxin has been identified as a
potent attractant for eosinophils and Th2 lymphocytes.21-27 Chemokines are small proteins with a molecular weight in the range of 8 to 12 kD. There are 4 different groups designated as CXC, CC, C, and
CX3C, depending on the presence of 4 cysteins in highly conserved
positions.28-30 Eosinophils mainly express receptors of the
CC group of chemokines (CCR1 and CCR3), whereas in T lymphocytes, a
great variety of chemokine receptors is found (CCR1-3 and
CXCR3-5).28 The receptor for eotaxin, CCR3, is expressed on
hematopoietic cells involved in allergic responses: eosinophils,
basophils, and a subset of T lymphocytes (Th2 cells).31-35
In this study, we show that the chemoattractant eotaxin is strongly
expressed in fibroblasts of HD tissues. Our data indicate that
HD-derived cell lines induce the expression of eotaxin in fibroblasts
by TNF-. Eotaxin is then able to attract via its receptor CCR3
eosinophils and Th2 lymphocytes in tumor tissues. We therefore suggest
that eotaxin contributes to the characteristic histopathologic features
of Hodgkin's lymphoma.
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MATERIALS AND METHODS |
Cell culture.
Human cell lines analyzed in this study were as follows: the Hodgkin
cell lines, L428, L1236, KM-H2, L591, HD-LM2, and HD-MyZ; the
pre-B-cell line, Blin-1; the T-cell lines, Molt-4 and Jurkat; the
mature B-cell line, BL-60, Daudi; the myelocytic-monocytic cell line,
U937; the breast cancer cell line, R30C; adenocarcinoma cell line,
HeLa; and normal human dermal fibroblasts (NHDF). All cell
lines were maintained in RPMI 1640 (Seromed-Biochrom, Hamburg, Germany), 10% heat-inactivated fetal calf serum, 2 mmol/L L-glutamine, and penicillin-streptomycin except for NHDF maintained in Basal Medium
Eagle (BME; GIBCO, Karlsruhe, Germany). The human Th2 cell clone PM18.8
(a generous gift from F. Sallusto, Basel, Switzerland26) was maintained in RPMI supplemented with 2 mmol/L
L-glutamine, 1% nonessential amino acids,
1% pyruvate, 50 µg/mL kanamycin, 5 × 10 5
mol/L 2-mercaptoethanol (GIBCO), and 5% human serum (Sigma,
Deisenhofen, Germany). Phytohemagglutinin (PHA) was
purchased from Boehringer Mannheim (Mannheim, Germany); human
recombinant IL-2, TNF-, and neutralizing antibody against TNF-
were purchased from Calbiochem (Bad Soden, Germany). For cocultivation
experiments, confluent NHDF and cell lines (1 × 106 cells/mL medium) were incubated for 24 hours in
serum-free RPMI before cocultivation. Subsequently, NHDF and cell lines
were cocultured for 48 hours in 6-well plates separated by micropore
membranes (Falcon, Heidelberg, Germany) before cells were harvested for mRNA extraction.
Northern blot analysis.
Total RNA preparations were performed using the guanidium
isothiocyanate-phenol chloroform method as described
previously.36 For Northern analysis, 10 to 30 µg of total
RNA was subjected to gel electrophoresis on a 1.1% formaldehyde-1.2%
agarose gel and transferred to a nylon membrane (Appligene, Heidelberg,
Germany). After UV cross-linking, the membrane was prehybridized
(ExpressHyb hybridization solution; Clontech, Heidelberg, Germany) at
68°C for 1 hour. The blots were hybridized with a
32P-random prime-labeled DNA probe overnight at 68°C.
Probes were human eotaxin (290 bp, entire coding region) and GAPDH (249 bp of coding region) cDNAs. The membranes were washed for 40 minutes at
room temperature in 2× SSC, 0.1% sodium dodecyl sulfate (SDS) and then for 40 minutes at 50°C in 0.5% SSC, 0.1% SDS. All
experiments were performed in triplicate.
Enzyme-linked immunosorbent assay (ELISA).
ELISA was performed by coating 100 µL of mouse antihuman eotaxin
monoclonal antibody (MoAb; R&D Systems, Wiesbaden, Germany) onto
96-well immunoplates (Nunc, Wiesbaden, Germany) at a concentration of 5 µg/mL in carbonate buffer overnight at 4°C. Plates were washed 3 times with phosphate-buffered saline (PBS)/Tween 20, and 250 µL/well
of blocking buffer (PBS containing 4% bovine serum albumin [BSA])
was added for 2 hours at 37°C. After washing the plates (PBS/Tween
20), 100 µL recombinant human eotaxin (R&D Systems) in various
concentration (10 pg up to 1,000 ng) or supernatant of cultured cell
lines was added and incubated for 1.5 hours at 37°C. Plates were
washed 3 times, and 100 µL of a rabbit antihuman eotaxin polyclonal
antibody 1:2,000 diluted in PBS/1% BSA was added to each well. After
the wash, 0.5 µg/mL of a horseradish peroxidase-linked antirabbit IgG
derived from goats (Sigma) was diluted 1:1,000 in PBS/1% BSA and added
for 20 minutes at 37°C. After incubation and washing, plates were
developed using the o-phenylenediamine dihydrochloride substrate method
according to the instructions of the manufacturer (Sigma). Plates were
read at 490 nm on an ELISA reader. Under these conditions, this assay was sensitive to 50 pg/mL.
Chemotaxis assay.
Chemotactic factors diluted in assay medium were added to the 12-well
tissue culture plates (Costar, Cambridge, MA) in a final volume of 500 µL. Collagen-coated (mouse Typ IV collagen in 0.01 N HCl; Becton
Dickinson, Heidelberg, Germany) transwells (5-µm pores) were inserted
into each well and 1 to 5 × 105 cells of the human
Th2 cell clone PM18.8 expressing the CCR3 receptor for eotaxin were
added to the top chamber in a final volume of 100 µL. The plate was
then incubated at 37°C for 2.5 to 4 hours. The number of migrated
cells across the membrane was counted in a Neubauer chamber. Monoclonal
anti-eotaxin antibody (R&D Systems) and isotype control antibody (mouse
IgG1,  ; Becton Dickinson) were used in a concentration of 10 µg/mL
for 30 minutes.
Immunohistology.
Five-micrometer sections of frozen tissue blocks were stained using the
immunoalkaline phosphatase (APAAP) method.37 The primary
antibody was monoclonal anti-eotaxin antibody (R&D Systems) used in a
concentration of 1:500. Frozen sections of nodular sclerosing classical
Hodgkin's disease cases were subjected to double labelings. The
sections were first incubated with anti-CD3 (clone UCHT1; Dako,
Glostrup, Denmark) or alternatively with the
anti-macrophage-associated antigen (Ber-MAC3; Dako). Bound antibodies
were visualized with the streptavidin/biotin/peroxidase technique. This
step was followed by incubation with the anti-eotaxin MoAb that was
visualized with the APAAP technique using new fuchsin as chromogen.
In situ hybridization.
The cRNA probe was prepared by subcloning an eotaxin gene cDNA fragment
(290 bp; kindly provided by J. Bartels, Kiel, Germany38) in
the run-off transcription vector pGEM1 (Promega Biotec, Heidelberg, Germany). After linearization, run-off antisense transcripts with incorporation of 35S-labeled UTP and CTP were generated
using T7 RNA polymerases (Promega-Biotech, Madison, Wi). In situ
hybridization for the detection of eotaxin transcripts was performed as
described previously using microwave irradiation before the
hybridization.6 Slides were hybridized with 4 × 105 cpm of labeled probes overnight at 50°C.
| |
RESULTS |
Eotaxin is expressed in fibroblasts of HD tissues.
To evaluate the causes of tissue eosinophilia and T-lymphocyte
infiltration in HD, we examined whether the eosinophil- and Th2
lymphocyte-specific chemoattractant eotaxin is expressed in HD tissues.
We performed immunohistology of 9 cases of the nodular sclerosis and 1 case of the mixed cellularity subtypes by using a human anti-eotaxin
MoAb alone or in conjunction with a T-cell or a macrophage-specific
marker (Fig 1). Most of the spindle shaped eotaxin-expressing cells located within the collagen tissue bands in
cases with nodular sclerosing Hodgkin's disease did not show a
coexpression of CD3 (Fig 1C). However, a number of cells expressing macrophage-associated antigen were found to coexpress eotaxin (data not
shown). This implies that a proportion of macrophages in Hodgkin's
disease does express eotaxin but that the majority of the
eotaxin-positive cells represent fibroblasts. Hodgkin/Reed-Sternberg cells and other reactive cells do not express the chemokine. Frozen sections from reactive lymphoid tissue and of cutaneous biopsies with
unspecific chronic dermatitis served as negative controls. Eotaxin was
not expressed in lymphatic or dermal connective tissues (data not
shown). Using in situ hybridization, eotaxin transcripts were found in
10 of 16 cases of classical HD (6 of 8 nodular sclerosis, 4 of 7 mixed
cellularity, and 1 unclassifiable). Labeled cells were found in the
connective tissue of the fibroseptae (nodular sclerosis type), around
blood vessels, and in capsula and subcapsula areas
(Fig 2). In addition, eotaxin-positive
cells were observed in the cellular infiltrates. By morphology these
cells may represent fibroblasts or, in some cases, also macrophages.
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| Fig 1.
Immunohistology of HD tissues. Immunohistology
of frozen sections of nodular sclerosis subtype of HD stained for
eotaxin using a monoclonal anti-eotaxin antibody (red reaction
product-APAAP technique). (A and B) Eotaxin-expressing cells are
located within the collagen tissue bands. Hodgkin/Reed-Sternberg cells
and other reactive cells are eotaxin negative. (C) Double labeling for
CD3 (brown reaction product-streptavidin/biotin method) and eotaxin in
a case of nodular sclerosing classical HD shows that most of the
spindle-shaped eotaxin-expressing cells do not coexpress CD3.
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| Fig 2.
In situ hybridization of HD lymph nodes. In situ
hybridization with eotaxin antisense probe is shown. Eotaxin-specific
signals are found around blood vessels. Labeled cells were also
observed in the cellular infiltrates. Using morphology, these cells may
represent fibroblasts or, in some cases, macrophages (solid arrow).
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Eotaxin is induced in fibroblasts after cocultivation with
Hodgkin/Reed-Sternberg cells.
Next, we determined eotaxin mRNA and protein expression in HD-derived
cell lines (Fig 3). In accordance with
immunohistology, the majority of Hodgkin cell lines HD-MyZ, L428, L591
(Fig 3, lanes 1, 3, and 4), and KM-H2, HD-LM2 (data not shown) did not show eotaxin mRNA or protein expression. Only the Hodgkin cell line
L1236 contained low levels of eotaxin mRNA (Fig 3, lane 2). However,
protein expression could not be detected by ELISA in the culture medium
of Hodgkin cell lines, which was conditioned for 48 hours (data not
shown). Other hematopoietic cells, such as pre-B (Blin-1), T (Molt-4),
and monocytic cells (U937), and nonhematopoietic breast cancer (R30C)
and adenocarcinoma cells (HeLa) also did not show eotaxin mRNA
expression (data not shown).
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| Fig 3.
Expression of the chemoattractant eotaxin in Hodgkin cell
lines. Northern blot analysis of total RNA (30 µg) isolated from the
Hodgkin cell lines HD-MyZ (lane 1), L1236 (lane 2), L428 (lane 3), and
L591 (lane 4). The blot was hybridized with eotaxin- and subsequently
with GAPDH-specific cDNA probes.
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We hypothesized that Hodgkin/Reed-Sternberg cells that secrete high
levels of various cytokines could induce eotaxin in surrounding connective tissue cells. Furthermore, recombinant TNF- is known to
strongly stimulate eotaxin expression in
fibroblasts.38 Therefore, we cocultured
Hodgkin cell lines with normal human dermal fibroblasts. All tested
Hodgkin cell lines L1236, L428, and KM-H2 were able to induce eotaxin
mRNA expression in fibroblasts after cocultivation (Fig
4A, lanes 3 through 5). Cocultivation with non-Hodgkin
lymphoma cell lines of pre-B-cell (Blin-1; Fig 4A, lane 6), B-cell
(BL60, Daudi), and T-cell origin (Jurkat) did not induce eotaxin in
fibroblasts (data not shown). The Hodgkin cell lines as well as the
control cell lines did not express eotaxin after cocultivation with
fibroblasts, indicating that factors produced by fibroblasts are not
able to stimulate these cell lines (data not shown).
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| Fig 4.
Induction of eotaxin mRNA expression in normal human
dermal fibroblasts. Northern blot analysis of total RNA (10 µg)
isolated from fibroblasts. Blots were hybridized with eotaxin- and
subsequently with GAPDH-specific probes. (A) Untreated fibroblasts
(lane 1), fibroblasts after stimulation with 30 ng/mL TNF- (lane 2),
and fibroblasts after cocultivation with the Hodgkin cell lines L1236
(lane 3), L428 (lane 4), KM-H2 (lane 5), and the pre-B-cell line
Blin-1 (lane 6). (B) Fibroblasts after stimulation with 10 ng/mL
TNF- (lanes 1 and 2) and incubation with anti-TNF- antibodies
(lane 2). Fibroblasts after cultivation in supernatant of the Hodgkin
cell line L1236 (lanes 3 and 4) and incubation with anti-TNF-
antibodies (lane 4).
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We next examined whether TNF- secreted by Hodgkin cell lines might
be responsible for the observed induction of eotaxin in fibroblasts.
Therefore, we blocked TNF- in the culture medium of the Hodgkin cell
line L1236 by neutralizing antibodies. Supernatant of L1236 cells was
produced for 24 hours and anti-TNF- antibody was added 2 hours
before cultivation of fibroblasts in this supernatant for 48 hours.
Blocking of TNF- almost completely inhibited eotaxin mRNA expression
in fibroblasts (Fig 4B, lanes 2 and 4).
Eotaxin secreted by stimulated fibroblasts induces specific
chemotactic responses of human Th2 cells.
In supernatants of fibroblasts cocultured with Hodgkin cell lines
(L1236, L428, and KM-H2) for 48 hours, we detected by ELISA high levels
(~30 to 45 ng/mL) of eotaxin comparable to levels after stimulation
with TNF-, which served as a positive control ( Fig
5). In contrast, supernatants of fibroblasts cocultured with the
B-lymphoma cell line Blin-1 did not contain eotaxin protein. Supernatants of all cell lines (L1236, L428, and KM-H2) or of unstimulated fibroblasts were also conditioned for 48 hours and showed
undetectable levels of eotaxin (data not shown).
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| Fig 5.
Eotaxin protein levels of cell supernatants. Eotaxin
protein was measured by ELISA in supernatants of fibroblasts after
stimulation with 30 ng/mL TNF- or cocultivation with the Hodgkin
cell lines (L1236, L428, and KM-H2) and the pre-B-cell line (Blin-1).
Errors are shown as the standard deviation.
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To analyze functional activity of eotaxin secreted by fibroblasts, we
used a chemotaxis assay with the human T-helper 2 cell clone PM18.8
expressing the CCR3 receptor for eotaxin.21 This T-helper 2 cell clone exhibited a dose-dependent chemotactic response to
recombinant human eotaxin with desensitization at high doses (Fig 6A). PM18.8 cells showed a significant migratory
response only towards supernatants of stimulated fibroblasts containing eotaxin protein, whereas supernatants of all cell lines or unstimulated fibroblasts did not induce specific chemotaxis (Fig 6B). Specificity of
chemotactic responses was controlled by blocking the chemoattractant eotaxin with a human antieotaxin MoAb (Fig 6C). Anti-eotaxin antibodies efficiently inhibited migratory responses of the Th2 cells in contrast
to irrelevant antibodies of the same isotype (data not shown). These
data showed that helper T lymphocytes bearing the CCR3 receptor were
stimulated to chemotactic responses by eotaxin that was secreted by
fibroblasts cocultured with Hodgkin cell lines.
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| Fig 6.
Th2 lymphocyte chemotaxis in response to recombinant
eotaxin and to supernatants of Hodgkin cell lines and fibroblasts. (A)
The number of Th2 cells migrated at indicated concentrations of eotaxin
(in nanomoles per liter) is given relative to the number of Th2 cells
migrated at medium control (no chemokine), which was set arbitrarily at
1 (chemotaxis index). (B and C) ( ) Th2 cells migrated in response to
supernatants of cell lines indicated; ( ) Th2 cells migrated in
response to supernatant of fibroblasts stimulated with TNF- (left
panel) or to supernatants of fibroblasts cocultured with cell lines
indicated (right panel); ( ) migration of Th2 cells after blocking
the chemoattractant eotaxin with anti-eotaxin MoAb. Values of columns
are given relative to values of Th2 cells migrated at medium control,
which were set arbitrarily at 1 (chemotaxis index). Th2 cells migrated
for 2.5 hours (A and B) and for 4 hours (C), respectively. Values of
induction and inhibition of specific chemotactic responses are
statistically significant for all supernatants (P < .005 using the Student's t-test). Results are the mean values of 3 independent experiments and errors are shown as the standard
deviation.
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| |
DISCUSSION |
Hodgkin's disease is histopathologically characterized by the relative
scarcity of Hodgkin and Reed-Sternberg cells, by the neoplastic cell
clone, and for yet unknown reasons by an abundant infiltration of T
lymphocytes and often eosinophils. In this study, we investigated
whether the eosinophil- and Th2 lymphocyte-specific chemokine could
play a role in the pathobiology of this disease. As a first step, we
analyzed eotaxin expression in HD-derived cell lines. However, the
majority of these cell lines did not express the chemokine, with one
exception. Only the Hodgkin cell line L1236 contained small amounts of
eotaxin mRNA that were not translated to protein.
In parallel, we analyzed lymph nodes of the nodular sclerosis and mixed
cellularity subtypes of HD by in situ hybridization and
immunohistology. We show here that eotaxin mRNA and protein are
strongly expressed in fibroblasts and in a proportion of macrophages of
HD tissues, whereas neoplastic cells are indeed devoid of eotaxin. This
finding and the absence of eotaxin in control tissues such as normal
lymphoid tissue and cutaneous biopsies indicate that expression of
eotaxin in HD tissues may contribute to the recruitment of eosinophils
and T lymphocytes.
We hypothesized that Hodgkin/Reed-Sternberg cells producing cytokines
could thereby induce expression of eotaxin in fibroblasts. To verify
this hypothesis, we cocultured Hodgkin cell lines with human dermal
fibroblasts. Our data show that neoplastic cells strongly stimulate
fibroblasts to express the chemoattractant eotaxin. We also provide
evidence that production of TNF- by Hodgkin/Reed-Sternberg cells is
responsible for the induction of eotaxin in fibroblasts, because
blocking of TNF- by a neutralizing antibody prevented eotaxin mRNA
expression. In dermal fibroblasts, expression of eotaxin is known to be
stimulated by recombinant TNF-, suggesting that eotaxin may serve as
a potential agonist for eosinophil and T-lymphocyte infiltration in
patients with inflammatory skin diseases.38
Next, we examined the functional consequences of eotaxin expression by
fibroblasts testing eotaxin containing supernatants of Hodgkin cell
lines cocultured with fibroblasts in chemotaxis assays. The human
T-helper 2 cell clone PM18.8 that expresses the CCR3 receptor for
eotaxin showed specific chemotactic responses to eotaxin secreted by
stimulated fibroblasts. These findings indicate that binding of eotaxin
to its receptor on Th2 cells and eosinophils may contribute to the
recruitment of these cells in HD. Interestingly, the majority of cells
composing the tumor tissue are CD4+ T lymphocytes with a
T-helper 2 (Th2)-like immunophenotype.20
Are Th2 cells and eosinophils involved in the pathobiology of HD? It
was reported that Th2 cells represent not a selective population that
might recognize a common tumor antigen.39 Irrespective of
their specificity, they are rather recruited by chemoattractants such
as eotaxin and stimulate tumor growth via cytokines of the TNF family
that lead to proliferation and cellular activation of
Hodgkin/Reed-Sternberg cells.15 Eosinophils also contribute to tumor cell proliferation induced by ligands of the TNF
family.14,15 Therefore, eosinophils and Th2 cells after
recruitment by the chemoattractants are important elements in the
development and phenotype of HD.
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FOOTNOTES |
Submitted December 21, 1998; accepted May 4, 1999.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Franziska Jundt, MD, Max Delbrück
Center for Molecular Medicine, Robert-Rössle-Str. 10, D-13122
Berlin, Germany; e-mail: fjundt{at}mdc-berlin.de.
| |
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