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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2463-2470
Differential Chemokine Expression in Tissues Involved by Hodgkin's
Disease: Direct Correlation of Eotaxin Expression and Tissue
Eosinophilia
By
Julie Teruya-Feldstein,
Elaine S. Jaffe,
Parris R. Burd,
Douglas
W. Kingma,
Joyce E. Setsuda, and
Giovanna Tosato
From the Laboratory of Pathology, Hematopathology Section, National
Cancer Institute, National Institutes of Health, Bethesda; and the
Center for Biologics Evaluation and Research, Food and Drug
Administration, Bethesda, MD.
 |
ABSTRACT |
Hodgkin's disease (HD) is a lymphoid malignancy characterized by
infrequent malignant cells surrounded by abundant inflammatory cells.
In this study, we examined the potential contribution of chemokines to
inflammatory cell recruitment in different subtypes of HD. Chemokines
are small proteins that are active as chemoattractants and regulators
of cell activation. We found that HD tissues generally express higher
levels of interferon- -inducible protein-10 (IP-10), Mig, RANTES,
macrophage inflammatory protein-1 (MIP-1), and eotaxin, but not
macrophage-derived chemotactic factor (MDC), than tissues
from lymphoid hyperplasia (LH). Within HD subtypes, expression of IP-10
and Mig was highest in the mixed cellularity (MC) subtype, whereas
expression of eotaxin and MDC was highest in the nodular sclerosis (NS)
subtype. A significant direct correlation was detected between evidence
of Epstein-Barr virus (EBV) infection in the neoplastic cells and
levels of expression of IP-10, RANTES, and MIP-1. Levels of eotaxin
expression correlated directly with the extent of tissue eosinophilia.
By immunohistochemistry, IP-10, Mig, and eotaxin proteins localized in
the malignant Reed-Sternberg (RS) cells and their variants, and to some
surrounding inflammatory cells. Eotaxin was also detected in
fibroblasts and smooth muscle cells of vessels. These results provide
evidence of high level chemokine expression in HD tissues and suggest
that chemokines may play an important role in the recruitment of
inflammatory cell infiltrates into tissues involved by HD.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
HODGKIN'S DISEASE (HD) is a lymphoid
malignancy characterized by infrequent malignant Reed-Sternberg (RS)
and Hodgkin's cells within an environment of nonmalignant cells,
including T cells, macrophages, fibroblasts, plasma cells, eosinophils,
and neutrophils. The occurrence of relatively rare neoplastic cells within a context of reactive cells has suggested that a prominent local
inflammatory response to the RS and Hodgkin's cells is a key feature
of this malignancy. The intense inflammation could reflect an
insufficient and/or ineffective antitumor response that may itself
contribute to the disease.
A number of studies have documented that HD is a neoplasia associated
with abnormal cytokine production.1-3 Excess production of
the inhibitory cytokine, interleukin (IL)-10, may contribute to reduced
T-cell immunity, and abnormally high levels of IL-6, IL-1, and tumor
necrosis factor (TNF)- may account for some of the constitutional
symptoms that are commonly associated with HD.1,4 Other
aspects of HD, including peripheral blood eosinophilia, plasmacytosis,
and thrombocytosis could also be contributed by abnormally high
cytokine levels of IL-3 and IL-5, IL-6 and IL-11, respectively.4 However, systemic cytokine imbalances are
unlikely to explain the characteristic cellular infiltrates that
surround the malignant cells. Rather, the nature of cellular
infiltrates in HD tissues could be explained on the basis of certain
chemokines being locally produced promoting selective cell migration.
Recent studies in an athymic mouse model have described a host response
to Epstein-Barr virus (EBV)-immortalized cells and identified two
mediators of this response as the CXC chemokines IP-10 and
Mig.5-7 Increased production of IP-10 and Mig was also identified in the EBV-positive lymphomatous tissues representative of
lymphomatoid granulomatosis and nasal or nasal-type T/natural killer
(NK) cell lymphoma.8 Chemokines are members of
a family of small proteins that are active as chemoattractants and cell activators.9 Some members of this family have received
considerable attention because they display selectivity of cell targets
and receptors. This selectivity has suggested the possibility that the
cellular composition of inflammatory responses may, in part, be a
function of the chemokines being produced at a site. Except for
preliminary results on expression of IL-8, a neutrophil chemoattractant and activating factor, and the related monocyte chemotactic peptide-1 (MCP-1) that attracts and activates monocytes, there is limited information on the involvement of other chemokines in the pathogenesis of the cellular infiltrates that characterize HD and its histologic subtypes.1,3
In this study, we examined the potential contribution of chemokines to
the inflammatory response in HD tissues and the various disease
subtypes. In particular, we have focused on the CXC chemokines, IP-10
and Mig, that are chemoattractant for T and NK cells and their
relationship to positivity with EBV, and the CC chemokine eotaxin that
is a chemoattractant for eosinophils and its relationship to tissue eosinophilia.
| |
MATERIALS AND METHODS |
Case selection.
Lymph node biopsies were retrieved from the consultation files of one
of us (E.S.J.) in the Hematopathology Section, Laboratory of Pathology,
National Cancer Institute, National Institutes of Health (NIH). Cases
included: HD, 20 cases, further subclassified as mixed cellularity
(MC), 6 cases; nodular sclerosis (NS), 9 cases; nodular lymphocyte
predominant (NLP), 5 cases; and 6 control cases of reactive lymphoid
hyperplasia (RLH). All patients were human immunodeficiency virus (HIV)
negative. HD cases were classified according to the Revised European
American Lymphoma (REAL) classification.10 By
immunohistochemistry, the neoplastic cells (RS, Hodgkin's or "popcorn cells") stained positively with LeuM1 (CD15) and BerH2 (CD30) in the MC and NS subtypes and positively with L26 (CD20) in the
NLP subtype. The extent of tissue eosinophilia was determined by two of
us (J.T.F. and E.S.J.) by counting the number of eosinophils present in
at least 20 separate high powered fields using an ocular grid eyepiece
and calculating the mean number of eosinophils per sample. Within a
given biopsy section, we selected areas involved by HD containing the
greatest proportion of eosinophils. Samples were classified as having 0 eosinophils/high powered field, 1 to 25 eosinophils/high powered field,
or >25 eosinophils/high powered field.
EBV in situ hybridization.
In situ hybridization used an EBV probe specific for EBV-encoded small
RNAs (EBER), as described previously11 using an automated system (Ventana Medical System, Inc, Tuscon, AZ).
Reverse transcriptase-mediated polymerase chain reaction (RT-PCR).
RNA extraction from paraffin-embedded tissue was performed as
previously described.8 Briefly, 6 to 10 20-µm paraffin
sections were deparaffinized three times in xylene (with heating at
55°C for 10 minutes), twice in 100% ethanol, and twice in 70%
ethanol. Sections were suspended in 1 mL extraction buffer (10 mmol/L
NaCl, 50 mmol/L Tris-HCL, pH 7.4, 20 mmol/L EDTA, 1% sodium dodecyl sulfate [SDS]) at 55°C overnight with 500 µg/µL
proteinase K. After addition of 1 mL of RNA Trizol (GIBCO/BRL, Life
Technologies, Gaithersburg, MD) and 200 µL of chloroform, followed by
centrifugation, the aqueous phase was combined with an equal volume of
isopropanol. The precipitated pellet was washed with 70% ethanol and
resuspended in diethylpyrocarbonate (DEPC)-treated water.
RT-PCR applied to highly degraded RNA obtained from paraffin-embedded
tissues was performed as previously described.8 Briefly,
RNA samples were DNAse treated (GIBCO/BRL, Life Technologies), then
subjected to an initial assay for amplifiable contaminating genomic DNA
using primers specific for glyceradehyde-3-phosphate dehydrogenase
(G3PDH) mRNA. Positive samples were retreated with DNase, negative
samples (2 to 5 µg) were reverse transcribed using an RNase H-RT
(Superscript; GIBCO/BRL, Life Technologies). The resultant cDNA (25 to
100 ng) was amplified as previously described.8 The amount
of cDNA used for each amplification reaction was based for each sample on the results of PCR for G3PDH showing equivalent amounts of product
amplified from all samples. The selection of G3PDH was based on the
observation that G3PDH mRNA is not known to vary in human tisses
depending on disease status. Primers, listed in Table 1, were designed for amplification of
short amplicons (80 to 130 bp) from highly degraded RNA and spanned at
least one splice junction. Genomic DNA could be distinguished from mRNA
or cDNA. Amplifications were performed in a thermocycler (Stratagene
Robocycler, La Jolla, CA) adding 1.25 U Taq polymerase (GIBCO/BRL)
after heating at 94°C for 3 minutes ("Hot Start"); followed
by a predetermined number of amplification cycles (94°C, 45 seconds; primer annealing temperature as specified in Table 1 and
extension at 72°C); and maintained at 4°C until analysis. The
number of amplification cycles was determined experimentally for each
primer pair to fit the linear part of the sigmoid curve reflecting the
relationship between the number of amplification cycles and amount of
PCR product. PCR products were detected by quantitating incorporated
32P-labeled nucleotides
[-32P]deoxycytidine triphosphate (dCTP)
(specific activity of  3,000 Ci/mmol) obtained from Amersham, Inc
(Arlington Heights, IL). The entire amplification reaction (50 µL)
was analyzed by electrophoresis on 8% acrylamide (Long Ranger; AT
Biochem, Malvern, PA) Tris-borate EDTA gels (polyacrylamide gel
electrophoresis [PAGE]), followed by autoradiography
and quantitation by phosphorimage analysis using ImageQuantTM v3.3
software (Molecular Dynamics, Sunnyvale, CA). Band
integrations were obtained as the sum of values for all pixels after
subtraction of background (areas around each sample). Integrated values
for each sample were then normalized for the results of parallel RT-PCR
amplification for G3PDH expressed as pixels. The results of RT-PCR
analysis are presented as absolute numbers of normalized arbitrary
units (pixels)/sample. The ability of the RT-PCR assay to detect
quantitative differences in mRNA for each gene product was assessed in
experiments where the input cDNA derived from RNA extracted from
paraffin-embedded tissues was first serially diluted (100 ng to 1 ng)
and then subjected to PCR amplification. Using paraffin-embedded
tissues positive for a given gene product along with appropriate
negative controls, we verified that the intensity of the PCR product
correlated with the dilution of input cDNA in the range used for PCR
(25 to 100 ng). Variability of results from different experiments was
minimized by use of standard control RNA preparations in parallel PCR.
Experiments were considered evaluable only if standard control PCR
results were within 15% of the mean.
IP-10, Mig, and eotaxin immunohistochemistry.
Reactions were performed as previously described.8 Briefly,
to enhance chemokine detection, tissue sections were first treated with
a Target Retrieval Solution (DAKO Corp, Carpenteria, CA) in a microwave
pressure cooker (Nordic Ware, Minneapolis, MN) at maximum power (800 W)
for 8 minutes, then washed in 0.05 mol/L Tris-HCL saline (TBS, pH 7.6 containing 5% fetal calf serum [FCS]; GIBCO Laboratories, Grand
Island, NY) for 30 minutes. The slides were incubated with primary
antibodies including rabbit antihuman IP-10 purified antibody (1:1,000
dilution, Peprotech Inc, Rocky Hill, NJ), or rabbit antihuman Mig
antiserum (1:5,000 dilution, a generous gift from Dr Joshua Farber,
National Institute of Allergy and Infectious Diseases
[NIAID], NIH) overnight at room temperature, or rabbit
antihuman eotaxin antiserum (1:40 dilution, Peprotech Inc) for 30 minutes at room temperature. Antibody dilutions were made with TBS
containing 10% FCS and 0.1% (wt/vol) NaN3. Bound
antibodies were detected with a biotin-conjugated universal secondary
antibody formulation, which recognizes rabbit immunoglobulins (Ventana
Medical Systems). After addition of an avidin-horseradish peroxidase
conjugate, the enzyme complex was visualized with 3,3'-diaminobenzdine
tetrachloride (DAB) and copper sulfate.
Statistical analysis.
Geometric means, standard errors of the mean (SEM) used conventional
formulas. The significance of group differences was calculated by the
Wilcoxon rank sums test. The significance of nonparametric measures of
association was calculated by the Kendall Tau test.
| |
RESULTS |
To assess cytokine and chemokine gene expression in HD tissues, total
RNA was extracted from formalin-fixed, paraffin-embedded tissues (total
number, 20) involved by HD of the MC (6 cases), NS (9 cases), and NLP
(5 cases) subtypes. In situ hybridization for the EBV-encoded small
RNAs (EBERs) showed neoplastic cells latently infected with EBV in 7 of
19 cases (no tissue remained in the paraffin block from one case).
Selected patient and tissue information is listed in
Table 2. Control RNA was extracted from formalin-fixed, paraffin-embedded tissues representative of reactive lymphoid hyperplasia (RLH, 6 cases). All control cases of RLH tested
EBV-negative by EBER-1 in situ hybridization. Using a semiquantitative RT-PCR analysis of tissues involved by HD, we found the PCR products for interferon (IFN)-, TNF-, and for the chemokines Mig, IP-10, RANTES, MIP-1, MDC, and eotaxin to be amplified at variable levels (representative results shown in Fig 1).
When compared with RLH tissues (Fig 2),
levels of expression of IP-10, Mig, RANTES, MIP-1, and eotaxin were
significantly higher in HD tissues (IP-10, P = .04; Mig,
P = .01; RANTES, P = .03; MIP-1, P = .04;
eotaxin, P = .04). In contrast, MDC expression levels
were similar in the two groups (P = .73).
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| Fig 1.
Patterns of cytokine and chemokine mRNA expression in HD
tissues shown by RT-PCR analysis. Total cellular RNA, extracted from
paraffin-embedded tissues representative of HD MC, NS, NLP, and of
lymphoid hyperplasia, was subjected to RT-PCR analysis using
appropriately designed primers.
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| Fig 2.
Levels of chemokine mRNA expression in HD tissues and
lymphoid hyperplasia. Total cellular RNA, extracted from
paraffin-embedded tissues diagnosed with HD ( ) and lymphoid
hyperplasia ( ) was subjected to semiquantitative RT-PCR. After
normalization to a standard RNA preparation and to G3PDH, the results
of phosphorimage analysis are shown and plotted logarithmically as the
geometric means (x/ SEM) of normalized arbitrary units
(pixels)/group for each respective chemokine. SEMs were too small to be
distinguished from the mean.
|
|
The variability in levels of cytokine and chemokine gene expression in
HD tissues prompted us to examine whether the presence of EBV in the
malignant cells and/or the histological subtype might correlate with
certain patterns of cytokine and/or chemokine gene expression. Previous
experiments had demonstrated that, in athymic mice, EBV-infected human
lymphoblastoid cells elicit a characteristic cytokine and chemokine
response, including elevated expression of murine IFN-, IL-6,
TNF-, IP-10, and Mig.6,7 By contrast, EBV-negative
Burkitt cells generally do not elicit this response. We found mean
tissue levels of IP-10, Mig, RANTES, and MIP-1 expression to be
higher in EBV-positive than in EBV-negative HD tissues
(Fig 3), and this difference was
significant for IP-10 (P = .05, Wilcoxon rank sums test),
RANTES (P = .005), and MIP-1, (P = .02) and
approached significance for Mig (P = .1). By contrast, expression levels of MDC and eotaxin were similar (P = .97 in both cases) in EBV-positive and negative HD tissues (Fig
3). Thus, the presence of EBV in HD tissues is generally associated
with higher level expression of certain chemokines, including IP-10, Mig, RANTES, and MIP-1.
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| Fig 3.
Levels of chemokine mRNA expression in EBV-positive ()
and EBV-negative () HD tissues. Total cellular RNA, extracted from
paraffin-embedded tissues diagnosed with MC, NS, or NLP HD was
subjected to semiquantitative RT-PCR. After normalization to a standard
RNA preparation and to G3PDH, the results of phosphorimage analysis are
shown and plotted logarithmically as the geometric means (x/ SEM) of
normalized arbitrary units (pixels)/group for each respective
chemokine. SEMs were too small to be distinguished from the mean.
|
|
Because EBV infection is most frequent in the MC disease subtype (60%
to 70% positive) of HD as compared with the NS (approximately 40%
positive) and NLP (usually EBV-negative) subtypes,10,12 this group might also display increased expression of those
EBV-associated cytokines and chemokines compared with the other disease
subtypes. The seven EBV-positive HD cases studied here were classified
as belonging to the MC subtype in five cases and to the NS subtype in
two cases. When analyzed by subtype (Table
3), the MC group expressed geometric mean levels of IP-10, Mig, and
MIP-1 that were higher compared with the other subgroups, and this
difference reached significance for IP-10 (P = .01) and Mig
(P = .04). Expression of RANTES, which correlated with the
highest degree of significance with EBV-positive status, was most
abundant in the NS subtype, which was largely due to the high levels of
RANTES expression by the two EBV-positive cases in this group.
Paraffin-embedded sections sequential to those used for RNA extractions
were stained with a rabbit antiserum to either human IP-10 or Mig. All
HD tissues studied (Table 2), representative of the MC subtype (6 cases), the NS subtype (9 cases), and the NLP subtype (5 cases) stained
positively for IP-10 and Mig, albeit with variations in intensity
(Fig 4). Consistent with the results of
RT-PCR analysis, staining for these chemokines was generally more
prominent in MC cases than in the other two histologic subtypes. Control RLH tissues generally did not stain or stained very faintly for
IP-10 and Mig (Fig 4). In general, HD tissue staining for these
chemokines was intracellular, the patterns of staining for IP-10 and
Mig were indistinguishable, and positivity for Mig was somewhat more
intense than for IP-10. The brightest cells staining for Mig and IP-10
were identified morphologically as RS and Hodgkin's cells. In general,
staining appeared to be more intense in RS cells in EBV positive versus
EBV negative cases. Other cells staining less intensely for these
chemokines were identified morphologically as endothelial cells lining
capillary vessels, macrophages, lymphocytes, and occasionally,
fibroblasts. These results document the presence of IP-10 and Mig
proteins in HD tissues and identify the RS and Hodgkin's cells as
positive for these chemokines.
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| Fig 4.
Immunohistochemical analysis of IP-10, Mig, and eotaxin
protein expression in HD tissues: MC, NS, and NLP, and lymphoid
hyperplasia. Paraffin-embedded tissue sections were stained with
hematoxylin and eosin (H&E), an anti-IP-10 heteroantiserum (IP-10), an
anti-Mig heteroantiserum (Mig), and an antieotaxin heteroantiserum
(eotaxin). Primary antibodies were detected with biotinylated
antirabbit IgG, followed by streptavidin-peroxidase complexes.
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As detailed above, levels of eotaxin and MDC expression in HD tissues
did not correlate with evidence of tissue infection with EBV. Because
eotaxin has been reported to serve as a specific chemoattractant for
eosinophils, we examined whether a correlation existed between the
degree of tissue infiltration with eosinophils and levels of eotaxin
expression in HD tissues. Levels of eosinophil infiltration were
estimated without knowledge of the results of PCR analysis by scoring
histology slides stained with hematoxylin/eosin. A highly significant
direct correlation (P = .0038) was identified between the
extent of eosinophil infiltration (defined on the basis of the mean
number of eosinophils/high powered field) and levels of HD tissue
expression of eotaxin (Fig 5). By contrast, no significant direct correlation was identified between tissue eosinophilia and levels of expression of IP-10, Mig, MIP-1, and RANTES. As a group, the NS subtype displayed both the highest levels of
tissue eosinophilia and of eotaxin expression when compared with the
other subtypes (Table 3). Although levels of MDC expression in HD
tissues, as a group, were found not to differ significantly from those
of RLH tissues (P = .7, Fig 2), within HD subtypes, MDC
expression was significantly higher in the NS subtype as compared with
the other subtypes (P = .002, Table 3).
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| Fig 5.
Correlation of eotaxin mRNA expression and grade of
tissue eosinophilia in HD. Tissue eosinophilia was quantified by
counting the mean number of eosinophils/high powered field (at least 20 high powered fields were examined in each specimen). Tissue samples
were classified as having 0 eosinophils/high powered field; 1 to 25 eosinophils/high powered field; or >25 eosinophils/high powered
field.
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Paraffin-embedded sections sequential to those used for RNA extractions
were stained with a rabbit antiserum to eotaxin, including HD tissues
representative of the MC (5 cases), NS (7 cases), and NLP (4 cases)
subtypes, as well as control RLH tissues (9 cases). Consistent with
RT-PCR results, eotaxin protein expression was generally more intense
in the NS subtype (3 cases) compared with the other subtypes and
control RLH. Cells staining for eotaxin were identified morphologically
as RS and Hodgkin's cells, fibroblasts, macrophages, lymphocytes, and
medial smooth muscle cells of medium and large-sized vessels (Fig 4).
| |
DISCUSSION |
In the present study, we have explored a potential role for chemokines
in the pathobiology of HD. Overall, HD tissues displayed higher levels
of expression of the chemokines IP-10, Mig, MIP-1, RANTES, and
eotaxin, but not MDC, when compared with lymph node tissues diagnosed
with RLH. Within HD tissues, we found major differences in chemokine
gene expression among the different disease subtypes. Mig and IP-10
were expressed at significantly higher levels in the MC subtype
compared with the other subtypes, whereas eotaxin and MDC were
expressed preferentially in the NS subtype. RANTES expression was high
in both the MC and NS subtypes, and Mig was high in the NLP subtype.
On the basis of previous studies6,7 in athymic mice that
had identified a pattern of chemokine response induced by EBV-infected, but not uninfected, B cells, we looked for differences of chemokine expression in EBV-positive and negative HD tissues. Similar to the
situation in mice,6,7 we found levels of IP-10, Mig, and
RANTES to be higher in EBV-positive than in EBV-negative HD tissues.
MIP-1 expression also was significantly higher in EBV-positive than
in EBV-negative HD tissues. By contrast, eotaxin and MDC expression
levels were similar in HD tissues with or without evidence of EBV
infection. When we analyzed the potential relationship between eotaxin
expression and eosinophil infiltration, a highly significant
correlation emerged, suggesting that eotaxin is a critical mediator of
eosinophil recruitment in HD tissues.
Several factors have been proposed to promote eosinophil attraction,
including platelet activating factors, RANTES, IL-16, MCP3, MCP4,
myeloid progenitor inhibitory factors 1 and 2 (MPIF-1 and 2),
hemofiltrate C-C chemokine-2 (HCC-2), secretoneurin,
eotaxin, and eotaxin-2.13-23 The latter two chemokines have
received considerable attention because, unlike all other factors, they
appear to signal through a single receptor, CCR3, that is expressed at
high levels on eosinophils and T-helper cells, but is not expressed on
neutrophils or monocytes.18,24-29 This observation might
explain why we observe a rich eosinophilic and T-cell inflammatory
infiltrate in HD tissues where there is increased eotaxin expression.
These results suggest that, in addition to its previously recognized
functions in allergic and inflammatory disorders,30-33 eotaxin is likely to play an important role in promoting eosinophil recruitment to HD tissues.
Previous studies have documented production of abnormally high levels
of IFN- and various cytokines in HD.1-4 Because some of
these mediators can play an important role in regulation of chemokine
production, it is not surprising that we found high level expression of
certain chemokines in HD tissues. Expression of IP-10 and Mig that are
IFN- inducible chemokines is consistent with the previously
recognized abundance of IFN- in HD.1,34,35 Expression of
eotaxin, which is inducible by IL-3,17 is consistent with
increased IL-3 levels reported in this malignancy (data not shown).4 However, predictions on chemokine expression are
difficult, particularly in situations, such as HD, in which abnormal or
unbalanced production involves so many cytokines that participate in
complex networks.
The CXC chemokines, IP-10 and Mig, share a common receptor, CXCR3,
which is expressed on T and NK cells, but is undetectable on
monocyte/macrophages, neutrophils, B cells, and endothelial cells.36,37 Accordingly, IP-10 and Mig are chemoattractants for T and NK cells.37 Based on this information, one might
expect greater levels of infiltration with T, NK, and other cells in EBV-positive than in EBV-negative HD tissues. However, previous studies
have failed to identify histologic and immunohistochemical differences
between EBV-positive and EBV-negative HD, except those expected from
the different frequencies of EBV infection in the MC (60% to 70%), NS
(about 40%), and NLP (usually EBV negative) subtypes. Of note, one
study suggested that EBV-positivity or latent membrane protein 1 (LMP1) protein expression was a favorable prognostic
factor in HD,38 a result that is consistent with the known
antitumor effects of IP-10 and Mig.6,7,39
Immunohistochemical studies localized IP-10 and Mig to Hodgkin's and
RS cells and to some surrounding inflammatory cells. We know that
virtually all Hodgkin's and RS cells are infected with EBV in
virus-positive HD cases and display a type II virus latency, with
expression of EBNA1 and LMP1 proteins, but not other EBV latency
proteins.4,40,41 LMP1, an integral membrane protein, is
emerging as a multifunctional protein that plays a critical role in EBV
immortalization and is responsible for many of the phenotypic changes
characteristic of EBV-immortalized cells. Because LMP-1 serves as a
potent activator of the transcription factor NF- B,42-44
it may promote the production of a variety of cytokines and chemokines,
including IP-10, Mig, RANTES, and MIP1-, genes that contain B
elements. In athymic mice, we found that LMP1 expression alone in
EBV-negative Burkitt cells induced a host response that included
production of murine IP-10 and Mig.39 Thus, LMP1 is likely
to represent an important inducer of IP-10 and Mig expression within
the EBV-infected Hodgkin's and RS cells, as well as by other
inflammatory cells reactive to the neoplastic cells.
Expression of MDC mRNA has been shown to be enhanced by IL-1,
TNF-, and lipopolysaccharide (LPS)45 and
can promote chemoattraction of monocytes, monocyte-derived dendritic
cells, and NK cells acting through the CCR4 receptor.46 It
is intriguing that MDC is expressed at markedly high levels in the NS
subtype of HD, and this result will require further investigation.
The abundance of inflammatory cells surrounding few neoplastic cells
and the associated abnormal or unbalanced production of cytokines have
been interpreted as reflective of an intense, but ineffective,
antitumor response.4 HD patients display a variety of
T-cell immune defects, including the absence of CD8-positive T cells
surrounding the neoplastic cells and a failure to develop LMP-1-specific cytotoxic cells that may allow RS and Hodgkin's cells
to escape immune destruction.4 Nevertheless, patients with
HD do not develop systemic EBV-positive lymphoproliferative disease, as
may be observed in cases of congenital or acquired severe T-cell
immunodeficiency. One interesting feature of the T cells infiltrating
the neoplastic cells in HD is their failure to express the activation
marker CD26 molecule that possesses dipeptidyl peptidase IV
activity.4 Recently, it was found that chemokines can serve
as substrates for CD26.47 Once truncated by CD26,
chemokines can display functional differences from the native
molecules, suggesting that CD26 processing may represent an important
physiological mechanism for regulation of chemokine function.47
Thus, in addition to other previously reported immune abnormalities,
the results presented here provide evidence for the occurrence of broad
chemokine expression in HD tissues that could explain some of the
characteristic cellular infiltrates in the different subtypes.
Persistent chemokine stimulation by EBV and other stimuli combined with
a potentially defective chemokine processing mechanism may contribute
to a stagnant antitumor response in HD.
| |
ACKNOWLEDGMENT |
We thank Dr Barry Cherney, Jared Berkowitz, and Karen Jones for
laboratory assistance; Andrew Weiss for technical assistance with EBV
in situ hybridizations; and Dr Laszlo Krenacs, Dr Xu Yao, and Dr
Leticia Quintanilla-Fend for technical advice and assistance with
immunohistochemical analyses.
| |
FOOTNOTES |
Submitted August 19, 1998; accepted December 3, 1998.
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.
Presented in part at the 39th Annual Meeting of the American Society of
Hematology, held in San Diego, CA, December 5-9, 1997.
Address reprint requests to Julie Teruya-Feldstein, MD,
Hematopathology Section, Laboratory of Pathology, National Cancer
Institute, National Institutes of Health, Bldg 10, Room 2A33, 10 Center
Dr, MSC 1500, Bethesda, MD 20892-1500; e-mail: jtf{at}helix.nih.gov.
| |
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ABSTRACT
INTRODUCTION