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CHEMOKINES
From the Institute of Pathology and the Theodor Kocher
Institute, University of Bern, Switzerland.
Lymph nodes with Hodgkin disease (HD) harbor few neoplastic cells
in a marked leukocytic infiltrate. Since chemokines are likely to be
involved in the recruitment of these leukocytes, the expression of
potentially relevant chemokines and chemokine receptors were
studied in lymph nodes from 24 patients with HD and in 5 control lymph nodes. The expression of regulated on activation, normal
T cell expressed and secreted (RANTES), monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein
(MIP)-1 Hodgkin disease (HD) is characterized by the
presence of few neoplastic mononuclear Hodgkin cells and polynuclear
Reed-Sternberg (H-RS) cells surrounded by a dense nonneoplastic
leukocytic infiltrate consisting of lymphocytes, plasma cells,
granulocytes, and macrophages.1 In the nodular sclerosis
(NS) and mixed cellularity (MC) subtypes, CD4+ T cells are
particularly frequent in this infiltrate. They almost exclusively have
the CD45RO+ and CD45RB+ phenotype and are in a
state of activation that, based on their cytokine expression, appears
to be related to a T-helper 2 (TH2)-mediated immune
response.2-4 H-RS cells express various cell surface
molecules, including CD58 (intercellular adhesion molecule 1),
CD40, CD30, and CD80 (B7-1) as well as major histocompatibility complex
class II molecules,5,4 and produce numerous cytokines,
such as interleukin (IL)-1, IL-5, IL-6, IL-9, macrophage-colony
stimulating factor, tumor necrosis factor (TNF)- Few studies have addressed the role of chemokines in HD. For instance,
the IL-8 gene expressed by reactive cells in lymph nodes involved by HD
is related to the presence of neutrophilic granulocytes.8
Studies based mainly on reverse-transcription polymerase chain reaction
technology show that HD tissues also express higher levels of inducible
protein 10 (IP-10), monokine induced by interferon It is likely that lymphocytes and other leukocytes in the background of
HD do not solely represent residual nonfunctioning tissues but may be
attracted by and also interact with neoplastic cells and potentially
affect the tumor progression. Such an "inflammatory" infiltrate
could therefore represent a potential therapeutic mechanism to control
the spread of the disease or to reduce tumor growth and/or volume.
Thus, to better understand the mechanisms involved in the recruitment
or trapping of nonneoplastic leukocytic infiltrates in HD, we studied
the expression patterns of the T-cell-attracting CC chemokines RANTES,
monocyte chemotactic protein (MCP)-1, MIP-1 Cell culture
Tissue samples
Preparation of cell suspensions from fresh tissues Control and HD lymph nodes were cut into small pieces and gently pressed with a glass homogenizer. Dissociated cells were collected, and the remaining tissue pieces were digested for 2 × 30 minutes at 37°C with collagenase V (1 mg/mL, Sigma Chemical, St Louis, MO) in 10% Hanks balanced salt solution (HBSS) supplemented with 5% horse serum (HS), 0.5 mM MgCl2, 0.6 mM MgSO4, and 1.3 mM CaCl2, and with Hepes added to 10 mM (pH 7.4). Cells were pooled and strained through a 40-µm-wide mesh, washed twice, and resuspended in HBSS and 5% HS at a final concentration of 107/mL.35S-labeled riboprobes Probes for in situ hybridization were prepared as previously described.12 Briefly, the following complementary DNA (cDNA) fragments were used: a 410-base pair (bp) EcoRI - ApaI fragment (position 1-411 of the coding sequence) of the human RANTES cDNA (Genentech, San Francisco, CA), subcloned into a pBluescript KS+ expression vector (Stratagene, La Jolla, CA); a 650-bp NotI - HindIII fragment of the human MCP-1 cDNA (provided by T. Yoshimura, Frederick, MD), subcloned into a pBluescript SK ; a 351-bp SmaI
fragment (position 81-371 of the coding sequence) of the human MIP-1
cDNA, subcloned into a pGEM-7 (Invitrogen, Groningen, Netherlands); a
531-bp EcoRI fragment (position 1-531 of the coding
sequence) of the human MIP-1 cDNA (provided by R. Gillitzer,
Würzburg, Germany), subcloned into a pBluescript SK+;
and a 1.1-kilobase BamHI - SalI fragment of human CCR5 cDNA (provided by C. Combadière, Paris, France), subcloned into a pBluescript II SK+. After linearization with the
appropriate restriction enzymes, sense and antisense probes were
generated by means of SP6, T3, or T7 RNA polymerases (Roche
Diagnostics, Basel, Switzerland) and 35S-CTP (Amersham,
Arlington Heights, IL). The labeled probes were size-reduced by
alkaline hydrolysis to an average length of 100 to 200 bases before precipitation.
In situ hybridization In situ hybridization of sections from formaldehyde-fixed and paraffin-embedded tissues was performed with minor modifications as previously described.12 Tissue sections were dewaxed and rehydrated in graded ethanol. After treatment with 100 µg/mL proteinase K (Roche Diagnostics) in 100 mM Tris-HCl, pH 8.0, and 50 mM EDTA at 37°C for 30 minutes, tissues were hybridized with the indicated labeled sense or antisense probes overnight at 50°C in a moist chamber. With the exception of proteinase K digestion at 1 µg/mL, sorted cells on slides were treated identically. Nonhybridized probe was removed by treatment with 20 µg/mL RNAse A and 1 U/mL RNAse T1 (Sigma Chemical). Slides were dipped into NTB-2 emulsion (Eastman-Kodak, New Haven, CT) diluted 1:2 in 800 mM ammonium acetate, pH 7.5. After exposure in the dark at 4°C for 4 weeks, slides were developed in Kodak PL-12 solution and counterstained with Gill's hematoxylin.Cells were considered to be positive for messenger RNA (mRNA) expression when they had at least 3 times as many silver grains as the highest background obtained with the corresponding sense probe. In tissue sections, we evaluated 5 randomly selected fields (0.16 mm2) and calculated the mean value of positive cells, expressed as percentage of total nucleated cells. For evaluation of sorted cells, at least 500 cells per population were counted. The cells labeled with the sense probe never exceeded 5% of the cells labeled with the antisense probe. Immunohistochemistry All paraffin-embedded tissue samples were routinely studied by immunohistochemistry with commercially available antibodies directed against leukocyte common antigen, CD20, CD79a, CD3, CD30, CD15, EMA, Epstein-Barr virus (EBV)-latent membrane protein, J-chain as well as kappa and lambda light chains. Tissue from 7 HD and 4 control lymph nodes were snap-frozen and cut into 5-µm-thick sections. After fixation in acetone and rehydration, tissue sections were incubated for 60 minutes at room temperature with 1:100 dilution of anti-CCR5 (clone 2D7, PharMingen, San Diego, CA) or anti-CCR3 (clone 7B11, Leukosite, Cambridge, MA) as well as anti-CXCR3 (clone LS11). Isotype-matched mouse immunoglobulin (Ig)-G (Dako, Glostrup, Denmark) was used as control. After washing with Tris-buffered saline, slides were incubated for 45 minutes with a biotin-conjugated goat antimouse IgG (Dako). Following washing, slides were incubated for 45 minutes with an alkaline phosphatase- or horseradish peroxidase-conjugated avidin-biotin complex (Dako). The color reaction was developed with New Fuchsin (Sigma Chemical) or diaminobenzidine (Merck, Gibbstown, NJ). Sections were counterstained with Gill's hematoxylin.Fluorescence-activated cell sorting and analysis Cells isolated from 2 cases of NS and 2 control lymph nodes were labeled with anti-CD3, anti-CD4, anti-CD8, anti-CD14, anti-CD19, or anti-CD20 monoclonal antibodies (mAbs) (all from Pharmingen), diluted according to the manufacturer's instructions, sorted on polylysine-coated glass slides (Menzel Gläser, Braunschweig, Germany) using a FACS Vantage (Becton Dickinson Immunocytometry Systems, Basel, Switzerland), and subsequently hybridized with sense and antisense probes for RANTES, MCP-1, MIP-1, MIP-1, and CCR5.
For double immunostainings, cell suspensions were prepared from 5 fresh HD tissues and 5 control lymph nodes. Cells were first incubated with mouse Abs against CCR5 (clone 45523.111, R&D Systems, Minneapolis, MN), CCR3, or CXCR3 (see above) followed by phycoerythrin (PE)- or fluorescein isothiocyanate (FITC)-conjugated antimouse IgG F(ab')2 fragments (Southern Biotechnologies, Birmingham, AL). Second antigen staining was performed with PE- or FITC-conjugated mouse Abs against CD3, CD4, CD8, and CD19 (all from PharMingen). Isotype-matched mouse IgG was used as a control. Additionally, suspensions of L428 and KMH2 cell lines, cultured with or without ConA or LPS, were stained with mAbs against CCR5, CCR3, or CXCR3 (see above) and analyzed for receptor expression on FACScan. Chemotaxis assay Cell suspensions from lymph nodes with HD were prepared as described above and kept overnight in RPMI at 37°C. Cell migration was measured in 48-well chemotaxis chambers (Neuro Probe, Cabin John, MD). Phytohemagglutinin (PHA)-activated peripheral blood lymphocytes were used as a positive control in the migration assay. In brief, chemokines in Hepes-buffered RPMI 1640 supplemented with pasteurized plasma protein (Swiss Red Cross Laboratory, Bern, Switzerland) were added to the lower wells and 100 000 cells resuspended in the same medium to the upper wells. Polyvinylpyrrolidone-free polycarbonate membranes (Poretics, Livermore, CA) with 3-µm pores coated with type IV collagen were used. After incubation for 2 hours, the membrane was removed, washed on the upper side with phosphate-buffered saline, fixed, and stained. Migrated cells were counted at 1000 × magnification in 5 randomly selected fields per well. The assay was performed in triplicate.
Expression of CC chemokine genes in lymph nodes with HD Cells expressing RANTES mRNA were the most numerous, were evenly distributed, and constituted 25% (SE, 9%) of all nucleated cells of the nonneoplastic leukocytic infiltrate of HD lymph nodes. The average percentage (SE) of cells expressing MCP-1, MIP-1, and MIP-1 was
9.0% (2.5%), 7.5% (2.3%), and 12.5% (3.8%), respectively (Figure
1). As observed for RANTES, positive
cells were found largely in the background infiltrate. MCP-1 and, in
particular, MIP-1 transcripts were occasionally found in
connective-tissue fibroblasts, especially in the NS subtype. H-RS
cells, recognized by their morphology, consistently lacked
hybridization signals for all the chemokines analyzed (Figure 1). The
chemokine gene expression pattern was similar, in both qualitative and
quantitative terms, at the time of first diagnosis and in relapses.
There was no dependence on the EBV status or on the histological
subtype. In control lymph nodes with follicular or diffuse lymphatic
hyperplasia, chemokine-expressing cells never exceeded 1% of the
entire cell populations, and the positive cells were scattered
throughout the lymphoid tissue without relation to any particular
anatomical structure of the lymph node.
We also analyzed 3 T-cell lymphomas. Scattered signals for all 4 chemokines were observed throughout the involved lymph nodes. Interestingly, in a single case of ALCL, expression for RANTES and MCP-1 was restricted to neoplastic cells, with only rare transcripts in the reactive infiltrate (data not shown). Chemokine expression pattern in T lymphocytes and macrophages The markedly increased expression of RANTES, MCP-1, MIP-1, and
MIP-1 in HD as compared with control lymph nodes prompted us to
assess the nature of the chemokine-producing cells. Single-cell suspensions were obtained from lymph nodes of 2 patients with NS
subtype HD and negative EBV status and from 2 control lymph nodes. The
cells were sorted for CD3, CD4, CD8, CD14, and CD19 and were analyzed
on slides for chemokine expression by in situ hybridization. As shown
in Table 1, in lymph nodes with HD,
RANTES expression was markedly up-regulated in CD4+ and
CD8+ T cells, which represented 46% (mean of 2 experiments) and 13.3% of the sorted cells, respectively. By contrast,
the expression of MCP-1, MIP-1, and MIP-1 was up-regulated in
CD14+ macrophages, which constituted 9.0% of the cells
sorted from the nonneoplastic leukocytic infiltrate. In control lymph
nodes, chemokine expression was low or moderate, except for MIP-1 in macrophages.
Expression of CCR3 and CCR5 We studied the expression of 2 receptors that appear particularly relevant for the action of the detected chemokines, in particular CCR5 and CCR3 for RANTES and CCR5 for MIP-1 and MIP-1. Cells expressing CCR3 and CCR5 were very rare in control lymph nodes. In
contrast, both receptors were strongly expressed in about half the
nonneoplastic leukocytes of lymph nodes involved by HD (Figure 2). Immunohistochemical stainings
suggested that both chemokine receptors were absent in H-RS cells. We
thus analyzed 2 HD-derived cell lines, L428 and KMH2, by flow
cytometry. Both were negative for CCR3 and CCR5 even after the cells
were cultured for 10 days in the presence of ConA or LPS (data not
shown). We also studied the expression of these receptors in T cells
freshly isolated from control and HD lymph nodes. Compared with control
lymph nodes, a marked up-regulation of CCR5 (expressed as mean
percentage [SE]) was found in CD4+ T cells (1.5%
[0.4%] and 44.2% [6.3%], respectively) but not in
CD8+ T cells (1.3% [0.5%] and 10.0% [4.4%],
respectively), whereas CCR3 expression was moderately up-regulated in
both subsets (15.2% [2.5%] and 17.2% [1.1%] for
CD4+ and CD8+ T cells, respectively), as shown
in Figure 2. We then compared the expression of CCR3 and CCR5 in T
cells from HD with the expression of CXCR3, which is the receptor for
IP-10 and Mig, ie, chemokines involved in T-cell chemotaxis and known
to be highly expressed in HD.9 Immunohistochemically,
CXCR3 did not appear to be up-regulated in HD lymph nodes. It was less
commonly expressed than CCR3 and CCR5, since it was detected only in
about one fifth of the nonneoplastic leukocytes of both HD and control
lymph nodes (data not shown). Flow cytometry studies on
lymphocytes freshly isolated from HD and control lymph nodes, however,
showed a moderate up-regulation of CXCR3 expression in CD4+
T cells (51.7% [6.3%] and 28.2% [2.6%], respectively) but not in other lymphocytes subsets, ie, CD8+ cells or B
cells.
Of the nonneoplastic leukocytic infiltrate sorted from HD lymph nodes,
38% (SE, 3.2%) consisted of CD19+ B cells. Unexpectedly,
36.6% (8.8%) and 49.6% (19.9%) of this lymphocyte subset showed
CCR3 and CCR5 expression, respectively. Similar results were obtained
by sorting B cells with anti-CD20 antibodies. No expression of these
receptors was found in B cells of control lymph nodes (Figure
3). To assess whether CCR5 protein expression in HD lymph nodes is due to de novo synthesis or to relocation of pre-existing receptor to the cell surface, we performed in situ hybridization studies on formaldehyde-fixed and
paraffin-embedded tissue samples. CCR5 gene expression could be
detected in approximately 10% of the nonneoplastic cells of HD lymph
nodes (Figure 4) whereas it was not
detected in control lymph nodes. The studies on freshly isolated cells
from HD lymph nodes showed CCR5 gene expression in the same cell subset
identified by flow cytometry, namely, in CD4+ T cells and
CD19+ B cells and, in addition, also in CD14+
macrophages (Figure 4).
Migration assays with nonneoplastic cells of HD To further characterize the biological properties of the CCR5, CCR3, and CXCR3 receptors, we tested the migratory capacity of freshly isolated cells from HD lymph node. IP-10 (ligand of CXCR3) and RANTES (ligand of CCR3 and CCR5) elicted a migration response with typical bimodal concentration dependence (Figure 5). The highest numbers of migrated cells were obtained with IP-10 and RANTES. Maximum migration activity was reached at 100 nM for both chemokines. Only a weak but significant migration was observed with MIP-1, whereas no response to MCP-1 was
observed (data not shown).
We demonstrate a prominent expression of the T-cell-attracting
chemokines RANTES, MCP-1, MIP-1 Whether the marked up-regulation of all the 4 analyzed chemokines in HD
represent a disease-specific phenomenon is arguable. However, we never
observed a comparable high expression of RANTES in chronically inflamed
tissues.20 In addition, in the 3 lymph nodes with T-cell
lymphoma, including one Hodgkin-like anaplastic large-cell lymphoma,
only few chemokine-expressing cells were detected by in situ
hybridization in the nonneoplastic leukocytic infiltrates. Therefore,
the chemokine profile observed in the present work can reflect an
unusual state of cellular activation occurring specifically in
HD.3,4 The marked up-regulation of CCR3 and CCR5 in HD as
assessed by immunohistochemistry and by flow cytometry may also be
related to similar mechanisms. CCR3 binds RANTES, MCP-2/3/4, eotaxin,
and eotaxin-221-26 and is strongly expressed on eosinophils
as well as on some T subsets.27 CCR5 recognizes MIP-1 It is generally assumed that T lymphocytes in the nonneoplastic
leukocytic infiltrates of HD are associated with a
TH2-mediated immune response.2-4 Our findings
of a prominent eotaxin gene expression in HD (data not shown) confirm
previous studies9 and support the notion that T cells in
the nonneoplastic infiltrate of HD may represent functionally
differentiated TH2 cells. An increasing body of evidence,
however, suggests that CCR5 is characteristic of the TH1
helper phenotype.30-33 Thus, the finding of CCR5
up-regulation in HD may indicate that the characteristics of T
lymphocytes surrounding H-RS cells are consistent not only with a
TH2 status, but also with a TH1 profile. A
possible TH1 mediation of the local immune response is
further sustained by our finding of a moderate CXCR3 up-regulation in
CD4+ T cells from HD lymph nodes and by the migration
activity of freshly isolated nonneoplastic cells from HD lymph nodes
after exposure to the natural ligand of CXCR3, IP-10. It is possible that a deregulated cytokine production in HD leads to an excessive chemokine receptor up-regulation in T cells. However, cytokines known
to be highly expressed in HD tissues, such as IL-13,7 TNF- A novel and unexpected finding of this study is the expression of CCR3 and CCR5 on B cells isolated from lymph nodes with HD. We did not detect CCR3 and CCR5 on B lymphocytes isolated from control lymph nodes. To our knowledge, studies on chemokine receptors have been carried out on peripheral blood lymphocytes, which, compared with lymphocytes directly isolated from diseased tissues, possibly have a different chemokine receptor expression. We do not know whether CCR3 and CCR5 expression on B cells reflects a HD-specific disregulation of the cytokine/chemokine network or if it represents a more general phenomenon. So far, we were unable to demostrate similar expression patterns on B lymphocytes isolated from inflamed nonneoplastic lymph nodes, a panel of non-Hodgkin lymphomas and B lymphocytes isolated from samples with colonic cancers (data not shown). The biological significance of this finding in the context of HD is unknown. Functional assays are clearly limited by the small numbers of available fresh tissues. The expression of CCR3 and CCR5 on B cells, however, is not necessarily linked to migration but may also mediate increased IgE and IgG4 production.35 In conclusion, our data indicate that CC chemokines attracting T cells play an important role in the formal pathogenesis of HD. The recruitment of nonneoplastic leukocytes in HD is most likely sustained by an autocrine loop of activation and may not be ascribed solely to the presence of H-RS cells. Up-regulation of CCR3 and CCR5 appears to be characteristic of the nonneoplastic leukocytic infiltrates of nodal HD. Additional studies are clearly needed to further elucidate the potential role of CC chemokine receptors in B-cell chemotaxis and/or activation in tissues.
We thank M. Lis for the excellent technical work, C. Vallan for cell-sorting expertise, and M. Baggiolini for useful discussion and critical reading of the manuscript.
Submitted May 8, 2000; accepted November 6, 2000.
Supported by Swiss National Science Foundation grants 31-52427.97 (L.M.) and 31-53961.98 (C.M.) and the Foundation San Salvatore, Lugano, Switzerland (L.M.).
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: Luca Mazzucchelli, Institute of Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland; e-mail: mazzucch{at}patho.unibe.ch.
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  Y. Ma, L. Visser, H. Roelofsen, M. de Vries, A. Diepstra, G. van Imhoff, T. van der Wal, M. Luinge, G. Alvarez-Llamas, H. Vos, et al. Proteomics analysis of Hodgkin lymphoma: identification of new players involved in the cross-talk between HRS cells and infiltrating lymphocytes Blood, February 15, 2008; 111(4): 2339 - 2346. [Abstract] [Full Text] [PDF]
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 G. Badr, G. Borhis, D. Treton, C. Moog, O. Garraud, and Y. Richard HIV Type 1 Glycoprotein 120 Inhibits Human B Cell Chemotaxis to CXC Chemokine Ligand (CXCL) 12, CC Chemokine Ligand (CCL)20, and CCL21 J. Immunol., July 1, 2005; 175(1): 302 - 310. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
(Mig), regulated
on activation, normal T cell expressed and secreted (RANTES),
macrophage inflammatory protein (MIP)-1
) and
HD lymph nodes (
). The graphs represent the mean percentage (SE) of
stained cells of 5 distinct experiments.
