|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Prepublished online as a Blood First Edition Paper on April 17, 2002; DOI 10.1182/blood-2002-01-0099.
REVIEW ARTICLE
From the Amgen Research Institute, Ontario Cancer
Institute, the Departments of Medical Biophysics and Immunology,
University of Toronto, Ontario, Canada.
The clinical and pathologic features of classical Hodgkin lymphoma
(cHL) reflect an abnormal immune response that is thought to be due to
the elaboration of a variety of cytokines by the malignant
Reed-Sternberg (RS) cells or surrounding tissues. The majority of cHL
cases are characterized by expression of tumor necrosis factor receptor
(TNFR) family members and their ligands, as well as an unbalanced
production of Th2 cytokines and chemokines. Activation of TNFR members
results in constitutive activation of nuclear factor- Classical Hodgkin lymphoma (cHL) is a lymphoid
malignancy with characteristic features that distinguish it from
nodular lymphocyte-predominant HL (NLPHL) and non-Hodgkin lymphomas
(NHLs).1,2 The malignant cells in cHL, termed the
Reed-Sternberg (RS) cells, constitute only a minor component of the
tumor, whereas the majority of the malignancy is composed of a mixed
inflammatory infiltrate variably composed of lymphocytes, eosinophils,
fibroblasts, macrophages, and plasma cells. Patients with cHL also
commonly present with constitutional symptoms such as fever, weight
loss, and night sweats, and an apparent systemic defect in
cell-mediated immune responses. Many of these distinctive clinical and
histopathologic features of cHL reflect an abnormal immune response
thought to be due largely to the effects of a wide variety of cytokines
and chemokines that are primarily produced by the RS cells, but also secondarily by the surrounding reactive infiltrate. This review summarizes the data on cytokine production in cHL, examines cytokine signaling, and discusses the role of cytokines in the clinical and
pathologic features of this disease.
Classical HL is now considered a distinct clinicopathologic entity from
NLPHL and can be divided into 4 morphologic subtypes: nodular sclerosis
cHL (NSHL), mixed cellularity cHL (MCHL), lymphocyte-rich cHL (LRCHL),
and lymphocyte-depleted cHL (LDHL).2 There are few data on
cytokine involvement in LRCHL and LDHL, because each disease comprises
less than 5% of all cHL cases. As a result, nearly all of the data on
the role of cytokines in cHL are derived from the study of NSHL and
MCHL cases.
Cytokines are low-molecular-weight proteins with a wide variety of
functions. They not only regulate immune and inflammatory responses but
also contribute to hematopoiesis, wound healing, and other biologic
processes. Cytokines are extremely potent molecules active in nanomolar
to picomolar concentrations. Typically, a cytokine either acts in a
paracrine manner to modulate the activity of surrounding cells, or in
an autocrine fashion to affect the cell that produced it. In the
context of cHL, cytokines produced by RS cells are thought to
contribute to the pathogenesis of this disease both by acting as
autocrine growth factors and by initiating and sustaining the reactive
infiltrate. Alternatively, cytokines produced by surrounding reactive
cells may be contributing to RS cell proliferation and survival.
The expression and activity of cytokines in cHL can be studied using
cell lines derived from RS cells and in primary cHL tissues. Each
approach has its limitations, so that a combination of both strategies
provides the most comprehensive information on the activity of a
specific cytokine. Cell lines derived from RS cells have been extremely
useful in the study of cHL.3,4 However, outgrowth of such
a cell line from cHL patient tissues is extremely rare, so that the few
cell lines available may not represent the full spectrum of clinical
and pathologic features of this disease. The RS cell lines that have
been established are overrepresentative of patients with advanced stage
disease, and those with disease involving pleural effusions, peripheral
blood, or bone marrow. Furthermore, only one cell line, L-1236, has
been definitively identified as being derived from RS
cells.5,6 Unequivocal proof that the other cell lines are
derived from RS cells is lacking, but extensive analysis of their
morphologic, phenotypic, and genetic features has led the research
community to generally regard most of them as being derived from RS
cells.3,4
Analysis of short-term cultures of primary cHL biopsy material is
hampered by the fragility of freshly isolated RS cells and contamination by the reactive infiltrate. Therefore, the activity of
cytokines on primary RS cells is difficult to demonstrate directly and
indirect evidence, such as the expression patterns of cytokines and
their receptors, activation of downstream signaling molecules, and
correlation of cytokine expression with expected pathologic features,
must be relied on. Because cytokines are active at very low
concentrations, methods for determining cytokine messenger RNA (mRNA)
and protein expression in primary tissues must be very sensitive.
Cytokine mRNA levels can be assessed in whole tissue extracts by
Northern analysis, but this method does not allow localization of
expression to specific cell populations, and may not be sufficiently
sensitive if the cytokine is expressed by a small population of cells.
In situ hybridization (ISH) techniques using radio-labeled RNA probes
have been very useful for detecting cytokine mRNA levels in
formalin-fixed, paraffin-embedded tissues. ISH is highly sensitive and
allows retention of the morphology of positively staining cells. mRNA
expression can also been studied on the single-cell level on RS cells
isolated from cell suspensions.7 However, the presence of
mRNA does not confirm the presence of the protein product, which
requires examination by immunohistochemistry (IHC). A combination of
ISH and IHC is therefore the most effective strategy for determining
cytokine expression in tissue sections.
The human adaptive immune response can be divided into 2 distinct
branches: the humoral immune response, which targets extracellular pathogens by stimulating B cells to produce antibodies, and the cell-mediated immune response, which targets intracellular pathogens by
activating CD8+ cytotoxic T cells and macrophages.
CD4+ helper T cells are crucial for regulating both types
of responses and can be classed into 2 mutually exclusive subsets: T
helper type 1 (Th1) and Th2 cells.8 Th1 cells, which
require interleukin 12 (IL-12) for their differentiation,
characteristically produce IL-2 and interferon- Th2 cytokines
IL-4 and IL-13.
Interleukin 4 and IL-13 are important cytokines that share many
biologic activities.9,10 Both IL-4 and IL-13 regulate the
humoral immune response by stimulating the proliferation and survival
of B cells and triggering Ig class switching. IL-4 (but not IL-13) is
required for the differentiation of Th2 cells.
 chain and an IL-13-specific receptor chain, IL-13R1. IL-4R expression has been demonstrated in 3 RS cell
lines21 but has not been investigated in primary cHL
samples. IL-13R1 is expressed by 6 RS cell lines
examined19,21 and by RS cells in 95% of cHL cases as
determined by ISH or IHC.19,20 The expression of both
IL-13 and its receptor by RS cells is consistent with a role for IL-13
as an autocrine growth factor for these cells. Indeed,
antibody-mediated neutralization of IL-13 in the IL-13+ RS
cell lines HDLM-2 and L-1236 led to a dose-dependent inhibition of
proliferation in both cell lines and the induction of apoptosis in
L-1236 cells (but not in HDLM-2 cells).14,18,21 However, treatment of the IL-13+ RS cell lines L-428 and KM-H2 with
the same anti-IL-13 antibody had no effect on cell proliferation.
IL-5. Interleukin 5 is a Th2 cytokine essential for the growth and differentiation of eosinophils. It is also a B-cell growth factor in mice (but not in humans).22 IL-5 is expressed by 2 of 6 RS cell lines11,18 and has been identified in primary RS cells from tumors with tissue eosinophilia.23 The proliferation of 2 IL-5+ RS cell lines (L-428, KM-H2) was not affected by antibody-mediated neutralization of IL-5, suggesting that IL-5 is not an autocrine growth factor for cHL.18 IL-6.
Interleukin 6 was first identified as a T cell-derived cytokine that
induces the maturation of B cells into antibody-producing plasma cells.
IL-6 also induces hematopoiesis from stem cells and acute phase
reactions by hepatocytes.24 IL-6 expression has been
widely studied in RS cell lines and in primary cHL cases by Northern
analysis, ISH, and IHC. IL-6 was expressed by 5 of 7 RS cell
lines,5,11,12,25 and in RS cells from 65% to 100% of cHL
cases.12,16,25-28 IL-6 was also occasionally expressed by
lymphocytes and macrophages within the reactive infiltrate. Interestingly, IL-6 expression was significantly higher in Epstein-Barr virus (EBV)+ cases of cHL versus EBV IL-9.
Interleukin 9 is a T-cell and mast cell growth factor that can also
potentiate IL-4-induced IgG4 and IgE production.30
Although IL-9 mRNA was not detected in unstimulated L-428 cells, it was identified in 5 of 12 (42%) cases of cHL by Northern
analysis.31 In 5 of these cases, including 2 that were
IL-9 IL-10.
Interleukin 10 is a Th2 cytokine with strong anti-inflammatory
properties. IL-10 inhibits T-cell growth, blocks IL-2 and IFN- Th1 cytokines IL-12.
Interleukin 12 is required for Th1-cell differentiation.34
In the context of cHL, IL-12 has been detected by IHC in 28 of 33 (85%) cases, expressed by reactive cells but not by RS
cells.35 The level of IL-12 expression varied from tumor
to tumor, ranging from a few or absent IL-12+ cells in some
cases to clusters of positive cells around RS cells in others.
IL-12+ cells could be detected within the reactive
infiltrate in all 22 EBV+ cases, but in only 5 of 10 EBV IL-2. Interleukin 2 is a principal growth factor for T cells, and also augments the cytolytic activity of natural killer (NK) cells.36 IL-2 was not expressed by any of 7 RS cell lines examined,5,11,37,38 and expression of IL-2 in primary cHL cases has been extremely variable. Eight cHL cases were negative for IL-2 mRNA by Northern analysis.16 More recently, Dukers et al found that less than 5% of RS cells and reactive lymphocytes were IL-2+ in 27 cases of NSHL tested using IHC.17 However, Hsu et al could demonstrate IL-2+ RS cells in 10 cases of NSHL by IHC, with a range of 30% to 75% IL-2+ RS cells.37 Three IL-2 receptor chains have been identified: IL-2R (CD25, Tac),
IL2R , and the common  (c) chain. These chains combine to form
3 different IL-2 receptor complexes distinguished by their binding
affinity for IL-2: the low-affinity ( chain only),
intermediate-affinity ( and chains), and high-affinity (,
, and c chains) receptors. The cytoplasmic domain of the chain is essential for signal transduction in response to IL-2, such
that only the intermediate- and high-affinity receptors are able to
transduce IL-2 signals.39 IL-2R expression has been
demonstrated in 5 of 6 RS cell lines11,37,38,40,41 and in
primary RS cells by IHC in 75% of cHL cases.37,40-44
IL-2R chain expression, however, is less consistent in both cultured and primary RS cells. Using IHC, Hsu et al37 could not
detect IL-2R on 2 RS cell lines (HDLM-2 and KM-H2) or on primary RS cells from 10 cases of cHL. However, Tesch et al used the same antibody
to detect IL-2R protein by IHC on 5 RS cell lines (including HDLM-2
and KM-H2) and in primary RS cells from 7 of 13 cases of cHL.41 Similarly, Trumper et al detected transcripts for
IL-2R in 50% to 75% of RS cells from all 6 cHL cases in which mRNA
expression levels were determined on single RS cells isolated from cell
suspensions.7 Several investigators have shown that
recombinant IL-2 does not affect the proliferation of cultured RS
cells,37,45,46 even in a cell line shown to express
high-affinity IL-2R.41 In summary, the weight of evidence
indicates that RS cells do not express IL-2 and variably express
IL-2R, and that exogenous IL-2 has no effect on RS cell growth.
Therefore, IL-2 is unlikely to be an autocrine growth factor in cHL.
IFN-
Chemokines are chemoattractant cytokines that regulate the
selective migration of leukocytes through binding to specific chemokine receptors differentially expressed on various leukocyte populations. Approximately 50 chemokines and 20 chemokine receptors have been identified in humans50 but only a few have been studied in
cHL (Table 2).
Most of the chemokines that have been studied in cHL are associated
with either a humoral or cell-mediated immune response, based on the
expression pattern of their receptors on Th1 and Th2
cells.51 Th1 cells express the chemokine receptors CXCR3 and CCR5 and therefore are attracted to sites of production of their
respective ligands. The ligands for CXCR3 include inducible protein 10 (IP-10) and monokine induced by IFN- Th2 chemokines Expression of TARC in cHL was first discovered using a serial gene expression analysis of RS cell lines.53 TARC was expressed by 4 RS cell lines examined, but absent in B-lymphoblastoid and NHL cell lines. TARC was also expressed by RS cells in 88% of cHL cases as determined by ISH or IHC.53,54 Cases of NSHL demonstrated stronger staining by IHC compared to MCHL cases. TARC was not expressed in NLPHL, and the majority of NHL cases were TARC , except
for a small number of ALCL and TCRBCL cases.53,54 Although
moderate to strong levels of CCR4 mRNA could be detected by reverse
transcription-polymerase chain reaction (RT-PCR) in 4 RS cell lines,
CCR4 expression could not be detected in primary RS cells by ISH.
However, a high proportion of the lymphocytes surrounding the RS cells
were CCR4+, consistent with an activated Th2-cell
phenotype.53
Although levels of MDC expression in cHL tissues as a group were not significantly different from those in normal lymphoid tissues, MDC expression among cHL subtypes was significantly higher in NSHL cases compared to MCHL cases.49 By IHC, 87% of cHL cases demonstrated MDC expression, primarily localized to RS cells.55 Eotaxin expression is higher in cHL tissues than in normal lymphoid
tissues, as demonstrated by RT-PCR.49 Within cHL subtypes, elevated eotaxin expression was preferentially associated with NSHL
cases. Eotaxin was detected by IHC in RS cells, fibroblasts, macrophages, and lymphocytes within cHL tissues, with more intense staining in NSHL than MCHL cases. Moreover, expression of eotaxin correlated with the number of eosinophils in the cHL tissue, suggesting that eotaxin contributes to eosinophil recruitment to cHL tissues. In
contrast to these findings, Jundt et al detected eotaxin mRNA in only 1 of 5 RS cell lines and could not detect eotaxin expression in primary
RS cells by IHC or ISH.56 They found that fibroblasts were
the major source of eotaxin with a minor contribution by macrophages.
Eotaxin expression could be induced in cultured fibroblasts separated
from cocultured RS cells by a micropore membrane, indicating that
soluble factors produced by the cultured RS cells stimulated the
up-regulation of eotaxin expression. The RS cell line L-1236 produces
high levels of TNF- Expression of CCR3 could not be demonstrated on RS cell lines by flow cytometry or on primary RS cells by IHC.57 However, strong expression of CCR3 could be detected by IHC on about half of the cells within the cHL reactive infiltrate, compared to very rare CCR3 expression in control lymph nodes. Flow cytometry indicated that CCR3 was expressed not only on T cells in cHL tissue but also on B cells, an unexpected finding because normal B cells do not express CCR3.57 Whether this observation represents a cHL-specific dysregulation of CCR3 expression or a more general phenomenon is unclear. Th1 chemokines The Th1-associated chemokines IP-10, Mig-1, MIP-1, MIP-1,
and RANTES are expressed at higher levels in cHL tissues compared to
benign lymphoid tissues.49,57 In contrast to eotaxin, TARC and MDC, which are associated with the nodular sclerosis (NS) subtype
of cHL, expression levels of IP-10, Mig-1, and MIP-1 were higher in
MCHL cases.49 Elevated expression of these chemokines was
also associated with EBV+ cHL cases. IP-10 and Mig-1
immunoreactivity was strongest in RS cells but also present in
endothelial cells, macrophages, lymphocytes, and fibroblasts. CCR5, the
receptor for MIP-1 and MIP-1, was not present on cultured or
primary RS cells but was expressed on approximately half of the cells
within the reactive infiltrate, including CD4+ T cells and
B cells.57 The expression of CXCR3, the receptor for IP-10
and Mig-1, was moderately up-regulated in the CD4+ T-cell
population.57
IL-8 Interleukin 8 is a potent neutrophil recruitment factor that binds to the chemokine receptors CXCR1 and CXCR2 on neutrophils. IL-8 mRNA was detected by ISH in 20 of 33 cases of cHL and its level correlated with the density of tissue neutrophilia.58 IL-8 was predominantly expressed by cells within the reactive infiltrate and could be detected in RS cells in only 3 cases.
Members of the tumor necrosis factor (TNF) family of receptors and
ligands play important roles in the pathogenesis of cHL. Approximately
25 TNF receptor (TNFR) members have been identified in normal tissues,
including TNFRI, TNFRII, CD40, CD30, CD27, OX40, receptor activator of
nuclear factor
TNF- was identified as a macrophage product
mediating cytotoxicity against certain cell types, especially
transformed cell lines. Subsequently, TNF- has been shown to play
important roles in inflammation, tissue remodeling, and wound
healing.60 TNF- enhances the phagocytic and
microbicidal activities of macrophages and stimulates the production of
other proinflammatory cytokines including IL-1 and IL-6. In the context
of cHL, TNF- expression at the mRNA and protein levels has been
demonstrated in 7 RS cell lines.5,11,26,61,62 TNF- was
detected by Northern analysis in all 19 cHL cases
examined,63 and by IHC or ISH in primary RS cells in 69%
of cHL cases examined in 6 studies.26,61,62,64-66 Cells
within the reactive infiltrate, including lymphocytes and macrophages,
were also TNF-+. TNF- can use 2 receptors called
TNFRI (p55) and TNFRII (p75).60 These receptors have been
studied in only a small number of primary tumors and not at all in RS
cell lines. Ryffel et al used IHC to examine malignant lymphomas
(including 4 cases of cHL) for the expression of TNFRI and TNFRII. Two
cHL cases contained TNFRII+ RS cells and one had
TNFRI+ RS cells.67 Treatment of the RS cell
lines HDLM-2 and KM-H2 with recombinant TNF- did not stimulate or
suppress cellular proliferation.46
Lymphotoxin CD40 CD40/CD40L-mediated contacts between B and T cells are required for the generation of T cell-dependent humoral immune responses. Activation of CD40 on B cells stimulates proliferation and mediates Ig class switching in conjunction with IL-4 and IL-13.68 Surface CD40 expression was detected in 4 RS cell lines examined by flow cytometry.32,69 O'Grady et al first studied CD40 expression in primary cHL by IHC and found strong membrane or cytoplasmic staining of RS cells in 26 of 37 (70%) cases.70 In contrast, CD40 expression was much weaker in normal lymphoid tissues and present in only 3 of 23 cases of B-cell NHL. Strong CD40 expression as determined by IHC was subsequently reported in primary RS cells in a total of 190 cHL cases.32,69,71,72 However, CD40 expression was not exclusive to cHL, because 105 of 127 B-cell NHLs stained weakly positive for CD40.32The activation of CD40 on a cell requires contact with CD40L expressed
on the surface of a neighboring cell. CD40L is absent on cultured and
primary RS cells, but is present on CD4+ T cells within cHL
tissues.69,71,72 Numbers of CD40L+ T cells
were increased in cHL tissues compared to normal lymphoid tissues. The
CD40L+ T cells were usually located in close proximity to
RS cells, with an average of 2.5 to 5 CD40L+ T cells
surrounding a single RS cell.71 In contrast, the malignant cell population and reactive component of cases of CD40+
B-cell NHL failed to express significant levels of CD40L. Treatment of
RS cell lines with soluble trimeric CD40L to activate CD40 stimulated
the release of IL-8, enhanced secretion of IL-6, TNF- CD40 signaling pathways can be activated by the latent membrane
protein-1 (LMP-1) of EBV. Approximately 40% of cHL cases from immunocompetent patients in Western countries are associated with EBV
infection and viral sequences can be detected within RS
cells.74-76 RS cells show a type II pattern of EBV latency
antigen expression, with expression of LMP-1, LMP-2, and Epstein-Barr
nuclear antigen-1 (EBNA-1). EBV LMP-1 can mimic CD40 signaling in a
ligand-independent and constitutive manner77 because the
cytoplasmic portions of CD40 and LMP-1 recruit many of the same
signal-transducing molecules, including members of the TNFR-associated
factor (TRAF) family78,79 (discussed below in NF- CD30 CD30 is expressed on RS cells from virtually all cases of cHL.80 Several cells within cHL tumors express CD30L, allowing potential activation of CD30 on neighboring RS cells. CD30L expression could not be detected in cultured RS cells by Northern analysis,81 flow cytometry,82 or RT-PCR.83 By IHC, however, weak expression of CD30L could be detected in primary RS cells in all cHL cases examined.82,83 However, RS cells demonstrated cytoplasmic staining without membrane reactivity; therefore, it remains unclear whether primary RS cells express CD30L on their surfaces. However, several other cell populations within the reactive infiltrate express CD30L, including eosinophils84 and mast cells.85 Circulating eosinophils from cHL patients expressed higher CD30L levels than cells from healthy donors.84Activation of CD30 induces significantly different responses in
different CD30+ lymphoma cell lines. This was first
demonstrated by Smith et al who showed that CD30L activation stimulated
proliferation of the CD30+ RS cell line HDLM-2 but had no
effect on the proliferation of the CD30+ RS cell lines
KM-H2 and L-428.86 In contrast, CD30L stimulation of the
CD30+ ALCL cell line KARPAS-299 induced cytotoxic cell
death. These investigations were extended by Gruss et al who found that
CD30 could also stimulate the proliferation of the RS cell line L-540, but had cytotoxic effects on 6 of an additional 7 CD30+
ALCL cell lines,87 results subsequently confirmed by other groups.84,85 Hsu and Hsu also found that activation of
CD30 induced increased proliferation of L-428 and KM-H2 cells and of enriched RS cells from primary patient material.83 Like
CD40 activation, CD30 activation increased the secretion of IL-6,
TNF- RANK RANKL is a member of the TNF ligand family that plays a role in osteoclast differentiation, activation of mature osteoclasts, and interactions between T cells and dendritic cells. RANKL binds to 2 receptors, RANK and osteoprotegerin (OPG). RANK, RANKL, and OPG are all expressed by L-428, KM-H2, and HDLM-2 cells.89 RANK can be also detected by IHC in primary RS cells from both NSHL and MCHL cases. Activation of RANK in RS cell lines by soluble RANKL up-regulates the expression of several cytokines, including IFN-, IL-9, IL-13, and
IL-15. However, treatment of these RS cell lines with soluble RANKL, or
inhibition of RANK-RANKL interactions between cultured RS cells, has no
effect on the proliferation or survival of these
cells.89
Several cytokines that do not belong to the previously discussed
groups, including IL-1, TGF-
IL-1 Interleukin 1 is a potent proinflammatory cytokine.90 IL-1 has 2 distinct forms (IL-1 and IL-1) that bind to the same receptor and have identical biologic activities. With respect to cHL, 3 of 6 RS cell lines were positive for IL-1,11,91 and IL-1
has been detected in cHL tissues in 58% of cases examined by IHC or
ISH.64-66,92,93 In most instances, IL-1 was expressed predominantly by RS cells, but was also seen in lymphocytes,
granulocytes, and macrophages. Recombinant IL-1 had no effect on the
proliferation of HDLM-2 or KM-H2 cells.46
TGF- has potent anti-inflammatory
effects. It suppresses B- and T-cell proliferation and the cytolytic activity of NK cells, and stimulates fibroblast proliferation and
collagen synthesis.94 The RS cell line L-428 produces
TGF- mRNA and secretes a high-molecular-weight form of TGF-
protein that is active at physiologic pH.95 Using IHC,
Kadin et al first identified TGF- in primary RS cells from 6 of 8 cases of NSHL but not in 4 cases of MCHL or 1 case of
LDHL.96 TGF-+ RS cells were typically
located near zones of necrosis and at the margins of collagen bands.
Subsequently, ISH was used to show that TGF- transcripts were
present in eosinophils from cases of NSHL but absent in RS cells,
suggesting that eosinophils are the major source of TGF- in cHL and
that the RS cell immunoreactivity in the previous study represented
secondary binding and uptake by RS cells.97 Interestingly,
Newcom and Gu were able to detect TGF- in RS cells of predominantly
NSHL cases by both IHC and ISH.98 In short, although the
cellular source of TGF- is unclear, this cytokine is
characteristically expressed in the NS subtype of cHL.
Hematopoietic growth factors Hematopoietic growth factors include IL-3, IL-7, granulocyte-macrophage colony stimulating factor (GM-CSF), and macrophage-CSF (M-CSF).99 IL-3 stimulates colony formation of erythroid, megakaryocyte, eosinophil, basophil, and monocyte lineages, whereas IL-7 is a growth factor for progenitor B and T cells and mature T cells. GM-CSF is a differentiation factor for granulocytic and monocytic cells, whereas M-CSF is a growth and differentiation factor for macrophages and their progenitors.Expression of IL-3 protein was not detected in 6 RS cell lines examined,11 and IL-3 mRNA was detected in only 2 of 8 cases of cHL by Northern analysis.16 Exogenous IL-3 had no effect on the proliferation of HDLM-2 or KM-H2 cells.46 IL-7 mRNA was detected in RS cells from 24 of 31 cases of cHL, but identified in only 1 of 10 cases of lymphoblastoid lymphoma and in no cases of chronic B-lymphocytic leukemia.100 GM-CSF expression was detected in 2 of 6 RS cell lines11,18 but not in 8 cHL cases examined by Northern analysis.16 Exogenous GM-CSF had no effect on the proliferation of HDLM-2 or KM-H2 cells.46 L428 and 2 sublines expressed M-CSF and its receptor, the product of the proto-oncogene c-fms. However, only one of the sublines showed any evidence that M-CSF could act as an autocrine growth factor.101 Although M-CSF was detected by IHC in primary RS cells from 100% of cHL cases in one study,102 and 75% of cHL cases in another,103 c-fms mRNA expression could not be detected in primary RS cells.7,104
STAT signaling The interaction of cytokines with their specific cell surface receptors triggers the activation of intracellular signaling cascades that ultimately have effects on multiple cellular functions. The earliest event is the activation of Janus kinase (Jak) family members, which then phosphorylate substrates crucial for the transduction of cytokine signals. One of the most important substrates is the family of signal transducer and activator of transcription (STAT) proteins.105 STATs are latent transcription factors residing in the cytoplasm that become activated by phosphorylation on a single tyrosine residue. This phosphorylation is carried out by Jak family members activated in response to cytokine receptor stimulation. Tyrosine phosphorylation leads to STAT dimerization and translocation of the activated transcription factor to the nucleus, where it stimulates transcription resulting in changes to gene expression. Seven members of the STAT family have been identified, STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6, and each is activated by a distinct set of cytokines (reviewed by Leonard and O'Shea105).STAT6. Interleukin 4 and IL-13 are the primary activators of STAT6,106 and its pivotal role in signaling of these cytokines has been demonstrated in mice deficient for STAT6, which show impaired proliferation of B and T cells in response to IL-4, and abrogation of Ig class switching and Th2 cytokine production.107-109 Additionally, STAT6 is involved in the expression of Th2 chemokines, including eotaxin, TARC, and MDC.110,111 All 5 RS cell lines examined demonstrated constitutive STAT6 phosphorylation, which was shown to be due to autocrine secretion of IL-13 in HDLM-2 and L-1236 cells.14 Nuclear staining of phospho(P)-STAT6 was present in primary RS cells from 78% of cHL cases, whereas it was rarely detected in the reactive infiltrate.14 In cHL subtypes, STAT6 activation was present in 95% of NSHL cases, but in only 50% of MCHL cases. P-STAT6 expression was rare in normal lymphoid tissue, and among NHLs it was present only in a minority of ALCL and TCRBCL cases. P-STAT6 expression was associated with IL-13 expression in cHL cases, consistent with the active signaling of IL-13 in primary RS cells that would be expected for an autocrine growth factor. STAT3.
STAT3 plays a role in oncogenesis, being involved in both
hematolymphoid and solid tumors (reviewed by Bowman et
al112). A wide range of cytokines activates STAT3,
including the IL-6 family of cytokines, IL-10, and cytokines whose
receptors use the STAT5.
STAT5 is activated by several cytokines, including those that use the
NF-  B. The
NF-B family of transcription factors plays a pivotal role in
inflammation, proliferation, and prevention of apoptosis.
A functional NF- Activation of NF- Six distinct TRAF molecules have been identified, termed TRAF1 through
TRAF6.78,79 Signal transduction via TRAF2, TRAF5, and
TRAF6 is linked to NF- Given the role of NF- NF- B activity in RS cell lines were
studied by overexpressing a dominant-negative form of IB-
(IB- N). This molecule contains an N-terminal truncation which
allows it to bind to NF-B but not release it. Overexpression of
IB-N in stably transfected RS cells reduced constitutive NF-B DNA binding activity and markedly decreased cell
proliferation.128 Although there was no effect on
spontaneous cell death, IB-N-expressing cultured RS cells
underwent apoptosis in response to serum starvation, whereas
mock-transfected cells were resistant to apoptosis under the same
conditions. Additionally, IB-N-expressing RS cells showed
strongly diminished tumor growth in severe combined immunodeficiency mice.128 Adenovirus-mediated expression of IB-N
allowed for even more efficient inhibition of NF-B, and resulted in
massive spontaneous apoptosis of RS cell lines.129 NF-B
activation promotes RS cell proliferation and survival by up-regulating
expression of the cell-cycle regulator cyclin D2 and the antiapoptotic
proteins A1, c-IAP2, TRAF1, and bcl-xL.129 Indeed,
overexpression of bcl-xL in IB-N-expressing L428 cells
partially rescued them from apoptosis. Bcl-xL is also expressed in
primary RS cells in a large majority of cHL cases.130
Another prosurvival target of NF-B activation in cHL is CD40. A
positive feedback loop may be established because activation of CD40 by
CD40L leads to NF-B activation.129
Two mechanisms of constitutive NF-B activation in RS cells have been
identified: constitutive stimulation of receptors that lead to NF-B
activation, and dysregulation of IB--mediated control through
mutations of the IKBA gene. HDLM-2 and L-1236 cells
demonstrate constitutive NF-B activation but do not have mutations
of their IKBA genes.131,132 The high turnover
rate of wild-type IB- in these cells suggests that the
constitutive NF-B activation in these cell lines is due to
continuous upstream signaling through NF-B activating
pathways.126 TNFR family molecules and EBV LMP-1 are
commonly expressed in primary RS cells and are known to activate
NF-B in various cell systems. In particular, activation of
CD40133 and RANK89 has been shown to increase NF-B DNA-binding activity in RS cell lines.
Mutations of IKBA gene.
Mutations of the IKBA gene leading to impaired regulation of
NF- B- protein incapable of binding to NF-B.
However, this work was done using only partially purified primary RS
cells, so it was not conclusively shown that the IKBA
mutations were resident in the malignant cell population. In 2 subsequent studies, IKBA mutations were demonstrated in
primary RS cells using single-cell PCR. Emmerich et al sequenced the
IKBA genes of RS cells from 10 cases of cHL.134
In one case, one IKBA allele contained a point mutation
introducing a stop codon such that a C-terminally truncated IB-
protein would be produced; the other IKBA allele was
wild-type. The IKBA gene from cells within the reactive
infiltrate was also wild-type, indicating that the IKBA
mutation was restricted to the RS cells. Jungnickel et al sequenced the
IKBA gene of RS cells from 3 EBV and 2 EBV+ cases of cHL.132 Mutations identified in
the IKBA genes from 2 of the EBV cases were
restricted to the RS cells and absent in the reactive infiltrate. RS
cells from one case had deletions of one nucleotide in one
IKBA allele and 2 nucleotides in the other allele. Both deletions led to frameshifts, precluding the synthesis of a full-length IB- protein by these cells. RS cells in the other case of
EBV cHL contained a deletion of 2 nucleotides in one
IKBA allele, whereas the other allele was wild-type. These
data indicate that mutations of the IKBA gene are
present in primary RS cells from a minority of cHL cases; however, the
significance of monoallelic mutation is unclear, because loss of
IB- activity would presumably require inactivation of
both alleles.
Cytokines and RS cell proliferation and survival Abnormal activation of NF-B due to the action of TNFR-related
molecules or mutations of the IKBA gene is clearly important for the proliferation and survival of RS cell lines. These mechanisms also likely occur in primary RS cells, because these cells usually express TNFR family molecules, are surrounded by cells expressing ligands for these receptors, and demonstrate nuclear localization of
activated RelA. Additionally, IL-13 has been identified as an autocrine
growth and survival factor for RS cell lines, and the expression of
IL-13, IL-13R1, and nuclear P-STAT6 in primary RS cells indicates
that IL-13 signaling is operational in vivo. Given that IL-13 and CD40
(a TNFR family member) promote the proliferation and survival of normal
B-cells,135-137 a function for IL-13 and CD40 (and other
TNFR members) as autocrine growth factors for RS cells is not
surprising, because RS cells are derived from B cells.
Activation of NF- Under physiologic conditions, survival signals delivered by T cells
within the germinal center are very short-lived. Surface expression of
CD40L on T cells is rapidly down-regulated on binding to
CD40142 and IL-4 production by activated T cells is
transient.143 CD40 stimulates proliferation in part
through NF- Cytokines and the reactive infiltrate Eosinophils.
Lymph nodes involved by cHL often show evidence of an eosinophilic
infiltrate. Cytokines and chemokines may contribute to this
eosinophilia both by increasing the production of eosinophils and
stimulating their recruitment to the site of cHL involvement. IL-3,
IL-5, and GM-CSF regulate eosinophilopoiesis in the bone marrow.145 IL-5 is particularly important, inducing
terminal differentiation of immature eosinophils, stimulating the
release of eosinophils into the circulation, and prolonging eosinophil survival. In the context of cHL, the expression of IL-5 correlates with
tissue eosinophilia.23 Chemokines may also contribute to the recruitment of eosinophils to lymph nodes involved by cHL. As
mentioned above, expression levels of eotaxin, a potent recruitment factor for eosinophils, correlate with tissue eosinophilia in cHL.49 Importantly, eotaxin expression in fibroblasts and
airway epithelial cells in vitro can be stimulated by IL-13, an effect that shows synergy with TNF- T cells.
T cells constitute a significant component of the reactive infiltrate
in cHL. In immunocompetent cHL patients, the CD4/CD8 ratio within the
reactive infiltrate is elevated to 4:1 to 6:1.149-152 Moreover, the majority of CD4+ T cells in the infiltrate
show features of Th2 cells.153 The increase in
CD4+ T-cell numbers in cHL tumors is associated with a
decrease in CD4+ T cells in the peripheral blood,
consistent with a displacement of these cells from the circulation into
the involved tissues.154 The CD4+ T cells
forming rosettes around RS cells are not directed against a
common antigen,155 and may be nonspecifically recruited to the site by chemoattractants such as TARC, MDC, and eotaxin produced by
cHL tissues. The expression of these chemokines can be stimulated by
IL-13 and TNF-
cases.160-162 Although EBV-specific cytotoxic T
lymphocytes (CTLs) can be detected in the peripheral blood of patients
with EBV+ cHL, no CTLs targeting EBV proteins expressed by
RS cells (including LMP-1 and LMP-2) can be identified within the
tumors.163,164 These data indicate that EBV-specific CTLs
that could potentially target the RS cells either fail to penetrate the
tumor site or fail to function within the tumor microenvironment. It is
possible that anti-inflammatory cytokines produced by the surrounding
cHL tissues are responsible for this effect (see below).
Fibrosis.
Nodular sclerosis HL is characterized by the presence of collagenous
bands dividing the tumor into nodules. Newcom and O'Rourke showed that
soluble factors from NSHL tissues may contribute to this fibrosis,
because supernatants of cell cultures from primary NSHL cases can
potentiate the growth of fibroblasts in vitro.165 The most
likely candidate is TGF- 1 protein are present in
higher numbers in NSHL cases.20 A role for IL-13 in
fibrosis would be consistent with its ability to stimulate collagen
synthesis in vitro.169,171 IL-13 is also a potent
stimulator and activator of TGF- in vivo, and mediates pulmonary
fibrosis in a mouse model largely through activation of
TGF-.172
Cytokines and clinical symptoms Patients with cHL often present with "B" symptoms, including fever, weight loss, and night sweats. Although the exact cause of these symptoms is unclear, it is thought that one or more cytokines elaborated by cHL tumors may be responsible. Several studies have examined the relationship between IL-6 expression in either serum or cHL tissues and the presence of "B" symptoms, with conflicting results. Two studies found that patients with "B" symptoms had higher serum IL-6 levels compared to asymptomatic patients,173,174 whereas 3 other studies found no such correlation.175-177 Foss et al did not detect a difference in the levels of IL-6 expression in cHL tissues between symptomatic and asymptomatic patients.26 Ree et al found that most patients with small- to medium-sized IL-1+ cells within the reactive infiltrate of their tumors had "B" symptoms; however, most patients with "B" symptoms did not have detectable numbers of these cells.93 Another study did not find a correlation between the presence of IL-1+ RS cells and "B" symptoms.66 Blay et al found that cHL patients had increased serum levels of IL-1 compared to healthy patients, but there was no correlation with "B" symptoms.176 Two other studies found elevated serum IL-1 levels to be rare in cHL patients.173,174 Benharroch et al found a correlation between expression of TNF- by primary RS cells and the presence of
"B" symptoms66; however, this was not found in another
study.26 No correlation between serum TNF- levels and
"B" symptoms could be detected in cHL
patients.173,174,176 In short, although the known biologic
activities of many of these cytokines are consistent with
constitutional symptoms seen in cHL patients, there is no firm evidence
implicating any particular cytokine in their pathogenesis.
Cytokines and impairment of cellular immunity Patients with untreated cHL frequently exhibit a systemic defect in cell-mediated immunity (reviewed by Slivnick et al178). The defect occurs in patients of all stages of disease and can persist in long-term survivors. Humoral immunity, on the other hand, is intact and often overactive, as exemplified by increased serum IgE levels in 30% to 50% of untreated cHL patients.179,180 The impairment in cell-mediated immunity is manifested as delayed hypersensitivity to new and recall antigens and increased susceptibility to bacterial, fungal, and viral infections. T-cell proliferation in response to T-cell mitogens and autologous mixed lymphocyte reactions is depressed, and in vitro synthesis of the Th1 cytokines IL-2 and IFN- is reduced. It is
unclear whether the impaired cellular immune response is due to a
primary cellular defect or the action of anti-inflammatory cytokines
produced by cHL tissues. TGF- (produced primarily by the NS subtype)
and IL-10 (produced by EBV+ cHL cases) are both potent
anti-inflammatory cytokines. The unbalanced production of Th2 cytokines
could also prevent the development of an effective Th1-driven
cell-mediated immune response.
Another potential mediator of the defect in cell-mediated
immunity is soluble IL-2R
Most cases of cHL are characterized by constitutive
activation of NF-
The above scenario fits well with the clinical features of NSHL,
but is more problematic for MCHL, a subtype more commonly associated
with EBV compared to NSHL. The presence of EBV may be altering the
expression of cytokines and chemokines (Figure 1B). Constitutive
NF- Detailed understanding of the different cytokines and chemokines that contribute to the pathogenesis of cHL has provided insights into the pathophysiology, immune dysfunction, and symptomatology associated with this disease. It is hoped that this understanding of the role of cytokines will translate into the development of novel treatment strategies for patients with cHL. Therapeutics that target those cytokines and signaling pathways that contribute to the proliferation and survival of RS cells, or rectify the cell-mediated immune defect that causes an impaired antitumor response, may be helpful in these patients. However, given the important role of cytokines in the overall function of normal immune and inflammatory reactions, such therapeutic strategies must be carefully chosen as to not significantly impair the overall immune function of these patients during treatment.
The authors thank Dr Randy D. Gascoyne and Dr Joseph M. Connors for critical review of the manuscript and Dr Mary Saunders for scientific editing.
Submitted January 15, 2002; accepted February 14, 2002.
Prepublished online as Blood First Edition Paper, April 17, 2002; DOI 10.1182/blood-2002-01-0099.
Supported in part by grants from the Canadian Institute of Health Research and the National Cancer Institute of Canada.
Reprints: Tak W. Mak, Amgen Research Institute/Ontario Cancer Institute, 620 University Ave, Ste 706, Toronto, ONT, Canada M5G 2C1; e-mail: tmak{at}oci.utoronto.ca.
1.
Harris NL, Jaffe ES, Stein H, et al.
A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group.
Blood.
1994;84:1361-1392 2. Stein H, Delsol G, Pileri S, et al. Hodgkin lymphoma. In: Jaffe ES,Harris NL,Stein H,Vardiman JW, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001:237-254. 3. Drexler HG. Recent results on the biology of Hodgkin and Reed-Sternberg cells, II: continuous cell lines. Leuk Lymphoma. 1993;9:1-25[Medline] [Order article via Infotrieve]. 4. Stein H, Diehl V, Marafioti T, Jox A, Wolf J, Hummel M. The nature of Reed-Sternberg cells, lymphocytic and histiocytic cells and their molecular biology in Hodgkin's disease. In: Mauch PM,Armitage JO,Diehl V,Hoppe RT,Weiss LM, eds. Hodgkin's Disease. Philadelphia, PA: Lippincott Williams & Wilkins; 1999:121-138.
5.
Wolf J, Kapp U, Bohlen H, et al.
Peripheral blood mononuclear cells of a patient with advanced Hodgkin's lymphoma give rise to permanently growing Hodgkin-Reed Sternberg cells.
Blood.
1996;87:3418-3428
6.
Kanzler H, Hansmann ML, Kapp U, et al.
Molecular single cell analysis demonstrates the derivation of a peripheral blood-derived cell line (L1236) from the Hodgkin/Reed-Sternberg cells of a Hodgkin's lymphoma patient.
Blood.
1996;87:3429-3436
7.
Trumper LH, Brady G, Bagg A, et al.
Single-cell analysis of Hodgkin and Reed-Sternberg cells: molecular heterogeneity of gene expression and p53 mutations.
Blood.
1993;81:3097-3115 8. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145-173[CrossRef][Medline] [Order article via Infotrieve].
9.
Paul WE.
Interleukin-4: a prototypic immunoregulatory lymphokine.
Blood.
1991;77:1859-1870 10. Zurawski G, de Vries JE. Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B cells, but not on T cells. Immunol Today. 1994;15:19-26[CrossRef][Medline] [Order article via Infotrieve]. 11. Klein S, Jucker M, Diehl V, Tesch H. Production of multiple cytokines by Hodgkin's disease derived cell lines. Hematol Oncol. 1992;10:319-329[Medline] [Order article via Infotrieve]. 12. Hsu SM, Xie SS, Hsu PL, Waldron JA Jr. Interleukin-6, but not interleukin-4, is expressed by Reed-Sternberg cells in Hodgkin's disease with or without histologic features of Castleman's disease. Am J Pathol. 1992;141:129-138[Abstract].
13.
Herbst H, Foss HD, Samol J, et al.
Frequent expression of interleukin-10 by Epstein-Barr virus-harboring tumor cells of Hodgkin's disease.
Blood.
1996;87:2918-2929
14.
Skinnider BF, Elia AJ, Gascoyne RD, et al.
Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma.
Blood.
2002;99:618-626
15.
Newcom SR, Ansari AA, Gu L.
Interleukin-4 is an autocrine growth factor secreted by the L-428 Reed-Sternberg cell.
Blood.
1992;79:191-197 16. Merz H, Fliedner A, Orscheschek K, et al. Cytokine expression in T-cell lymphomas and Hodgkin's disease. Its possible implication in autocrine or paracrine production as a potential basis for neoplastic growth. Am J Pathol. 1991;139:1173-1180[Abstract]. 17. Dukers DF, Jaspars LH, Vos W, et al. Quantitative immunohistochemical analysis of cytokine profiles in Epstein-Barr virus-positive and -negative cases of Hodgkin's disease. J Pathol. 2000;190:143-149[CrossRef][Medline] [Order article via Infotrieve].
18.
Kapp U, Yeh WC, Patterson B, et al.
Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells.
J Exp Med.
1999;189:1939-1946
19.
Skinnider BF, Elia AJ, Gascoyne RD, et al.
Interleukin 13 and interleukin 13 receptor are frequently expressed by Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma.
Blood.
2001;97:250-255 20. Ohshima K, Akaiwa M, Umeshita R, Suzumiya J, Izuhara K, Kikuchi M. Interleukin-13 and interleukin-13 receptor in Hodgkin's disease: possible autocrine mechanism and involvement in fibrosis. Histopathology. 2001;38:368-375[CrossRef][Medline] [Order article via Infotrieve]. 21. Oshima Y, Puri RK. Suppression of an IL-13 autocrine growth loop in a human Hodgkin/Reed-Sternberg tumor cell line by a novel IL-13 antagonist. Cell Immunol. 2001;211:37-42[CrossRef][Medline] [Order article via Infotrieve].
22.
Sanderson CJ.
Interleukin-5, eosinophils, and disease.
Blood.
1992;79:3101-3109
23.
Samoszuk M, Nansen L.
Detection of interleukin-5 messenger RNA in Reed-Sternberg cells of Hodgkin's disease with eosinophilia.
Blood.
1990;75:13-16
24.
Kishimoto T, Akira S, Narazaki M, Taga T.
Interleukin-6 family of cytokines and gp130.
Blood.
1995;86:1243-1254
25.
Jucker M, Abts H, Li W, et al.
Expression of interleukin-6 and interleukin-6 receptor in Hodgkin's disease.
Blood.
1991;77:2413-2418 26. Foss HD, Herbst H, Oelmann E, et al. Lymphotoxin, tumour necrosis factor and interleukin-6 gene transcripts are present in Hodgkin and Reed-Sternberg cells of most Hodgkin's disease cases. Br J Haematol. 1993;84:627-635[Medline] [Order article via Infotrieve]. 27. Herbst H, Samol J, Foss HD, Raff T, Niedobitek G. Modulation of interleukin-6 expression in Hodgkin and Reed-Sternberg cells by Epstein-Barr virus. J Pathol. 1997;182:299-306[CrossRef][Medline] [Order article via Infotrieve]. 28. Beck A, Pazolt D, Grabenbauer GG, et al. Expression of cytokine and chemokine genes in Epstein-Barr virus-associated nasopharyngeal carcinoma: comparison with Hodgkin's disease. J Pathol. 2001;194:145-151[CrossRef][Medline] [Order article via Infotrieve].
29.
Kube D, Holtick U, Vockerodt M, et al.
STAT3 is constitutively activated in Hodgkin cell lines.
Blood.
2001;98:762-770 30. Soussi-Gounni A, Kontolemos M, Hamid Q. Role of IL-9 in the pathophysiology of allergic diseases. J Allergy Clin Immunol. 2001;107:575-582[CrossRef][Medline] [Order article via Infotrieve].
31.
Merz H, Houssiau FA, Orscheschek K, et al.
Interleukin-9 expression in human malignant lymphomas: unique association with Hodgkin's disease and large cell anaplastic lymphoma.
Blood.
1991;78:1311-1317
32.
Carbone A, Gloghini A, Gattei V, et al.
Expression of functional CD40 antigen on Reed-Sternberg cells and Hodgkin's disease cell lines.
Blood.
1995;85:780-789 33. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683-765[CrossRef][Medline] [Order article via Infotrieve]. 34. Gately MK, Renzetti LM, Magram J, et al. The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annu Rev Immunol. 1998;16:495-521[CrossRef][Medline] [Order article via Infotrieve].
35.
Schwaller J, Tobler A, Niklaus G, et al.
Interleukin-12 expression in human lymphomas and nonneoplastic lymphoid disorders.
Blood.
1995;85:2182-2188
36.
Smith KA.
Interleukin-2: inception, impact, and implications.
Science.
1988;240:1169-1176 37. Hsu SM, Tseng CK, Hsu PL. Expression of p55 (Tac) interleukin-2 receptor (IL-2R), but not p75 IL-2R, in cultured H-RS cells and H-RS cells in tissues. Am J Pathol. 1990;136:735-744[Abstract]. 38. Tesch H, Herrmann T, Abts H, Diamantstein T, Diehl V. High affinity IL-2 receptors on a Hodgkin's derived cell line. Leuk Res. 1990;14:953-960[CrossRef][Medline] [Order article via Infotrieve]. 39. Minami Y, Kono T, Miyazaki T, Taniguchi T. The IL-2 receptor complex: its structure, function, and target genes. Annu Rev Immunol. 1993;11:245-268[CrossRef][Medline] [Order article via Infotrieve]. 40. Schwarting R, Gerdes J, Ziegler A, Stein H. Immunoprecipitation of the interleukin-2 receptor from Hodgkin's disease derived cell lines by monoclonal antibodies. Hematol Oncol. 1987;5:57-64[Medline] [Order article via Infotrieve]. 41. Tesch H, Gunther A, Abts H, et al. Expression of interleukin-2R alpha and interleukin-2R beta in Hodgkin's disease. Am J Pathol. 1993;142:1714-1720[Abstract]. 42. Strauchen JA, Breakstone BA. IL-2 receptor expression in human lymphoid lesions. Immunohistochemical study of 166 cases. Am J Pathol. 1987;126:506-512[Abstract]. 43. Sheibani K, Winberg CD, van de Velde S, Blayney DW, Rappaport H. Distribution of lymphocytes with interleukin-2 receptors (TAC antigens) in reactive lymphoproliferative processes, Hodgkin's disease, and non-Hodgkin's lymphomas. An immunohistologic study of 300 cases. Am J Pathol. 1987;127:27-37[Abstract]. 44. Agnarsson BA, Kadin ME. The immunophenotype of Reed-Sternberg cells. A study of 50 cases of Hodgkin's disease using fixed frozen tissues. Cancer. 1989;63:2083-2087[CrossRef][Medline] [Order article via Infotrieve]. 45. Newcom SR, Kadin ME, Ansari AA. Production of transforming growth factor-beta activity by Ki-1 positive lymphoma cells and analysis of its role in the regulation of Ki-1 positive lymphoma growth. Am J Pathol. 1988;131:569-577[Abstract]. 46. Hsu SM, Hsu PL. Lack of effect of colony-stimulating factors, interleukins, interferons, and tumor necrosis factor on the growth and differentiation of cultured Reed-Sternberg cells. Comparison with effects of phorbol ester and retinoic acid. Am J Pathol. 1990;136:181-189[Abstract]. 47. Farrar MA, Schreiber RD. The molecular cell biology of interferon-gamma and its receptor. Annu Rev Immunol. 1993;11:571-611[CrossRef][Medline] [Order article via Infotrieve]. 48. Gerdes J, Kretschmer C, Zahn G, Ernst M, Jones DB, Flad HD. Immunoenzymatic assessment of interferon-gamma in Hodgkin and Sternberg-Reed cells. Cytokine. 1990;2:307-310[CrossRef][Medline] [Order article via Infotrieve].
49.
Teruya-Feldstein J, Jaffe ES, Burd PR, Kingma DW, Setsuda JE, Tosato G.
Differential chemokine expression in tissues involved by Hodgkin's disease: direct correlation of eotaxin expression and tissue eosinophilia.
Blood.
1999;93:2463-2470 50. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000;12:121-127[CrossRef][Medline] [Order article via Infotrieve]. 51. Sallusto F, Lanzavecchia A, Mackay CR. Chemokines and chemokine receptors in T-cell priming and Th1/Th2-mediated responses. Immunol Today. 1998;19:568-574[CrossRef][Medline] [Order article via Infotrieve].
52.
Imai T, Nagira M, Takagi S, et al.
Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine.
Int Immunol.
1999;11:81-88
53.
van den Berg A, Visser L, Poppema S.
High expression of the CC chemokine TARC in Reed-Sternberg cells. A possible explanation for the characteristic T-cell infiltrate in Hodgkin's lymphoma.
Am J Pathol.
1999;154:1685-1691 54. Peh SC, Kim LH, Poppema S. TARC, a CC chemokine, is frequently expressed in classic Hodgkin's lymphoma but not in NLP Hodgkin's lymphoma, T-cell-rich B-cell lymphoma, and most cases of anaplastic large cell lymphoma. Am J Surg Pathol. 2001;25:925-929[CrossRef][Medline] [Order article via Infotrieve]. 55. Hedvat CV, Jaffe ES, Qin J, et al. Macrophage-derived chemokine expression in classical Hodgkin's lymphoma: application of tissue microarrays. Mod Pathol. 2001;14:1270-1276[CrossRef][Medline] [Order article via Infotrieve].
56.
Jundt F, Anagnostopoulos I, Bommert K, et al.
Hodgkin/Reed-Sternberg cells induce fibroblasts to secrete eotaxin, a potent chemoattractant for T cells and eosinophils.
Blood.
1999;94:2065-2071
57.
Buri C, Korner M, Scharli P, et al.
CC chemokines and the receptors CCR3 and CCR5 are differentially expressed in the nonneoplastic leukocytic infiltrates of Hodgkin disease.
Blood.
2001;97:1543-1548 58. Foss HD, Herbst H, Gottstein S, Demel G, Araujo I, Stein H. Interleukin-8 in Hodgkin's disease. Preferential expression by reactive cells and association with neutrophil density. Am J Pathol. 1996;148:1229-1236[Abstract]. 59. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001;104:487-501[CrossRef][Medline] [Order article via Infotrieve]. 60. Wallach D, Varfolomeev EE, Malinin NL, Goltsev YV, Kovalenko AV, Boldin MP. Tumor necrosis factor receptor and Fas signaling mechanisms. Annu Rev Immunol. 1999;17:331-367[CrossRef][Medline] [Order article via Infotrieve]. 61. Hsu PL, Hsu SM. Production of tumor necrosis factor-alpha and lymphotoxin by cells of Hodgkin's neoplastic cell lines HDLM-1 and KM-H2. Am J Pathol. 1989;135:735-745[Abstract]. 62. Kretschmer C, Jones DB, Morrison K, et al. Tumor necrosis factor alpha and lymphotoxin production in Hodgkin's disease. Am J Pathol. 1990;137:341-351[Abstract].
63.
Sappino AP, Seelentag W, Pelte MF, Alberto P, Vassalli P.
Tumor necrosis factor/cachectin and lymphotoxin gene expression in lymph nodes from lymphoma patients.
Blood.
1990;75:958-962 64. Ruco LP, Pomponi D, Pigott R, et al. Cytokine production (IL-1 alpha, IL-1 beta, and TNF alpha) and endothelial cell activation (ELAM-1 and HLA-DR) in reactive lymphadenitis, Hodgkin's disease, and in non-Hodgkin's lymphomas. An immunocytochemical study. Am J Pathol. 1990;137:1163-1171[Abstract]. 65. Xerri L, Birg F, Guigou V, Bouabdallah R, Poizot-Martin I, Hassoun J. In situ expression of the IL-1-alpha and TNF-alpha genes by Reed-Sternberg cells in Hodgkin's disease. Int J Cancer. 1992;50:689-693[Medline] [Order article via Infotrieve]. 66. Benharroch D, Prinsloo I, Apte RN, et al. Interleukin-1 and tumor necrosis factor-alpha in the Reed-Sternberg cells of Hodgkin's disease. Correlation with clinical and morphological "inflammatory" features. Eur Cytokine Netw. 1996;7:51-57[Medline] [Order article via Infotrieve]. 67. Ryffel B, Brockhaus M, Durmuller U, Gudat F. Tumor necrosis factor receptors in lymphoid tissues and lymphomas. Source and site of action of tumor necrosis factor alpha. Am J Pathol. 1991;139:7-15[Abstract]. 68. Banchereau J, Bazan F, Blanchard D, et al. The CD40 antigen and its ligand. Annu Rev Immunol. 1994;12:881-922[CrossRef][Medline] [Order article via Infotrieve].
69.
Gruss HJ, Hirschstein D, Wright B, et al.
Expression and function of CD40 on Hodgkin and Reed-Sternberg cells and the possible relevance for Hodgkin's disease.
Blood.
1994;84:2305-2314 70. O'Grady JT, Stewart S, Lowrey J, Howie SE, Krajewski AS. CD40 expression in Hodgkin's disease. Am J Pathol. 1994;144:21-26[Abstract]. 71. Carbone A, Gloghini A, Gruss HJ, Pinto A. CD40 ligand is constitutively expressed in a subset of T cell lymphomas and on the microenvironmental reactive T cells of follicular lymphomas and Hodgkin's disease. Am J Pathol. 1995;147:912-922[Abstract]. 72. Murray PG, Oates J, Reynolds GM, Crocker J, Young LS. Expression of B7 (CD80) and CD40 antigens and the CD40 ligand in Hodgkin's disease is independent of latent Epstein-Barr virus infection. J Clin Pathol: Mol Pathol. 1995;48:M105-M108. 73. Metkar SS, Naresh KN, Redkar AA, Nadkarni JJ. CD40-ligation-mediated protection from apoptosis of a Fas-sensitive Hodgkin's-disease-derived cell line. Cancer Immunol Immunother. 1998;47:104-112[CrossRef][Medline] [Order article via Infotrieve]. 74. Weiss LM, Chen YY, Liu XF, Shibata D. Epstein-Barr virus and Hodgkin's disease. A correlative in situ hybridization and polymerase chain reaction study. Am J Pathol. 1991;139:1259-1265[Abstract].
75.
Herbst H, Steinbrecher E, Niedobitek G, et al.
Distribution and phenotype of Epstein-Barr virus-harboring cells in Hodgkin's disease.
Blood.
1992;80:484-491 76. Hummel M, Anagnostopoulos I, Dallenbach F, Korbjuhn P, Dimmler C, Stein H. EBV infection patterns in Hodgkin's disease and normal lymphoid tissue: expression and cellular localization of EBV gene products. Br J Haematol. 1992;82:689-694[Medline] [Order article via Infotrieve].
77.
Uchida J, Yasui T, Takaoka-Shichijo Y, et al.
Mimicry of CD40 signals by Epstein-Barr virus LMP1 in B lymphocyte responses.
Science.
1999;286:300-303 78. Inoue J, Ishida T, Tsukamoto N, et al. Tumor necrosis factor receptor-associated factor (TRAF) family: adapter proteins that mediate cytokine signaling. Exp Cell Res. 2000;254:14-24[CrossRef][Medline] [Order article via Infotrieve].
79.
Arch RH, Gedrich RW, Thompson CB.
Tumor necrosis factor receptor-associated factors (TRAFs)
80.
Falini B, Pileri S, Pizzolo G, et al.
CD30 (Ki-1) molecule: a new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy.
Blood.
1995;85:1-14 81. Gruss HJ, DaSilva N, Hu ZB, Uphoff CC, Goodwin RG, Drexler HG. Expression and regulation of CD30 ligand and CD30 in human leukemia-lymphoma cell lines. Leukemia. 1994;8:2083-2094[Medline] [Order article via Infotrieve]. 82. Gruss HJ, Pinto A, Gloghini A, et al. CD30 ligand expression in nonmalignant and Hodgkin's disease-involved lymphoid tissues. Am J Pathol. 1996;149:469-481[Abstract]. 83. Hsu PL, Hsu SM. Autocrine growth regulation of CD30 ligand in CD30-expressing Reed-Sternberg cells: distinction between Hodgkin's disease and anaplastic large cell lymphoma. Lab Invest. 2000;80:1111-1119[Medline] [Order article via Infotrieve]. 84. Pinto A, Aldinucci D, Gloghini A, et al. Human eosinophils express functional CD30 ligand and stimulate proliferation of a Hodgkin's disease cell line. Blood. 1996;88:3299-3305. 85. Molin D, Fischer M, Xiang Z, et al. Mast cells express functional CD30 ligand and are the predominant CD30L-positive cells in Hodgkin's disease. Br J Haematol. 2001;114:616-623[CrossRef][Medline] [Order article via Infotrieve]. 86. Smith CA, Gruss HJ, Davis T, et al. CD30 antigen, a marker for Hodgkin's lymphoma, is a receptor whose ligand defines an emerging family of cytokines with homology to TNF. Cell. 1993;73:1349-1360[CrossRef][Medline] [Order article via Infotrieve].
87.
Gruss HJ, Boiani N, Williams DE, Armitage RJ, Smith CA, Goodwin RG.
Pleiotropic effects of the CD30 ligand on CD30-expressing cells and lymphoma cell lines.
Blood.
1994;83:2045-2056 88. Gruss HJ, Ulrich D, Braddy S, Armitage RJ, Dower SK. Recombinant CD30 ligand and CD40 ligand share common biological activities on Hodgkin and Reed-Sternberg cells. Eur J Immunol. 1995;25:2083-2089[Medline] [Order article via Infotrieve].
89.
Fiumara P, Snell V, Li Y, et al.
Functional expression of receptor activator of nuclear factor kappaB in Hodgkin disease cell lines.
Blood.
2001;98:2784-2790 90. Dinarello CA. Interleukin-1. In: Thomson AW, ed. The Cytokine Handbook. 3rd ed. San Diego, CA: Academic Press; 1998:35-72. 91. Hsu SM, Krupen K, Lachman LB. Heterogeneity of interleukin 1 production in cultured Reed-Sternberg cell lines HDLM-1, HDLM-1d, and KM-H2. Am J Pathol. 1989;135:33-38[Abstract]. 92. Hsu SM, Zhao X. Expression of interleukin-1 in Reed-Sternberg cells and neoplastic cells from true histiocytic malignancies. Am J Pathol. 1986;125:221-225[Abstract]. 93. Ree HJ, Crowley JP, Dinarello CA. Anti-interleukin-1 reactive cells in Hodgkin's disease. Cancer. 1987;59:1717-1720[CrossRef][Medline] [Order article via Infotrieve]. 94. Derynck R, Choy L. Transforming growth factor-beta and its receptors. In: Thomson AW, ed. The Cytokine Handbook. 3rd ed. San Diego, CA: Academic Press; 1998:593-636. 95. Newcom SR, Kadin ME, Ansari AA, Diehl V. L-428 nodular sclerosing Hodgkin's cell secretes a unique transforming growth factor-beta active at physiologic pH. J Clin Invest. 1988;82:1915-1921[Medline] [Order article via Infotrieve]. 96. Kadin ME, Agnarsson BA, Ellingsworth LR, Newcom SR. Immunohistochemical evidence of a role for transforming growth factor beta in the pathogenesis of nodular sclerosing Hodgkin's disease. Am J Pathol. 1990;136:1209-1214[Abstract]. 97. Kadin M, Butmarc J, Elovic A, Wong D. Eosinophils are the major source of transforming growth factor-beta 1 in nodular sclerosing Hodgkin's disease. Am J Pathol. 1993;142:11-16[Abstract].
98.
Newcom SR, Gu L.
Transforming growth factor beta 1 messenger RNA in Reed-Sternberg cells in nodular sclerosing Hodgkin's disease.
J Clin Pathol.
1995;48:160-163 99. Alexander WS. Cytokines in hematopoiesis. Int Rev Immunol. 1998;16:651-682[Medline] [Order article via Infotrieve]. 100. Foss HD, Hummel M, Gottstein S, et al. Frequent expression of IL-7 gene transcripts in tumor cells of classical Hodgkin's disease. Am J Pathol. 1995;146:33-39[Abstract].
101.
Paietta E, Racevskis J, Stanley ER, Andreeff M, Papenhausen P, Wiernik PH.
Expression of the macrophage growth factor, CSF-1 and its receptor c-fms by a Hodgkin's disease-derived cell line and its variants.
Cancer Res.
1990;50:2049-2055 102. Moreau A, Praloran V, Berrada L, Coupey L, Gaillard F. Immunohistochemical detection of cells positive for colony-stimulating factor 1 in lymph nodes from reactive lymphadenitis, and Hodgkin's disease. Leukemia. 1992;6:126-130[Medline] [Order article via Infotrieve]. 103. Zheng GG, Wu KF, Geng YQ, et al. Expression of membrane-associated macrophage colony-stimulating factor (M-CSF) in Hodgkin's disease and other hematologic malignancies. Leuk Lymphoma. 1999;32:339-344[Medline] [Order article via Infotrieve]. 104. Farhi DC. Lack of CSF-1 receptor message in Reed-Sternberg cells. Hematol Pathol. 1989;3:85-90[Medline] [Order article via Infotrieve]. 105. Leonard WJ, O'Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol. 1998;16:293-322[CrossRef][Medline] [Order article via Infotrieve]. 106. Wurster AL, Tanaka T, Grusby MJ. The biology of Stat4 and Stat6. Oncogene. 2000;19:2577-2584[CrossRef][Medline] [Order article via Infotrieve]. 107. Takeda K, Tanaka T, Shi W, et al. Essential role of Stat6 in IL-4 signalling. Nature. 1996;380:627-630[CrossRef][Medline] [Order article via Infotrieve]. 108. Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 1996;4:313-319[CrossRef][Medline] [Order article via Infotrieve]. 109. Takeda K, Kamanaka M, Tanaka T, Kishimoto T, Akira S. Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice. J Immunol. 1996;157:3220-3222[Abstract].
110.
Zhang S, Lukacs NW, Lawless VA, Kunkel SL, Kaplan MH.
Cutting edge: differential expression of chemokines in Th1 and Th2 cells is dependent on Stat6 but not Stat4.
J Immunol.
2000;165:10-14
111.
Mathew A, MacLean JA, DeHaan E, Tager AM, Green FH, Luster AD.
Signal transducer and activator of transcription 6 controls chemokine production and T helper cell type 2 cell trafficking in allergic pulmonary inflammation.
J Exp Med.
2001;193:1087-1096 112. Bowman T, Garcia R, Turkson J, Jove R. STATs in oncogenesis. Oncogene. 2000;19:2474-2488[CrossRef][Medline] [Order article via Infotrieve]. 113. Hanissian SH, Geha RS. Jak3 is associated with CD40 and is critical for CD40 induction of gene expression in B cells. Immunity. 1997;6:379-387[CrossRef][Medline] [Order article via Infotrieve]. 114. Gires O, Kohlhuber F, Kilger E, et al. Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins. EMBO J. 1999;18:3064-3073[CrossRef][Medline] [Order article via Infotrieve]. 115. De Vos J, Jourdan M, Tarte K, Jasmin C, Klein B. JAK2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells. Br J Haematol. 2000;109:823-828[CrossRef][Medline] [Order article via Infotrieve].
116.
Wang LH, Kirken RA, Erwin RA, Yu CR, Farrar WL.
JAK3, STAT, and MAPK signaling pathways as novel molecular targets for the tyrphostin AG-490 regulation of IL-2-mediated T cell response.
J Immunol.
1999;162:3897-3904 117. Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998;16:225-260[CrossRef][Medline] [Order article via Infotrieve]. 118. Izban KF, Ergin M, Martinez RL, Alkan S. Expression of the tumor necrosis factor receptor-associated factors (TRAFs) 1 and 2 is a characteristic feature of Hodgkin and Reed-Sternberg cells. Mod Pathol. 2000;13:1324-1331[CrossRef][Medline] [Order article via Infotrieve].
119.
Durkop H, Foss HD, Demel G, Klotzbach H, Hahn C, Stein H.
Tumor necrosis factor receptor-associated factor 1 is overexpressed in Reed-Sternberg cells of Hodgkin's disease and Epstein-Barr virus-transformed lymphoid cells.
Blood.
1999;93:617-623 120. Murray PG, Flavell JR, Baumforth KR, et al. Expression of the tumour necrosis factor receptor-associated factors 1 and 2 in Hodgkin's disease. J Pathol. 2001;194:158-164[CrossRef][Medline] [Order article via Infotrieve]. 121. Rayet B, Gelinas C. Aberrant rel/nfkb genes and activity in human cancer. Oncogene. 1999;18:6938-6947[CrossRef][Medline] [Order article via Infotrieve].
122.
Davis RE, Brown KD, Siebenlist U, Staudt LM.
Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells.
J Exp Med.
2001;194:1861-1874 123. Kordes U, Krappmann D, Heissmeyer V, Ludwig WD, Scheidereit C. Transcription factor NF-kappaB is constitutively activated in acute lymphoblastic leukemia cells. Leukemia. 2000;14:399-402[CrossRef][Medline] [Order article via Infotrieve].
124.
Bargou RC, Leng C, Krappmann D, et al.
High-level nuclear NF-kappa B and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells.
Blood.
1996;87:4340-4347 125. Wood KM, Roff M, Hay RT. Defective IkappaBalpha in Hodgkin cell lines with constitutively active NF-kappaB. Oncogene. 1998;16:2131-2139[CrossRef][Medline] [Order article via Infotrieve]. 126. Krappmann D, Emmerich F, Kordes U, Scharschmidt E, Dorken B, Scheidereit C. Molecular mechanisms of constitutive NF-kappaB/Rel activation in Hodgkin/Reed-Sternberg cells. Oncogene. 1999;18:943-953[CrossRef][Medline] [Order article via Infotrieve]. 127. Izban KF, Ergin M, Huang Q, et al. Characterization of NF-kappaB expression in Hodgkin's disease: inhibition of constitutively expressed NF-kappaB results in spontaneous caspase-independent apoptosis in Hodgkin and Reed-Sternberg cells. Mod Pathol. 2001;14:297-310[CrossRef][Medline] [Order article via Infotrieve]. 128. Bargou RC, Emmerich F, Krappmann D, et al. Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells. J Clin Invest. 1997;100:2961-2969[Medline] [Order article via Infotrieve].
129.
Hinz M, Loser P, Mathas S, Krappmann D, Dorken B, Scheidereit C.
Constitutive NF-kappaB maintains high expression of a characteristic gene network, including CD40, CD86, and a set of antiapoptotic genes in Hodgkin/Reed-Sternberg cells.
Blood.
2001;97:2798-2807 130. Chu WS, Aguilera NS, Wei MQ, Abbondanzo SL. Antiapoptotic marker Bcl-X(L), expression on Reed-Sternberg cells of Hodgkin's disease using a novel monoclonal marker, YTH-2H12. Hum Pathol. 1999;30:1065-1070[CrossRef][Medline] [Order article via Infotrieve]. 131. Cabannes E, Khan G, Aillet F, Jarrett RF, Hay RT. Mutations in the IkBa gene in Hodgkin's disease suggest a tumour suppressor role for IkappaBalpha. Oncogene. 1999;18:3063-3070[CrossRef][Medline] [Order article via Infotrieve].
132.
Jungnickel B, Staratschek-Jox A, Brauninger A, et al.
Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in Hodgkin's lymphoma.
J Exp Med.
2000;191:395-402
133.
Annunziata CM, Safiran YJ, Irving SG, Kasid UN, Cossman J.
Hodgkin disease: pharmacologic intervention of the CD40-NF kappa B pathway by a protease inhibitor.
Blood.
2000;96:2841-2848
134.
Emmerich F, Meiser M, Hummel M, et al.
Overexpression of I kappa B alpha without inhibition of NF-kappaB activity and mutations in the I kappa B alpha gene in Reed-Sternberg cells.
Blood.
1999;94:3129-3134
135.
McKenzie AN, Culpepper JA, de Waal Malefyt R, et al.
Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function.
Proc Natl Acad Sci U S A.
1993;90:3735-3739
136.
Punnonen J, Aversa G, Cocks BG, et al.
Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells.
Proc Natl Acad Sci U S A.
1993;90:3730-3734
137.
Defrance T, Carayon P, Billian G, et al.
Interleukin 13 is a B cell stimulating factor.
J Exp Med.
1994;179:135-143 138. Kuppers R, Rajewsky K. The origin of Hodgkin and Reed/Sternberg cells in Hodgkin's disease. Annu Rev Immunol. 1998;16:471-493[CrossRef][Medline] [Order article via Infotrieve].
139.
Marafioti T, Hummel M, Foss HD, et al.
Hodgkin and Reed-Sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription.
Blood.
2000;95:1443-1450 140. Lam KP, Kuhn R, Rajewsky K. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell. 1997;90:1073-1083[CrossRef][Medline] [Order article via Infotrieve]. 141. MacLennan IC. Germinal centers. Annu Rev Immunol. 1994;12:117-139[CrossRef][Medline] [Order article via Infotrieve]. 142. Yellin MJ, Sippel K, Inghirami G, et al. CD40 molecules induce down-modulation and endocytosis of T cell surface T cell-B cell activating molecule/CD40-L. Potential role in regulating helper effector function. J Immunol. 1994;152:598-608[Abstract].
143.
de Waal Malefyt R, Abrams JS, Zurawski SM, et al.
Differential regulation of IL-13 and IL-4 production by human CD8+ and CD4+ Th0, Th1 and Th2 T cell clones and EBV-transformed B cells.
Int Immunol.
1995;7:1405-1416
144.
Lomo J, Blomhoff HK, Jacobsen SE, Krajewski S, Reed JC, Smeland EB.
Interleukin-13 in combination with CD40 ligand potently inhibits apoptosis in human B lymphocytes: upregulation of Bcl-xL and Mcl-1.
Blood.
1997;89:4415-4424
145.
Rothenberg ME.
Eosinophilia.
N Engl J Med.
1998;338:1592-1600
146.
Matsukura S, Stellato C, Georas SN, et al.
Interleukin-13 upregulates eotaxin expression in airway epithelial cells by a STAT6-dependent mechanism.
Am J Respir Cell Mol Biol.
2001;24:755-761
147.
Hoeck J, Woisetschlager M.
STAT6 mediates eotaxin-1 expression in IL-4 or TNF-alpha-induced fibroblasts.
J Immunol.
2001;166:4507-4515 148. Zhu Z, Homer RJ, Wang Z, et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest. 1999;103:779-788[Medline] [Order article via Infotrieve].
149.
Poppema S, Bhan AK, Reinherz EL, Posner MR, Schlossman SF.
In situ immunologic characterization of cellular constituents in lymph nodes and spleens involved by Hodgkin's disease.
Blood.
1982;59:226-232
150.
Aisenberg AC, Wilkes BM.
Lymph node T cells in Hodgkin's disease: analysis of suspensions with monoclonal antibody and rosetting techniques.
Blood.
1982;59:522-527 151. Knowles DM II, Halper JP, Jakobiec FA. T-lymphocyte subpopulations in B-cell-derived non-Hodgkin's lymphomas and Hodgkin's disease. Cancer. 1984;54:644-651[CrossRef][Medline] [Order article via Infotrieve]. 152. Forni M, Hofman FM, Parker JW, Lukes RJ, Taylor CR. B- and T-lymphocytes in Hodgkin's disease. An immunohistochemical study utilizing heterologous and monoclonal antibodies. Cancer. 1985;55:728-737[CrossRef][Medline] [Order article via Infotrieve]. 153. Poppema S, Potters M, Emmens R, Visser L, van den Berg A. Immune reactions in classical Hodgkin's lymphoma. Semin Hematol. 1999;36:253-259[Medline] [Order article via Infotrieve]. 154. Romagnani S, Del Prete GF, Maggi E, et al. Displacement of T lymphocytes with the "helper/inducer" phenotype from peripheral blood to lymphoid organs in untreated patients with Hodgkin's disease. Scand J Haematol. 1983;31:305-314[Medline] [Order article via Infotrieve]. 155. Roers A, Montesinos-Rongen M, Hansmann ML, Rajewsky K, Kuppers R. Amplification of TCRbeta gene rearrangements from micromanipulated single cells: T cells rosetting around Hodgkin and Reed-Sternberg cells in Hodgkin's disease are polyclonal. Eur J Immunol. 1998;28:2424-2431[CrossRef][Medline] [Order article via Infotrieve].
156.
Andrew DP, Chang MS, McNinch J, et al.
STCP-1 (MDC) CC chemokine acts specifically on chronically activated Th2 lymphocytes and is produced by monocytes on stimulation with Th2 cytokines IL-4 and IL-13.
J Immunol.
1998;161:5027-5038
157.
Bonecchi R, Sozzani S, Stine JT, et al.
Divergent effects of interleukin-4 and interferon-gamma on macrophage-derived chemokine production: an amplification circuit of polarized T helper 2 responses.
Blood.
1998;92:2668-2671
158.
Sekiya T, Miyamasu M, Imanishi M, et al.
Inducible expression of a Th2-type CC chemokine thymus- and activation-regulated chemokine by human bronchial epithelial cells.
J Immunol.
2000;165:2205-2213
159.
Willenbrock K, Roers A, Blohbaum B, Rajewsky K, Hansmann ML.
CD8(+) T cells in Hodgkin's disease tumor tissue are a polyclonal population with limited clonal expansion but little evidence of selection by antigen.
Am J Pathol.
2000;157:171-175
160.
Oudejans JJ, Jiwa NM, Kummer JA, et al.
Analysis of major histocompatibility complex class I expression on Reed-Sternberg cells in relation to the cytotoxic T-cell response in Epstein-Barr virus-positive and -negative Hodgkin's disease.
Blood.
1996;87:3844-3851
161.
Oudejans JJ, Jiwa NM, Kummer JA, et al.
Activated cytotoxic T cells as prognostic marker in Hodgkin's disease.
Blood.
1997;89:1376-1382 162. Kandil A, Bazarbashi S, Mourad WA. The correlation of Epstein-Barr virus expression and lymphocyte subsets with the clinical presentation of nodular sclerosing Hodgkin disease. Cancer. 2001;91:1957-1963[CrossRef][Medline] [Order article via Infotrieve].
163.
Frisan T, Sjoberg J, Dolcetti R, et al.
Local suppression of Epstein-Barr virus (EBV)-specific cytotoxicity in biopsies of EBV-positive Hodgkin's disease.
Blood.
1995;86:1493-1501
164.
Chapman AL, Rickinson AB, Thomas WA, Jarrett RF, Crocker J, Lee SP.
Epstein-Barr virus-specific cytotoxic T lymphocyte responses in the blood and tumor site of Hodgkin's disease patients: implications for a T-cell-based therapy.
Cancer Res.
2001;61:6219-6226
165.
Newcom SR, O'Rourke L.
Potentiation of fibroblast growth by nodular sclerosing Hodgkin's disease cell cultures.
Blood.
1982;60:228-237 166. Ohshima K, Sugihara M, Suzumiya J, et al. Basic fibroblast growth factor and fibrosis in Hodgkin's disease. Pathol Res Pract. 1999;195:149-155[Medline] [Order article via Infotrieve].
167.
Shinozaki M, Kawara S, Hayashi N, Kakinuma T, Igarashi A, Takehara K.
Induction of subcutaneous tissue fibrosis in newborn mice by transforming growth factor beta 168. Sime PJ, O'Reilly KM. Fibrosis of the lung and other tissues: new concepts in pathogenesis and treatment. Clin Immunol. 2001;99:308-319[CrossRef][Medline] [Order article via Infotrieve]. 169. Chiaramonte MG, Donaldson DD, Cheever AW, Wynn TA. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. J Clin Invest. 1999;104:777-785[Medline] [Order article via Infotrieve].
170.
Fallon PG, Richardson EJ, McKenzie GJ, McKenzie AN.
Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent.
J Immunol.
2000;164:2585-2591
171.
Oriente A, Fedarko NS, Pacocha SE, Huang SK, Lichtenstein LM, Essayan DM.
Interleukin-13 modulates collagen homeostasis in human skin and keloid fibroblasts.
J Pharmacol Exp Ther.
2000;292:988-994
172.
Lee CG, Homer RJ, Zhu Z, et al.
Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1).
J Exp Med.
2001;194:809-821
173.
Kurzrock R, Redman J, Cabanillas F, Jones D, Rothberg J, Talpaz M.
Serum interleukin 6 levels are elevated in lymphoma patients and correlate with survival in advanced Hodgkin's disease and with B symptoms.
Cancer Res.
1993;53:2118-2122
174.
Gorschluter M, Bohlen H, Hasenclever D, Diehl V, Tesch H.
Serum cytokine levels correlate with clinical parameters in Hodgkin's disease.
Ann Oncol.
1995;6:477-482 175. Gause A, Scholz R, Klein S, et al. Increased levels of circulating interleukin-6 in patients with Hodgkin's disease. Hematol Oncol. 1991;9:307-313[Medline] [Order article via Infotrieve]. 176. Blay JY, Farcet JP, Lavaud A, Radoux D, Chouaib S. Serum concentrations of cytokines in patients with Hodgkin's disease. Eur J Cancer. 1994;30A:321-324[CrossRef][Medline] [Order article via Infotrieve]. 177. Seymour JF, Talpaz M, Hagemeister FB, Cabanillas F, Kurzrock R. Clinical correlates of elevated serum levels of interleukin 6 in patients with untreated Hodgkin's disease. Am J Med. 1997;102:21-28[Medline] [Order article via Infotrieve]. 178. Slivnick DJ, Ellis TM, Nawrocki JF, Fisher RI. The impact of Hodgkin's disease on the immune system. Semin Oncol. 1990;17:673-682[Medline] [Order article via Infotrieve]. 179. Romagnani S, Biagiotti R, Amadori A, et al. Hyperproduction of IgE and T-cell dysfunction in Hodgkin's disease. Int Arch Allergy Appl Immunol. 1980;63:64-72[Medline] [Order article via Infotrieve]. 180. Amlot PL, Slaney J. Hypergammaglobulinaemia E in Hodgkin's disease and its relationship to atopy or a familial predisposition to atopy. Int Arch Allergy Appl Immunol. 1981;64:138-145[Medline] [Order article via Infotrieve].
181.
Heaney ML, Golde DW.
Soluble cytokine receptors.
Blood.
1996;87:847-857 182. Gause A, Roschansky V, Tschiersch A, et al. Low serum interleukin-2 receptor levels correlate with a good prognosis in patients with Hodgkin's lymphoma. Ann Oncol. 1991;2:43-47[Abstract]. 183. Ambrosetti A, Nadali G, Vinante F, et al. Serum levels of soluble interleukin-2 receptor in Hodgkin disease. Relationship with clinical stage, tumor burden, and treatment outcome. Cancer. 1993;72:201-206[CrossRef][Medline] [Order article via Infotrieve]. 184. Barral-Netto M, Barral A, Santos SB, et al. Soluble IL-2 receptor as an agent of serum-mediated suppression in human visceral leishmaniasis. J Immunol. 1991;147:281-284[Abstract]. 185. Symons JA, Wood NC, Di Giovine FS, Duff GW. Soluble IL-2 receptor in rheumatoid arthritis. Correlation with disease activity, IL-1 and IL-2 inhibition. J Immunol. 1988;141:2612-2618[Abstract].
186.
Barton DP, Blanchard DK, Michelini-Norris B, Nicosia SV, Cavanagh D, Djeu JY.
High serum and ascitic soluble interleukin-2 receptor alpha levels in advanced epithelial ovarian cancer.
Blood.
1993;81:424-429 187. Damle RN, Advani SH, Gangal SG. Analysis of regulation of T-cell responses by soluble inhibitory factors from the sera of patients with Hodgkin's disease. Int J Cancer. 1992;50:192-196[Medline] [Order article via Infotrieve].   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Letter in Blood Online:
This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
25 pg/mL) by enzyme-linked immunosorbent assay (ELISA) in L-428
and HDLM-2 cells
) that
are regulated differently and have different affinities for individual NF-
a family of adapter proteins that regulates life and death.
Genes Dev.
1998;12:2821-2830
