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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 685-690
NEOPLASIA
Expression pattern of T-cell-associated chemokine receptors and
their chemokines correlates with specific subtypes of T-cell
non-Hodgkin lymphoma
Dan Jones,
Carl O'Hara,
Madeleine D. Kraus,
Antonio R. Perez-Atayde,
Aliakbar Shahsafaei,
Lijun Wu, and
David M. Dorfman
From the Department of Pathology, Brigham and Women's Hospital and
Harvard Medical School; the Department of Pathology, Boston Medical
Center; the Department of Pathology, Children's Hospital, Boston; the
Department of Pathology, LeukoSite, Inc, Cambridge, MA; and the
Department of Pathology, Washington University School of Medicine, St
Louis, MO.
 |
Abstract |
Chemokine receptors mediate the migration of lymphocytes through the
binding of soluble ligands, and their expression is differentially regulated in lymphocyte subsets. The pattern of chemokine receptor expression in T-cell non-Hodgkin lymphoma has not been previously studied. Using a panel of mouse monoclonal antibodies, we studied the
immunohistochemical expression of the Th1-associated chemokine receptor
CXCR3 in 141 patients with T-cell lymphoma, and we studied the
receptors CCR4 and CCR5 and some of their ligands in a subset of these
tumors. Expression of CXCR3 was typical of the smaller T cells in
angioimmunoblastic lymphoma (15 of 18 patients), angiocentric lymphoma
(3 of 3 patients), histiocyte-rich tumors (4 of 5 patients), and
unspecified T-cell lymphomas (17 of 39 patients). CXCR3 expression was
seen in only 1 of 15 patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma. In
contrast, all ALK-positive tumors showed diffuse reactivity for the
Th2-associated receptor CCR4 (5 of 5 patients). CCR4 expression
was also a consistent feature of the large-cell transformation of
mycosis fungoides. CCR5 expression showed no consistent
association with any T-cell tumor type. The chemokines Mig (CXCR3
ligand), TARC (CCR4 ligand), and MCP-2 (CCR5 ligand) were detected in
intratumoral blood vessels and histiocytes. Mig was also coexpressed by
a subset of CXCR3-positive tumor cells in 6 of 20 lymphomas.
MCP-2 was highly expressed in stromal cells in 3 patients with nodal
involvement by cutaneous T-cell lymphoma. As with normal T-cell
subsets, we demonstrated that there is frequent differential expression
of chemokine receptors in T-cell tumors, which may explain, in part,
the distinctive patterns of spread in different tumor subtypes.
(Blood. 2000;96:685-690)
© 2000 by The American Society of Hematology.
| |
Introduction |
Chemokines are soluble proteins that regulate
leukocyte migration and activation through binding to
transmembrane receptors differentially expressed on lymphocyte
subsets.1 It has recently been demonstrated that the
expression pattern of chemokine receptors in normal T-cell subsets
correlates with the pattern of cytokine secretion in these cells.
Specifically, the expression of the receptors CCR3, CCR4, and CCR8 is
associated with Th2-polarized T cells expressing the cytokines, IL-4
and IL-5.2-4 In contrast, CXCR3 expression is highest in
cells with a predominant Th1 pattern of cytokine
secretion.2,3,5 CCR5 is constitutively expressed in
circulating memory T cells and is differentially regulated on T-cell
activation in response to different cytokines.6-9
To date, the classification of T-cell lymphoma has been
largely based on morphologic or clinical criteria.10 For
example, mycosis fungoides (MF) and intestinal T-cell lymphoma are
defined based on sites of involvement and can have a wide range of
histologic appearances. Other tumors, such as angioimmunoblastic
lymphoma, are largely defined by morphologic criteria. Some
lymphoma types are defined by specific phenotypic criteria, such as
the presence of HTLV-I in adult T-cell leukemia-lymphoma and
of CD30 expression (± ALK) in anaplastic
large-cell lymphoma. We report that several of the T-cell-associated
chemokine receptors are differentially expressed in distinct
subtypes of T-cell lymphoma and are correlated with the expression of
other T-cell surface markers.
Materials and methods
All T-cell tumors diagnosed at Brigham and Women's
Hospital (Boston, MA) in the past 10 years were included if material
was available; additional cases were drawn from Boston Medical Center (Boston, MA), Washington University Hospital (St Louis, MO), and Children's Hospital (Boston, MA). Diagnosis was based on the revised European-American lymphoma (REAL) classification after examination of
routinely stained histologic sections and a panel of
immunohistochemical markers, including the B-cell marker CD20 (L26) and
the T-cell-associated markers CD3, CD45RO, and CD43
(Leu22).10 If fresh tissue was available, additional
immunostains for the T-cell markers CD2, CD4, CD5, and CD8 were
performed as previously described.11 Our specific criteria
for the diagnosis of anaplastic large-cell lymphoma and
angioimmunoblastic lymphoma have been previously published.12,13 Cases with a T-cell genotype and prominent vascular infiltration were regarded as angiocentric T-cell lymphoma. Predominant tumor cell size and presence of abundant admixed
histiocytes (ie, Lennert lymphoma) were recorded for cases in the REAL
category of peripheral T-cell lymphoma, unspecified.
Immunoperoxidase studies were performed on formalin-fixed,
paraffin-embedded material (for CXCR3, CD30, CD134/OX40) after microwave antigen retrieval and on cryostat sections using antibodies directed against the chemokine receptors CCR4 (1G1),14 CCR5 (3A9),5,15 CXCR3 (1C6),5,16 and the chemokines
TARC(2D8),14 Mig (4G10), and MCP-2 (2D5),17 and
the activation markers CD134/OX40 (ACT35; Pharmingen, San Diego,
CA) and CD30 (BerH2; DAKO, Carpinteria, CA). All
antibodies directed against chemokine receptors were tested for
specificity by the ability to stain to L1.2 stable transfectants
expressing the target chemokine receptor but not L1.2 transfectants
expressing other chemokine receptors.
Statistical analyses were performed on certain pairwise comparisons
using either Student t test or Fisher exact test methods, depending on analyzed sample size, using the
StatDirect package (Camcode, Ashwell, UK).
| |
Results |
Chemokine receptor expression
CXCR3 has been previously demonstrated to be expressed in most
circulating peripheral T cells. In normal lymph node and tonsil, numerous CXCR3-positive interfollicular T cells were noted by immunohistochemistry, comprising 20% to 50% of the total cellularity in these regions (Figure 1A). B cells, in
the follicles and mantle zone, were negative for CXCR3. We examined the
expression pattern of CXCR3 in paraffin and cryostat sections of 141 T-cell lymphomas of all histologic types. Sixty-six patients (47%)
showed CXCR3 positivity in more than 5% of tumor cells, with 45 patients showing diffuse reactivity in most tumor cells (Table
1). Diffuse CXCR3 expression was seen in
the smaller T cells from 15 of 18 patients with angioimmunoblastic
lymphoma, in 3 of 3 patients with angiocentric T cell lymphoma, and in
4 of 5 patients with histiocyte-rich T-cell lymphoma (Figure 1B,C).
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| Fig 1.
Expression of the chemokine receptor CXCR3.
(A) Normal tonsil shows staining of approximately 50% of T cells in
the interfollicular areas for CXCR3. B cells, in follicles and mantle
zones, are negative. (B) Angiocentric T-cell lymphoma of the lung shows
diffuse positivity for CXCR3 in the angioinvasive component. (C)
Histiocyte-rich T-cell (lymphoepithelioid) lymphoma shows a mixture of
predominantly small tumor lymphocytes and numerous CD68-positive
epithelioid histiocytes (inset, left). Tumor cells are positive for
CXCR3. Histiocytes show strong expression of Mig (inset, right).
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We also examined patients with CD30-positive anaplastic large-cell
lymphoma (ALCL) of T-cell or null lineage previously characterized by
immunostaining for the ALK kinase. Nuclear ALK1 immunohistochemical expression is a marker of the t(2;5) chromosomal translocation seen in
a subset of patients with ALCL. ALK-positive ALCL was negative for
CXCR3 in 14 of 15 patients (Figure 2C).
Among noncutaneous ALK-negative ALCL tumors, CXCR3 expression was more
variable, with 8 of 21 (38%) showing diffuse positivity. CXCR3 was
diffusely positive in 2 of 5 patients with primary cutaneous ALCL, all
of whom were ALK negative.
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| Fig 2.
Chemokine receptor expression in ALCL.
(A) Tumor shows a diffuse infiltrate of anaplastic cells with
cytoplasmic and nuclear reactivity for ALK (inset). CD30 was uniformly
positive (not shown). (B) Immunostain for CCR4 shows membrane and
granular cytoplasmic reactivity in all tumor cells. Admixed small
lymphocytes are negative. Immunostain for the CCR4 ligand TARC shows
staining of intratumoral blood vessels; tumor cells are negative
(inset). (C) Immunostain for CXCR3 is negative in tumor cells.
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Cutaneous T-cell lymphoma of the MF type showed strong CXCR3 expression
in 7 of 9 patients. CXCR3-positive cells included most of the
epidermotropic tumor cells and most lymphocytes infiltrating the
superficial dermis (Figure 3A). Two of 3 lymph node biopsies from patients with MF showed numerous
CXCR3-positive tumors in the sinuses and interfollicular areas,
including morphologically atypical cells with cerebriform nuclei. In MF
that underwent large-cell transformation, CXCR3 reactivity occurred
only in small lymphocytes in the lymph nodes of 5 of 8 patients; the
remaining patients were entirely negative for CXCR3 (data not shown).
Thus, there was a highly significant association between CXCR3
expression in low-grade MF but not in large-cell transformation of MF
(P = .002).
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| Fig 3.
Chemokine receptor expression in cutaneous lymphoma.
(A) Patch-stage MF with an epidermotropic and superficial dermal
infiltrate showing CXCR3 reactivity. CCR4 immunostain was negative (not
shown). (B) Cutaneous lymphoma with slack skin presentation shows
reactivity of the large epidermotropic tumor cells for CCR4. CXCR3
immunostain was negative (not shown). (C) Nodal large-cell
transformation of MF. Large tumor cells show diffuse reactivity for
CCR4; CXCR3 was positive only in admixed small lymphocytes (not shown).
(D) Increased MCP-2 in stromal cells in lymph node involvement by MF.
Interfollicular macrophages and nontumor mononuclear cells show MCP-2
expression in 4 of 4 patients with nodal involvement by low-grade MF.
Increased MCP-2 was not seen in nodal involvement by transformed MF
(not shown).
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We compared CXCR3 expression with immunohistochemical expression of 2 other T-cell-associated chemokine receptors, CCR4 and CCR5, in 48 T-cell tumors for which we had frozen, unfixed material available. In
non-neoplastic lymph nodes and tonsil, CCR4 was expressed in the
endothelium of most blood vessels and in a small fraction of
interfollicular T cells comprising approximately 1% of the overall
cellularity (data not shown). By immunohistochemistry, CCR5 was
predominantly expressed in endothelium and histiocytes and weakly
expressed in a small number of lymphocytes (data not shown). In
contrast, a subset of T-cell tumors showed diffuse expression of CCR4
(19 of 48, 40%), CCR5 (10 of 31, 32%), or both (Table 1).
The most striking finding was in ALK-positive ALCL, in which all 5 tumors tested showed diffuse positivity for CCR4 (Figure 2B). Tumor
cells typically showed membrane and granular cytoplasmic staining
patterns that resembled those seen in immunostains for granular
cytotoxic proteins such as TIA-1. CCR4 was positive in 3 of 6 ALK-negative, noncutaneous anaplastic tumors. CCR5 expression was seen
in 3 of 4 ALK-positive patients and in 1 of 6 ALK-negative anaplastic
tumors. Strong CCR4 positivity was present in 4 of 5 patients with
nodal large-cell transformation of MF (Figure 3C), with the remaining
patient showing focal CCR4 reactivity. In contrast, only 2 patients
with epidermotropic cutaneous lymphoma showed positive staining of
tumor cells for CCR4. Both cases were unusual; 1 patient had the
"slack-skin" variant of MF and a largely epidermotropic
infiltrate of large, irregular lymphocytes (Figure 3B), and the second
patient had an unclassifiable CD8-positive tumor (data not shown).
Chemokine expression in T-cell tumors
We also examined the immunohistochemical expression of high-affinity
ligands for these chemokine receptors, including Mig, which binds to
CXCR3, TARC, which binds to CCR4, and MCP-2, which binds to CCR5.
Variable staining for all 3 chemokines was seen in blood vessels and
admixed histiocytes (Table 1). TARC showed the strongest staining of
the muscular/adventitial layer of blood vessels and scattered stromal
cells in lymph node and connective tissue of the dermis (Figure 2B
inset and data not shown).
Mig immunostaining was more variable and was abundantly expressed in
macrophages of histiocyte-rich T-cell tumors (Figure 1C inset). Mig
expression was also seen in variable numbers of tumor cells in 6 of 21 patients with T-cell lymphoma, mostly those in the peripheral T-cell
lymphoma, unspecified category. All patients with Mig staining of tumor
cells also showed tumor expression of its receptor, CXCR3. MCP-2
immunostaining was not seen in normal lymphocytes or in any T-cell
tumors tested. However, we noted increased MCP-2 expression in various
stromal cells in 3 of 4 patients with nodal involvement by MF (Figure
3D). In only 1 of these patients were increased numbers of
CCR5-expressing tumor cells present (data not shown).
Correlation with expression of other surface activation markers
Using the same set of tumors, we previously reported that some
members of the tumor necrosis factor (TNF) receptor gene family, namely
CD30 and CD134/OX40, are differentially expressed in T-cell lymphoma.13 Expression of these markers of activated T
cells correlates with histologic tumor type (Table 1). For instance, ALK-positive ALCL is uniformly CD30-positive but almost always negative
for CD134/OX40. In contrast, angioimmunoblastic lymphoma nearly always
shows clusters of OX40-positive cells but not CD30 expression in tumor cells.
We compared our previous results for CD30 and CD134/OX40 with
those of the chemokine receptors. Coexpression of CD30 and CCR4 was
present in 8 of 11 patients with ALCL. Tumor cells in the large-cell
transformation of MF were also positive for both CCR4 and CD30 in 4 of
5 patients. However, 4 CCR4-positive non-anaplastic PTCLs were
uniformly negative for CD30 (Figure 4A
inset). Considering all tumor types, CD30 and CCR4 were coexpressed in
most tumor cells in 13 of 44 patients (30%), and neither was expressed
in 19 of 44 patients (43%). Thus, there was a significant association between CD30 and CCR4 coexpression in T-cell tumors (P = .04).
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| Fig 4.
Variability of chemokine receptor and TNF receptor
expression in nodal T-cell lymphoma.
(A) Nodal peripheral T-cell lymphoma with a predominant large-cell
morphology showing diffuse membrane and cytoplasmic reactivity for CCR4
in most tumor cells. CD30 immunostain is negative (inset). (B) Nodal
peripheral T-cell lymphoma with a predominant large-cell morphology
showing diffuse reactivity for CXCR3; CD134/OX40 immunostain was also
diffusely positive (inset). (C, D) Angioimmunoblastic T-cell lymphoma
in lymph node. CD134/OX40 immunostain highlights clusters of
OX40-positive larger tumor cells (C). CXCR3 immunostain is diffusely
positive in small- to intermediate-sized lymphocytes from the same
biopsy (D). Large, clear cells are variably positive.
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In contrast, CD134/OX40 and CXCR3 were coexpressed in 14 of 18 patients with angioimmunoblastic lymphoma (AIL), 4 of 5 patients with
histiocyte-rich T-cell tumors, and 3 of 3 patients with angiocentric T-cell lymphoma. Considering all tumor types, there was more than 50%
expression of CXCR3 and CD134/OX40 in tumor cells in 37 of 122 (30%)
patients and no significant expression of these
markers in 54 of 122 (44%) patients. Thus, there was a highly
significant association between the expression of these 2 markers
overall in T-cell non-Hodgkin lymphoma (P < .0001). However,
certain tumor types showed great variations in the extent of expression
of these markers. In AIL, CD134/OX40 and CXCR3 appeared to be expressed in nonidentical populations of lymphocytes within the tumor, based on a
comparison of serial sections (Figure 4C,D). OX40 was consistently expressed in the neoplastic clusters of larger cells with clear cytoplasm characteristic of AIL (Figure 4C). In contrast, CXCR3 was
more uniformly expressed in the small- and intermediate-sized lymphocytes, possibly representing reactive infiltrating T cells (Figure 4D).
In ALK-positive ALCL, only 1 patient each expressed CD134 and CXCR3. In
ALK-negative ALCL, there was no significant correlation between
CD134/OX40 and CXCR3, with 5 patients each expressing neither marker,
CXCR3 alone, or CD134 alone, and 6 patients expressing both. Similarly,
among the nonanaplastic large cell tumors, there was no correlation
noted between CXCR3 expression and that of CD134/OX40 (Figure 4B).
These results likely reflect the morphologic and immunophenotypic
heterogeneity of these categories.
| |
Discussion |
We present the immunohistochemical expression pattern of 3 T-cell-associated chemokine receptors, CXCR3, CCR4, and CCR5, in a
large series of T-cell lymphoma of all types. CXCR3 is expressed in
several tumor subtypes, including most cases of AIL, histiocyte-rich T-cell tumors, and angiocentric T-cell lymphoma. In these tumors, the
detection of CXCR3 is highly correlated with the coexpression of the
TNF receptor CD134/OX40. In contrast, ALK-positive ALCL shows
immunoreactivity for CCR4 and is negative for CXCR3 in most patients.
Lymphomas with a naive or immature phenotype, namely lymphoblastic
lymphoma and T-CLL, were predominantly negative for both CXCR3 and CCR4.
The expression patterns of ALK-negative anaplastic tumors and
peripheral T-cell lymphoma of unspecified type are highly variable with
regard to chemokine receptor expression, and there is no obvious
correlation with CD30 or CD134/OX40 expression. These findings provide
additional evidence that these categories are morphologically and
immunophenotypically heterogeneous and do not correlate with a distinct
T-cell phenotype.
In T-cell cultures and cell lines, expression of the chemokine
receptor CCR4 has been correlated with the Th2
phenotype.3,8,9,18 Our finding of the preferential
expression of CCR4 in CD30-positive anaplastic tumors is intriguing
given the frequent association of CD30 expression in normal T cells
with a Th2-like phenotype. Increased numbers of CD30-positive cells and
elevated levels of circulating soluble CD30 have been reported in
prototypic "Th2-type" inflammatory states.19-21 This
observation is hypothesized to be related to the induction of CD30
expression in T cells after production of the Th2 cytokine
IL-4.22,23 The pattern of cytokine expression in ALCL has
not been well-studied. However, 1 small study showed increased
expression of Th2 cytokines in cutaneous ALCL by transcriptional analysis.24 By demonstrating CCR4 expression and lack of
CXCR3, our study provides evidence for the phenotypic similarity of
ALK-positive ALCL to a Th2-like T-cell population.
Conversely, CXCR3 expression has been associated with cell lines and
primary cultures polarized toward Th1 cytokine
expression.3,5,8,9,18 Our finding that AIL and
histiocyte-rich T-cell lymphoma highly express CXCR3 and CD134/OX40
supports a Th1-like phenotype for these tumors. In this regard,
increased levels of the Th1 cytokine interferon-gamma (produced by
tumor-associated macrophages) have been previously reported in a small
series of Lennert lymphoma.25 We also noted abundant Mig
production by admixed histiocytes, suggesting an important role for
this chemokine interaction with CXCR3 in tumor dissemination or growth.
Angioimmunoblastic lymphoma is a complex tumor characterized by
morphologic, immunophenotypic, and genotypic instability and a high
rate of histologic progression.12,26,27 Historically, early
stages of this tumor (often labeled AILD) have been regarded as
pre-neoplastic or even reactive because occasional patients experience
nonprogression or even regression without treatment. Given this
complexity, it is likely that the phenotype of the tumor cell
population and cytokine expression pattern fluctuates over the course
of the disease. Indeed, increased levels of IL-2, IL-4, TNF- and
TNF- , soluble CD30, and interferon- have all been variably
reported in AIL/AILD.25,28,29 Our findings of distinct
populations of CD134-positive and CXCR3-positive populations of cells
within AIL is further evidence of tumor heterogeneity and shows that
these 2 receptors can be differentially regulated.
Each chemokine receptor typically binds a number of related
chemokines with varying affinity. This complexity makes identification of functionally relevant ligand-receptor interactions difficult. As an
initial step toward correlating receptor expression with chemokine
sources, we performed immunostaining for a high-affinity ligand for
each of the studied receptors. In normal and tumor lymphoid tissues,
Mig, TARC, and MCP-2 were all primarily localized to blood vessels and
admixed histiocytes. We did not note discernible differences in
chemokine expression in the stromal component of different T-cell tumor
subtypes in the small number of patients examined. Given the detection
sensitivity of immunohistochemistry, it is possible that some
chemokines are expressed at lower levels in other nodal cell types.
Correlation of chemokine expression with tumor localization is further
complicated by the ability of 1 chemokine to bind multiple receptors.
For instance, the CCR5 ligands RANTES, MIP-1, and MCP-2 can also
bind CCR1 or CCR2.17,30 Therefore, identification of an
altered pattern of chemokine expression does not immediately suggest a
target receptor. This point is well illustrated by our finding of
increased MCP-2 expression in stromal cells in patients with nodal
involvement by MF. CCR5, however, was not widely expressed in these
tumors, suggesting functional interactions of MCP2 with the other
binding partners, perhaps CCR2b present on T cells and histiocytes.31
We noted expression of the chemokine Mig in a subset of tumor cells in
some lymphomas that also expressed the receptor CXCR3. We previously
noted this as a consistent finding in CXCR3-positive B-cell
CLL.16 Whether endogenously produced Mig functions to deliver an autocrine signal in these tumors or, rather, to desensitize tumor cells to exogenous stimulation through CXCR3 remains to be explored.
Overall, our results confirm the distinctive nature of most recognized
subtypes of T-cell lymphoma that is correlated with expression patterns
of both chemokine receptors and TNF receptors. For instance, the
expression of CD30 and CCR4, but not CD134/OX40 or CXCR3, is the
typical phenotype of ALK-positive ALCL.13 Similarly, the
expression of CD134 in large cells and CXCR3 in smaller cells, but not
CD30, appears to be characteristic of AIL. In ALK-negative ALCL and the
unspecified category of PTCL, we have not yet identified distinct
patterns of chemokine receptor or TNF receptor expression, suggesting
that these are heterogeneous entities. Studies with additional T-cell
markers will be required before functional similarities between tumors
within this undifferentiated category are recognized.
| |
Acknowledgments |
We thank LeukoSite Incorporated (Cambridge, MA) for providing chemokine
receptor antibodies, Dr G. Pinkus for contributing cases, and J. Ebel
for preparing the manuscript.
| |
Footnotes |
Submitted September 28, 1999; accepted March 6, 2000.
Reprints: David Dorfman, Brigham and Women's Hospital,
Department of Pathology, 75 Francis St, Boston, MA 02115; e-mail: dmdorfman{at}bics.bwh.harvard.edu.
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.
| |
References |
1.
Piali L, Weber C, LaRosa G, et al.
The chemokine receptor CXCR3 mediates rapid and shear-resistant adhesion-induction of effector T lymphocytes by the chemokines IP10 and Mig.
Eur J Immunol.
1998;28:961[Medline]
[Order article via Infotrieve].
2.
Bonecchi R, Bianchi G, Bordignon PP, et al.
Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s.
J Exp Med.
1998;187:129[Abstract/Free Full Text].
3.
D'Ambrosio D, Iellem A, Bonecchi R, et al.
Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells.
J Immunol.
1998;161:5111[Abstract/Free Full Text].
4.
Zingoni A, Soto H, Hedrick JA, et al.
The chemokine receptor CCR8 is preferentially expressed in Th2 but not Th1 cells.
J Immunol.
1998;161:547[Abstract/Free Full Text].
5.
Qin S, Rottman JB, Myers P, et al.
The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions.
J Clin Invest.
1998;101:746[Medline]
[Order article via Infotrieve].
6.
Patterson BK, Czerniewski M, Andersson J, et al.
Regulation of CCR5 and CXCR4 expression by type 1 and type 2 cytokines: CCR5 expression is downregulated by IL-10 in CD4-positive lymphocytes.
Clin Immunol.
1999;91:254[Medline]
[Order article via Infotrieve].
7.
Loetscher P, Uguccioni M, Bordoli L, et al.
CCR5 is characteristic of Th1 lymphocytes [letter].
Nature.
1998;391:344[Medline]
[Order article via Infotrieve].
8.
Sallusto F, Lenig D, Mackay CR, Lanzavecchia A.
Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes.
J Exp Med.
1998;187:875[Abstract/Free Full Text].
9.
Sallusto F, Kremmer E, Palermo B, et al.
Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells.
Eur J Immunol.
1999;29:2037[Medline]
[Order article via Infotrieve].
10.
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[Free Full Text].
11.
Dorfman DM, Shahsafaei A, Nadler LM, Freeman GJ.
The leukocyte semaphorin CD100 is expressed in most T-cell, but few B- cell, non-Hodgkin's lymphomas.
Am J Pathol.
1998;153:255[Abstract/Free Full Text].
12.
Jones D, Jorgensen JL, Shahsafaei A, Dorfman DM.
Characteristic proliferations of reticular and dendritic cells in angioimmunoblastic lymphoma.
Am J Surg Pathol.
1998;22:956[Medline]
[Order article via Infotrieve].
13.
Jones D, Fletcher CDM, Pulford K, Shasafaei A, Dorfman DM.
CD30 and CD134/OX40 are expressed in non-overlapping subsets of peripheral T cell lymphoma.
Blood.
1999;93:3487[Abstract/Free Full Text].
14.
Campbell JJ, Haraldsen G, Pan J, et al.
The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells.
Nature.
1999;400:776[Medline]
[Order article via Infotrieve].
15.
Wu L, Paxton WA, Kassam N, et al.
CCR5 levels and expression pattern correlate with infectability by macrophage-tropic HIV-1, in vitro.
J Exp Med.
1997;185:1681[Abstract/Free Full Text].
16.
Jones D, Benjamin RJ, Shahsafaei A, Dorfman DM.
The chemokine receptor CXCR3 is expressed in a subset of B cells and is a marker for B cell chronic lymphocytic leukemia.
Blood.
2000;95:627[Abstract/Free Full Text].
17.
Ruffing N, Sullivan N, Sharmeen L, Sodroski J, Wu L.
CCR5 has an expanded ligand-binding repertoire and is the primary receptor used by MCP-2 on activated T cells.
Cell Immunol.
1998;189:160[Medline]
[Order article via Infotrieve].
18.
Annunziato F, Cosmi L, Galli G, et al.
Assessment of chemokine receptor expression by human Th1 and Th2 cells in vitro and in vivo.
J Leukoc Biol.
1999;65:691[Abstract].
19.
Caligaris-Cappio F, Bertero MT, Converso M, et al.
Circulating levels of soluble CD30, a marker of cells producing Th2- type cytokines, are increased in patients with systemic lupus erythematosus and correlate with disease activity.
Clin Exp Rheumatol.
1995;13:339[Medline]
[Order article via Infotrieve].
20.
Munk ME, Kern P, Kaufmann SH.
Human CD30+ cells are induced by Mycobacterium tuberculosis and present in tuberculosis lesions.
Int Immunol.
1997;9:713[Abstract/Free Full Text].
21.
D'Elios MM, Romagnani P, Scaletti C, et al.
In vivo CD30 expression in human diseases with predominant activation of Th2-like T cells.
J Leukoc Biol.
1997;61:539[Abstract].
22.
Annunziato F, Manetti R, Cosmi L, et al.
Opposite role for interleukin-4 and interferon-gamma on CD30 and lymphocyte activation gene-3 (LAG-3) expression by activated naive T cells.
Eur J Immunol.
1997;27:2239[Medline]
[Order article via Infotrieve].
23.
Nakamura T, Lee RK, Nam SY, et al.
Reciprocal regulation of CD30 expression on CD4+ T cells by IL-4 and IFN-gamma.
J Immunol.
1997;158:2090[Abstract].
24.
Yagi H, Tokura Y, Furukawa F, Takigawa M.
Th2 cytokine mRNA expression in primary cutaneous CD30-positive lymphoproliferative disorders: successful treatment with recombinant interferon-gamma.
J Invest Dermatol.
1996;107:827[Medline]
[Order article via Infotrieve].
25.
Ohnishi K, Ichikawa A, Kagami Y, et al.
Interleukin 4 and gamma-interferon may play a role in the histopathogenesis of peripheral T-cell lymphoma.
Cancer Res.
1990;50:8028[Abstract/Free Full Text].
26.
Kaneko Y, Maseki N, Sakurai M, et al.
Characteristic karyotypic pattern in T-cell lymphoproliferative disorders with reactive "angioimmunoblastic lymphadenopathy with dysproteinemia-type" features.
Blood.
1988;72:413[Abstract/Free Full Text].
27.
Schlegelberger B, Feller A, Godde E, Grote W, Lennert K.
Stepwise development of chromosomal abnormalities in angioimmunoblastic lymphadenopathy.
Cancer Genet Cytogenet.
1990;50:15[Medline]
[Order article via Infotrieve].
28.
Foss H-D, Anagnostopoulos I, Herbst H, et al.
Patterns of cytokine gene expression in peripheral T-cell lymphoma of angioimmunoblastic lymphadenopathy type.
Blood.
1995;10:2862.
29.
Pizzolo G, Stein H, Josimovic-Alasevic O, et al.
Increased serum levels of soluble IL-2 receptor, CD30 and CD8 molecules, and gamma-interferon in angioimmunoblastic lymphadenopathy: possible pathogenetic role of immunoactivation mechanisms.
Br J Haematol.
1990;75:485[Medline]
[Order article via Infotrieve].
30.
Luster AD.
Chemokines chemotactic cytokines that mediate inflammation.
N Engl J Med.
1998;338:436[Free Full Text].
31.
Moore BB, Keane MP, Addison CL, Arenberg DA, Streiter RM.
CXC chemokine modulation of angiogenesis: the importance of balance between angiogenic and angiostatic members of the family.
J Invest Med.
1998;46:113[Medline]
[Order article via Infotrieve].
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Abstract
Introduction