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NEOPLASIA
From the Amgen Institute, Ontario Cancer Institute, the
Department of Medical Biophysics, and the Department of Immunology,
University of Toronto, Ontario, Canada; the Department of Pathology,
British Columbia Cancer Agency, Vancouver, British Columbia, Canada;
the Department of Internal Medicine I, University of Saarland,
Homburg, Germany; the Department of Hematology/Oncology, University
Medical Center, Freiburg, Germany; and the Department of Oncologic
Pathology, Ontario Cancer Institute, Toronto, Ontario, Canada.
Hodgkin lymphoma (HL) is characterized by the abnormal expression
of multiple cytokines, accounting for its unique clinicopathologic features. We have previously shown that interleukin-13 (IL-13) is
secreted by HL cell lines and may serve as an autocrine growth factor.
To determine the frequency of IL-13 expression in lymphoma patients,
tissue sections from 36 patients with classical HL, 5 patients with
nodular lymphocyte predominance HL (NLPHL), and 23 patients with
non-Hodgkin lymphoma (NHL) were subjected to in situ hybridization. In
31 of 36 cases (86%) of classical HL patients of all histologic
subtypes, between 25% to almost 100% of Hodgkin and Reed Sternberg
(HRS) cells were positive for IL-13 expression. In contrast, in no case
of NLPHL and in only 4 of 23 NHL cases (1 of 5 T-cell-rich B-cell
lymphomas, 2 of 5 anaplastic large cell lymphomas, and 1 of 5 peripheral T-cell lymphomas) did the neoplastic cells express IL-13.
The expression of the IL-13 receptor chain Hodgkin lymphoma (HL) is unusual among malignancies
in that the neoplastic cells, the Hodgkin and Reed-Sternberg (HRS)
cells, make up only a small proportion of the clinically detectable
mass. The bulk of the tumor is composed of a reactive infiltrate of lymphocytes, eosinophils, plasma cells, histiocytes, and fibroblasts. Although HL has distinct clinical features and responses to treatment that warrant its distinction from the non-Hodgkin lymphomas (NHL), within HL there are variations in the composition of the inflammatory infiltrate, the morphology of the HRS cells, and the presence of the
Epstein-Barr virus (EBV).1 The clinicopathologic features of HL are consistent with an abnormal pattern of cytokine expression of
the HRS cells. These cells can express a variety of cytokines, including interleukin-2 (IL-2), IL-5, IL-6, IL-7, IL-9, IL-10, granulocyte-macrophage colony-stimulating factor, lymphotoxin- IL-13 is a pleiotropic cytokine secreted by activated T cells that
shares immunoregulatory characteristics with IL-4.6,7 IL-13 exerts its effects primarily on B cells and monocytes,
stimulating growth and immunoglobulin (Ig) class switching in B cells,
and up-regulation of the low-affinity IgE receptor and MHC class II on
B cells and monocytes. We have recently shown that IL-13 is expressed
by HL cell lines and in HRS cells from 4 cases of nodular sclerosis HL
(NSHL).8 In that study, antibody-mediated neutralization of
IL-13 inhibited proliferation of an HL cell line, suggesting that IL-13
might function as an autocrine growth factor for HL. As well as IL-13,
the HL cell lines examined expressed NF-IL3. Expression of the NF-IL3
gene is up-regulated by IL-4,9 a cytokine that shares
signaling pathways with IL-13.10 The expression of NF-IL3
by HL cells thus supports the existence of autocrine signaling by IL-13
in HL.
IL-13 signals are transduced via the IL-13 receptor (IL-13R) complex,
which varies in its composition among cell types.11,12 Two
distinct IL-13R chains have been identified, IL-13R To extend our investigations of the role of IL-13 in the pathogenesis
of HL, we analyzed the expression patterns of IL-13 and IL-13R Tissues and cell lines
HL cell lines L540Cy, L428, HD-LM2, and KM-H2 were provided by Dr
H. G. Drexler (Braunschweig, Germany). HL cell line L1236 and
Burkitt lymphoma (BL) cell line BL-31 were provided by Prof V. Diehl
(Cologne, Germany). A previous study12 demonstrated the
presence of IL-13R Probes
In situ hybridization The in situ hybridization procedure was performed as previously described.22 Sections were deparaffinized in xylene, rehydrated in series of decreasing ethanol concentrations, washed in saline for 5 minutes, and washed 2 × 5 minutes in phosphate-buffered saline (PBS). After fixation in 4% paraformaldehyde for 20 minutes and another 5-minute wash in PBS, sections were treated with 20 µg/mL proteinase K for 7.5 minutes at room temperature. After 5 minutes in 4% paraformaldehyde and another 2 × 5-minute washes in PBS, sections were acetylated for 10 minutes in a 0.1 M triethanolamine pH 8.0/0.25% acetic anhydride solution, washed for 5 minutes in PBS, and dehydrated. Approximately 150 µL hybridization solution (50% formamide, 0.3 M NaCl, 20 mM Tris-HCl, pH 8.0, 5 mM EDTA, 10 mM NaPO4, pH 8.0, 10% dextran sulfate, 1 × Denhardt's, 0.5 mg/mL yeast transfer RNA [tRNA], 10 mM DTT, and approximately 75 000 cpm/µL of labeled sense or antisense probe) was applied to each slide. Slides were overlain with coverslips and incubated overnight in a humid chamber at 55°C. The coverslips were removed by dipping slides into 5 × SSC containing 0.1% -mercaptoethanol. The slides were then immersed for 30 minutes in washing buffer (50%
formamide, 2 × SSC, 0.1% -mercaptoethanol) at 62°C, rinsed 2 × 15 minutes in NTE (0.5 M NaCl, 10 mM Tris-HCl, pH 7.5, 5 mM EDTA) at 37°C, treated for 30 minutes at 37°C with 20 µg/mL
RNaseA, and washed for 15 minutes in NTE. The slides were then
incubated for 25 minutes in washing buffer at 62°C, 15 minutes in
2 × SSC at 37°C, 15 minutes in 0.1 × SSC at 37°C, and
dehydrated. The slides were coated with Kodak NTB 2 emulsion
(Eastman Kodak, Rochester, NY) and stored at 4°C. After exposure for
10 to 14 days, the slides were developed in Kodak D19 (Eastman
Kodak) and counterstained with toluidine blue. The specificity
of the hybridization signal was verified by the corresponding lack of
signal when sense RNA probes were used. Cells were scored as positive
if the number of silver grains was at least 4-fold over background.
Control -actin mRNA was detected using a commercially available kit
(Dako, Carpinteria, CA), following the manufacturer's instructions.
Single-cell reverse transcriptase-polymerase chain reaction Single-cell suspensions were prepared from pathologic lymph nodes freshly isolated from 6 patients with HL who were not included in the in situ hybridization analysis. Individual HRS cells were identified by their CD30 expression and distinctive morphologic features (Figure 1) as previously described.23 In this study,23 the correct identity of the HRS cells in an EBV+ HL case was supported by demonstrating an EBV gene expression pattern that is seen in HL, BL, and nasopharyngeal carcinoma.24 The cDNA of individual HRS cells was synthesized using the global polyA-polymerase chain reaction (PCR) method as previously described.20 Only cases with a positive-actin signal were used for subsequent IL-13R 1 PCR.
IL-13R1 cDNA was amplified using the following primers: 5' CAT GAA
GAG GAT GCT GTG AAA TTC CCA ACA AAC 3' and 5' GTT AAA CAG AAA CAA TCC
CTG GTT GAA GAC TAC C 3'. PCR analysis was performed in a 50 µL
volume containing 200 nM of each primer, 1.5 mM MgCl2, 1.5 units AmpliTaq Gold (Perkin Elmer, Boston, MA), with 4% DMSO.
PCR conditions were as follows: denaturing at 94°C for 1 minute,
annealing at 58°C for 1 minute, and extension at 72°C for 2 minutes, for 40 cycles. Products were analyzed by agarose gel
electrophoresis. PCR products were confirmed by hybridization with a
[32P]-end-labeled internal oligonucleotide (5' ATG GGA
AAT CCA CTG ATA CAG ACA CCT CCA AGA GC 3'), as previously
described.20 Appropriate positive (cDNA from BL-31 or
KM-H2 cells) and negative (cells with no reverse transcriptase;
H20) controls were included.
IL-13 is expressed by HRS cells in a large majority of patients with HL IL-13 expression was analyzed by in situ hybridization in tissue samples from 36 patients with classical HL, 5 patients with NLPHL, and 23 patients with NHL. IL-13 transcripts were detected in HRS cells in 31 of 36 (86%) patients with classical HL (Table 1, Figure 2A). In contrast, the lymphocytic and histiocytic (L&H) cells in all 5 patients with NLPHL were negative for IL-13 (Table 1; Figure 2B). Similarly, only 1 of 5 patients with TCRBCL demonstrated IL-13 expression in less than 25% of the malignant cell population, and only 2 of 5 patients with ALCL were IL-13 positive (25% to 50% of cells). Only 1 of 5 patients with PTCL had scattered malignant cells (less than 10%) that expressed IL-13, and all 8 patients with DLBCL were negative for IL-13.
Among the classical HL cases, no significant differences in IL-13
expression were detected among subtypes of classical HL: 21 of 23 (91%) of nodular sclerosis cases, 8 of 10 (80%) of mixed cellularity
cases, and 2 of 3 (67%) of lymphocyte depletion cases contained
positive HRS cells (P = not significant) (Table
2). Nearly all cells expressing IL-13
demonstrated the morphology of HRS cells, with only rare small
lymphocytes in 19 of 36 (53%) cases also staining positively. Staining
of serial sections with either anti-CD30 or anti-CD15 to identify HRS
cells showed that the percentage of IL-13-expressing HRS cells varied
from case to case, ranging from 25% to almost 100%. A study of the
slides in the same hybridization batch and exposed for the same length of time revealed that there was no significant difference among the
different subtypes of classical HL in the percentage of HRS cells
staining positively for IL-13. Similarly, although the intensity of the
IL-13 signal varied from case to case, there was no significant difference in the distribution of signal intensity among subtypes of
classical HL.
All 5 IL-13 negative cases showed a positive signal for IL-13R IL-13R 1, and thus could become subject to autocrine stimulation, IL-13R1 expression was examined by in situ hybridization in 29 cases
of classical HL and was interpretable in 27 cases (see below). Twenty-four cases (89%) contained HRS cells positive for IL-13R1 expression (Figure 2C-F). No significant differences in IL-13R1 expression were detected among subtypes of classical HL: 16 of 17 (94%) of nodular sclerosis cases, 5 of 7 (71%) of mixed cellularity cases, and 3 of 3 (100%) of lymphocyte-depletion cases contained positive HRS cells (P = NS). The percentage of IL-13R1
positive HRS cells varied from 25% to 75% in different cases. In all
cases, IL13R1 expression was not limited to HRS cells, but was also present in a large proportion of cells in reactive infiltrates that
could be morphologically defined as lymphocytes and histiocytes (Figure
2C,F). IL-13R1 transcripts could not be detected in the fibroblasts
within the sclerotic bands in cases of NSHL. As a positive control, a
benign reactive tonsil was hybridized with the IL-13R1 probe.
Positive signals were obtained for cells morphologically resembling
histiocytes (including tingible-body macrophages in reactive germinal
centers) and numerous lymphocytes outside the germinal center (data not
shown). Two cases of HL that contained reactive germinal centers
with tingible-body macrophages did not show the IL-13R1 signal
in any cell population, and were therefore considered noninterpretable.
Of the 27 cases of classical HL analyzed for both IL-13 and IL-13R Expression of IL-13R 1 mRNA in individual HRS
cells, cDNA libraries of mRNA from HRS cells were constructed and analyzed by PCR with IL-13R1-specific primers. First, the presence of IL-13R1 sequences in 5 HRS cell lines (KM-H2, HD-LM2, L1236, L540Cy, and L428) was examined. IL-13R1 transcripts were detected in
all 5 cell lines (Figure 3). These
studies were extended to construct cDNA libraries from single HRS cells
from 6 patients with HL, including 4 patients with NSHL and 2 patients
with MCHL. In all 6 patients, IL-13R1 sequences were detected in
30% to 85% of HRS cells (Table 3;
Figure 4) and were confirmed
by hybridization with an internal oligonucleotide (data not
shown).
We have shown that IL-13 is expressed in a variable percentage of HRS cells in 86% of the classical HL cases examined. Transcripts for IL-13 are present in HRS cells of NSHL, MCHL, and LDHL, with no significant differences in the intensity of signal or percentage of positive cells between HL subtypes. The HRS cells appear to be the dominant source of IL-13, with rare lymphocytes showing a positive signal in approximately half of the cases. There were no morphologic differences between IL-13 positive and IL-13 negative cases, either in the presence of fibrosis or composition of reactive infiltrate. It is possible that IL-13 is still present in these "negative" cases but at levels undetectable by in situ hybridization. Alternatively, some cases of HL may be truly negative for IL-13, in which case other cytokines presumably play a role in their pathogenesis. Our data suggest that IL-13 expression is a basic property of HRS cells in the majority of cases of HL, regardless of histologic subtypes. IL-13 mRNA was not detected in the L&H cells of NLPHL, which shows
clinical, morphologic, and immunophenotypic features distinct from
those of classical HL.25,26 HRS cells in classical HL are
typically CD15+CD30+ and are negative for
B-cell markers in the majority of cases.1 Classical HL is
believed in many cases to be a B-lineage lymphoproliferative disorder
in which the HRS cells demonstrate clonal rearrangement and somatic
mutations of the Ig heavy chain genes but do not express Ig.27,28 The L&H cells of NLPHL, on the other hand,
demonstrate a B-cell phenotype, produce functional Ig, and are
typically CD15 IL-13 is produced predominantly by activated T cells and acts on several cell types.6,7 In B cells, IL-13 promotes survival and proliferation, as well as Ig class switching to IgG4 and IgE.6,7,29 IL-13 plays an important role in Th2 cell differentiation in the mouse,30 but its exact role in T-cell development in humans is unclear. Although some investigators have reported that human T cells lack surface IL-13 receptors,31 others have shown that T cells can respond to IL-13 in vitro.32 Human fibroblasts express the IL-13 receptor,10,14 and IL-13 has been shown to play a role in development of fibrosis in asthma33 and parasite-associated hepatic damage.34 In view of these effects, many features of HL, including the reactive infiltrate of T and B cells, histiocytes, as well as the fibrosis in NSHL, may be attributable to IL-13 expression. Indeed, it has been shown that in transgenic mice that overexpress IL-13 in the lung, elevated levels of IL-13 lead to the presence of a mononuclear infiltrate, eosinophilia, and fibrosis.33 Although the effects of IL-13 on target cells have been reasonably well
studied, the receptor complex through which it acts is much less well
understood. In the best characterized receptor complex, IL-13R In addition to HRS cells, many histiocytes and lymphocytes expressed
IL-13R IL-13 was also detected in 3 NHL cases that share some morphologic or immunophenotypic features with HL, including 1 of 5 cases of TCRBCL and 2 of 5 cases of ALCL. TCRBCL is an aggressive NHL that morphologically resembles HL because of its characteristic prominent reactive component of benign T cells and histiocytes,19,35 suggesting that it is also a malignancy with abnormal cytokine expression. Indeed, the neoplastic cells of both HL and TCRBCL have been shown to produce the CC chemokine TARC (thymus and activation-regulated chemokine), likely accounting for the prominent T-cell infiltration of both tumors.36 Although IL-13 transcripts were detected in the malignant cells of only one case of TCRBCL in this study, expression of IL-4, whose biologic effects overlap those of IL-13, was found by others in malignant cells of additional TCRBCL cases.37 HL shows an opposite expression pattern of these 2 related cytokines, namely, positive expression of IL-13 but negative expression of IL-4.4 These results suggest that IL-4 and IL-13 may contribute to a malignant phenotype to different degrees in different types of lymphomas. Because T cells are the predominant source of IL-13 secretion, we analyzed 9 cases of T-cell lymphomas for the presence of IL-13, including cases of ALCL and PTCL. ALCL shares some features with HL, including pleomorphic morphology of the neoplastic cells and CD30 expression.18 In situ hybridization studies showed that 2 cases of ALCL and one case of PTCL contained IL-13 positive cells. Unlike HL, these cases contained a homogeneous population of lymphoma cells without a prominent reactive infiltrate. These data do not permit us to conclude that IL-13 plays a defining role in the pathogenesis of subsets of T-cell lymphomas. In some tumors, IL-13 expression may merely reflect the retention of gene expression patterns of the cell of origin. In conclusion, we have shown that IL-13 and IL-13R
We thank J. Ho for excellent technical support; H. G. Drexler, B. Dörken, and V. Diehl for HL-derived and BL-derived cell lines; M. Bray for valuable critical comments; N. Le for statistical analysis; and M. Saunders for scientific editing.
Submitted April 14, 2000; accepted September 1, 2000.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Tak W. Mak, Ontario Cancer Institute/Amgen Institute, 620 University Ave, Suite 706, Toronto, Ontario, Canada M5G 2C1; e-mail: tmak{at}amgen.com.
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 C. Van Themsche, T. Alain, A. E. Kossakowska, S. Urbanski, E. F. Potworowski, and Y. St-Pierre Stromelysin-2 (Matrix Metalloproteinase 10) Is Inducible in Lymphoma Cells and Accelerates the Growth of Lymphoid Tumors In Vivo J. Immunol., September 15, 2004; 173(6): 3605 - 3611. [Abstract] [Full Text] [PDF]
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C. Guiter, I. Dusanter-Fourt, C. Copie-Bergman, M.-L. Boulland, S. le Gouvello, P. Gaulard, K. Leroy, and F. Castellano Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma Blood, July 15, 2004; 104(2): 543 - 549. [Abstract] [Full Text] [PDF]
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 Y. Wang, M. G. Malabarba, Z. S. Nagy, and R. A. Kirken Interleukin 4 Regulates Phosphorylation of Serine 756 in the Transactivation Domain of Stat6: ROLES FOR MULTIPLE PHOSPHORYLATION SITES AND Stat6 FUNCTION J. Biol. Chem., June 11, 2004; 279(24): 25196 - 25203. [Abstract] [Full Text] [PDF]
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Y. Trieu, X.-Y. Wen, B. F. Skinnider, M. R. Bray, Z. Li, J. O. Claudio, E. Masih-Khan, Y.-X. Zhu, S. Trudel, J. A. McCart, et al. Soluble Interleukin-13R{alpha}2 Decoy Receptor Inhibits Hodgkin's Lymphoma Growth in Vitro and in Vivo Cancer Res., May 1, 2004; 64(9): 3271 - 3275. [Abstract] [Full Text] [PDF]
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N. A. Marshall, L. E. Christie, L. R. Munro, D. J. Culligan, P. W. Johnston, R. N. Barker, and M. A. Vickers Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma Blood, March 1, 2004; 103(5): 1755 - 1762. [Abstract] [Full Text] [PDF]
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K. J. Savage, S. Monti, J. L. Kutok, G. Cattoretti, D. Neuberg, L. de Leval, P. Kurtin, P. D. Cin, C. Ladd, F. Feuerhake, et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma Blood, December 1, 2003; 102(12): 3871 - 3879. [Abstract] [Full Text] [PDF]
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H.-K. Chung, H. A. Young, P. K. C. Goon, G. Heidecker, G. L. Princler, O. Shimozato, G. P. Taylor, C. R. M. Bangham, and D. Derse Activation of interleukin-13 expression in T cells from HTLV-1-infected individuals and in chronically infected cell lines Blood, December 1, 2003; 102(12): 4130 - 4136. [Abstract] [Full Text] [PDF]
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T. Portis, P. Dyck, and R. Longnecker Epstein-Barr Virus (EBV) LMP2A induces alterations in gene transcription similar to those observed in Reed-Sternberg cells of Hodgkin lymphoma Blood, December 1, 2003; 102(12): 4166 - 4178. [Abstract] [Full Text] [PDF]
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C. Copie-Bergman, M.-L. Boulland, C. Dehoulle, P. Moller, J.-P. Farcet, M. J. S. Dyer, C. Haioun, P.-H. Romeo, P. Gaulard, and K. Leroy Interleukin 4-induced gene 1 is activated in primary mediastinal large B-cell lymphoma Blood, April 1, 2003; 101(7): 2756 - 2761. [Abstract] [Full Text] [PDF]
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 K. C.M. Straathof, C. M. Bollard, C. M. Rooney, and H. E. Heslop Immunotherapy for Epstein-Barr Virus-Associated Cancers in Children Oncologist, February 1, 2003; 8(1): 83 - 98. [Abstract] [Full Text] [PDF]
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M. Hinz, P. Lemke, I. Anagnostopoulos, C. Hacker, D. Krappmann, S. Mathas, B. Dorken, M. Zenke, H. Stein, and C. Scheidereit Nuclear Factor {kappa}B-dependent Gene Expression Profiling of Hodgkin's Disease Tumor Cells, Pathogenetic Significance, and Link to Constitutive Signal Transducer and Activator of Transcription 5a Activity J. Exp. Med., September 2, 2002; 196(5): 605 - 617. [Abstract] [Full Text] [PDF]
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S. Ek, C.-M. Hogerkorp, M. Dictor, M. Ehinger, and C. A. K. Borrebaeck Mantle Cell Lymphomas Express a Distinct Genetic Signature Affecting Lymphocyte Trafficking and Growth Regulation as Compared with Subpopulations of Normal Human B Cells Cancer Res., August 1, 2002; 62(15): 4398 - 4405. [Abstract] [Full Text] [PDF]
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B. F. Skinnider and T. W. Mak The role of cytokines in classical Hodgkin lymphoma Blood, May 29, 2002; 99(12): 4283 - 4297. [Abstract] [Full Text] [PDF]
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C. M. Bollard, C. Rossig, M. J. Calonge, M. H. Huls, H.-J. Wagner, J. Massague, M. K. Brenner, H. E. Heslop, and C. M. Rooney Adapting a transforming growth factor beta -related tumor protection strategy to enhance antitumor immunity Blood, May 1, 2002; 99(9): 3179 - 3187. [Abstract] [Full Text] [PDF]
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B. F. Skinnider, A. J. Elia, R. D. Gascoyne, B. Patterson, L. Trumper, U. Kapp, and T. W. Mak Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma Blood, January 15, 2002; 99(2): 618 - 626. [Abstract] [Full Text] [PDF]
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P. Fiumara, V. Snell, Y. Li, A. Mukhopadhyay, M. Younes, A. M. Gillenwater, F. Cabanillas, B. B. Aggarwal, and A. Younes Functional expression of receptor activator of nuclear factor kappa B in Hodgkin disease cell lines Blood, November 1, 2001; 98(9): 2784 - 2790. [Abstract] [Full Text] [PDF]
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P. Fiumara, F. Cabanillas, and A. Younes Interleukin-13 levels in serum from patients with Hodgkin disease and healthy volunteers Blood, November 1, 2001; 98(9): 2877 - 2878. [Full Text] [PDF]
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Top
Abstract
Introduction
/ IL-13R
): H20;
positive control (+): cDNA from BL-31 cells. MW = 100-bp
ladder.
harboring tumor cells of Hodgkin's disease.
Blood.
1996;87:2918-2929