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From the Département de Pathologie,*
Hôpital Henri Mondor, Créteil, France; Services d'Anatomie
Pathologique,
Hôpital Saint-Louis,
Paris, France; Hôpital Laennec,
Paris,
France; URA 1301 Institut Gustave Roussy,§
Villejuif, France; and Department of
Pathology,¶
University of Crete,
Heraklion, Greece
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T-cell lymphomas (6 of 6). In ALCLs, the pattern of
IL-10 mRNA-expressing cells showed an overlapping with the CD30
staining and preferential localization in sinusal and perifollicular
areas, thereby suggesting that IL-10-expressing cells were
tumor cells. Furthermore, IL-10 transcripts were detected in
the SU-DHL-1 anaplastic lymphoma cell line. No correlation with
Epstein-Barr virus profile was found, because all cases of ALCL
were negative for EBER 1 and 2 genes by in situ
hybridization. We confirmed the presence of human IL-10 mRNA by reverse
transcription-polymerase chain reaction in ALCLs as well as in NK-cell
lymphomas, whereas viral IL-10 was not detected. Thus,
human and not viral IL-10 is frequently expressed by tumor cells in
ALCLs and nasal NK-cell lymphomas. In view of its function in the
proliferation and the differentiation of cytotoxic T and NK
cells, and its immunosuppressive properties, IL-10 may
have a role in the pathogenesis of these
lymphomas.
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Introduction |
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ß T-cell receptor (TCR), whereas a small
subset of them express the TCR.4
The possible
involvement of cytokines in the pathogenesis of PTCL has been
investigated in a few studies, and evidence has been provided for an
association between cytokine profile of tumor cells and histological
subtype of the tumor.5-7
In this respect, the following
associations have been recorded: human T-cell lymphotrophic virus
1+ adult T-cell leukemia with interleukin
(IL)-2,1
angioimmunoblastic lymphadenopathy (AILD) with
tumor necrosis factor- and lymphotoxin,5
and
CD30+ anaplastic large cell lymphomas (ALCLs) with IL-9 and
IL-6.1,6,7
In addition, some other cytokines, such as IL-4,
interferon-, and IL-7, were also investigated, but no clear
association between cytokine profile of tumor cells and histotype was
reported.7
IL-10 was first characterized as a
T-cell-derived cytokine able to block interferon- production by
T-helper-1 cells and as a B cell-derived thymocyte growth
factor.8,9
IL-10 is produced by B cells, T cells,
monocytes/macrophages, and keratinocytes.10
The cloning and
sequencing of the murine and human IL-10 (hIL-10) genes revealed an
extensive homology with BCRF1 gene, an open reading frame of
Epstein-Barr virus (EBV).11
The product of the BCRF1 gene,
also called viral IL-10 (vIL-10), exhibits partial IL-10 activity
in vitro and may play a role during EBV
infection.11
IL-10 is a pleiotropic cytokine known to be an
important regulator of lymphoid and myeloid functions.10
It
is a growth factor for T lymphocytes in the mouse model and a growth
and differentiation factor for human activated B
cells.12,13
IL-10 participates in the promotion of
IL-2-activated mouse cytotoxic T-lymphocyte precursor to differentiate
into effector cytotoxic cells.14
In addition, IL-10 exerts
immunosuppressive activities: it inhibits antigen-specific T-cell
activation and blocks cytokine production by monocytes and macrophages
in both human and mouse models.10,15
IL-10 has been
described to induce natural killer (NK) cell proliferation and increase
of cytotoxic activity of these cells.16
To date, IL-10 has been described in various types of B-cell
lymphoproliferations, and the biological properties of IL-10 have
raised questions of the potential relevance of this cytokine in the
pathogenesis of B-cell lymphoproliferations. Indeed, IL-10 was
suggested to be a proliferation factor for B cells, which could act in
an autocrine pathway, in acquired immunodeficiency syndrome-related
lymphomas and Burkitt lymphomas.17-19
On the other hand,
although IL-10 can be produced by normal T cells, only a few cases of
PTCL, mostly human T-cell lymphotrophic virus 1-positive leukemia, were
studied.20
For this reason, we have investigated the
expression of IL-10 mRNA by in situ hybridization (ISH) in
39 cases of PTCL as well as in 7 cases of NK-cell lymphoma to see
whether this cytokine was expressed in these tumors. We have
particularly addressed the question of whether this expression could be
related to the histological subtype of the tumor and to the expression
of ß TCR, TCR, or NK-cell antigens. In addition, because
IL-10 gene has extensive homology with the BCRF1 gene of the EBV, we
have investigated in parallel the cases of this series for the presence
of EBV.
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Materials and Methods |
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Tissues from 46 patients with lymphomas of T-cell or NK-cell types
mainly retrieved from the files of the Département de Pathologie,
Hôpital Henri Mondor (Créteil, France) were included in
this study. One part of the material was routinely fixed, and the other
one was snap frozen in liquid nitrogen and stored at -80°C. The
diagnosis was based on histological and immunohistological data
available on both fixed and frozen tissue sections. PTCLs were divided
into ß and or TCR-silent T-cell lymphomas according to the
expression (or the nonexpression) of the TCR proteins using the ßF1
or TCR1 antibodies as previously described.4,21
NK-cell
lymphomas had the TCR-silent, CD2+, CD5-,
CD56+ phenotype, characteristic of normal NK cells and
NK-cell lymphomas, and no clonal TCR rearrangement was
detected.22
Lymphomas were classified according to the
updated Kiel classification23
and the Revised
European-American Lymphoma classification3
(Tables 1 to 3)
.
Lymphoblastic lymphomas and mycosis fungoides were excluded. Because
T-cell and null-cell ALCLs are now considered as a unique lymphoma
entity, five null-cell ALCLs were also selected in the present study.
The cytotoxic protein expression in 27 of these cases has been recently
reported elsewhere.21
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ISH for the Detection of IL-10 Transcripts
A pBS plasmid containing a 640-bp ApaI-AccI fragment of BCRF1/IL-10 cDNA was kindly provided by I. Joab.19 Sense and antisense riboprobes were synthesized using 35S-labeled UTP (1000 Ci/mmol, Amersham, Les Ulis, France) with the Riboprobe in vitro transcription system (Promega, Madison, WI). Fifty µCi of 35S-labeled UTP were added to the following reaction mixture: 1 µl of each adenosine, cytosine, and guanosine 5'-triphosphate (10 mmol/L each), 2 µl of 100 mmol/L dithiothreitol (DTT), 1 µl of RNase inhibitor, 4 µl of 5x transcription buffer (200 mmol/L Tris-HCl, pH 7.5, 30 mmol/L MgCl2, 10 mmol/L spermidine, and 50 mmol/L NaCl), 0.5 µg of linearized plasmid, and 15 U of T3 or T7 RNA polymerase, in a final volume of 20 µl. The reaction was allowed to proceed for 60 minutes at 37°C. The plasmid DNA was digested with 1 µl of DNase I (1 U/µl) for 10 minutes at 37°C. The size of 35S-labeled probes was adjusted to about 200 bases in length by alkaline hydrolysis in 80 mmol/L NaHCO3, 120 mmol/L Na2CO3, and 10 mmol/L DTT at 60°C for 15 minutes. After neutralization in 0.2 mol/L sodium acetate, pH 5.2, 1% acetic acid, and 10 mmol/L DTT, RNA probes were eluted on a Sephadex column (Pharmacia, Uppsala, Sweden) using a buffer containing 2 mol/L Tris-HCl, pH 7.5, 0.5 mol/L ethylenediaminetetraacetic acid, 10% sodium dodecyl sulfate, and 1 mol/L DTT and precipitated in ethanol.
Hybridization with sense and antisense probes were performed in parallel. Cryostat sections were fixed for 20 minutes in 4% paraformaldehyde and acetylated. For cytospins, cells were permeabilized in Triton 1/1000 in PBS for 15 minutes before acetylation. Slides were then dehydrated and air dried. Thirty µl of a hybridization mixture containing 50% deionized formamide, 10% dextran sulfate, 10 mmol/L DTT, 0.3 mol/L NaCl, 20 mmol/L Tris-HCl, pH 7.5, 5 mmol/L ethylenediaminetetraacetic acid, 10 mmol/L NaHPO4, pH 8, 0.4 mg/ml Denhardt's solution, 0.5 mg/ml yeast tRNA, and 1.5 x 106 cpm of 35S-labeled probe were applied on each section. Hybridization was performed overnight at 50°C. Excess of probe was removed by washing in 5x standard saline citrate (SSC) and 1 mmol/L DTT for 30 minutes at 42°C and then in 2x SSC, 50% formamide, and 1 mmol/L DTT for 20 minutes at 60°C. Slides were then subjected to digestion with 30 µg/ml RNase A for 30 minutes at 37°C and washed in 2x SSC for 15 minutes at 37°C and in 0.1x SSC for 15 minutes, dehydrated, and air dried before autoradiography (Hypercoat LM1; Amersham). Slides were stored at 4°C in the dark for 15 and 35 days and were developed in Kodak D19 developer (Kodak, Hemel, Hampstead, United Kingdom), rinsed, and fixed. Slides were finally counterstained in hematoxylin and mounted. Evaluation of the number of IL-10 mRNA-containing cells was performed under light microscope by quantification of positive cells. Results were expressed as the number of positive cells per mm2 of tissue sections. For quantification of IL-10-positive cases, we considered a case as positive when >35 positive cells/mm2 were observed. Sense probes were used as control in each experiment and gave no significant positive signal.
Three cases (cases 29, 32, and 37) of ALCL with available formalin-fixed tissues and showing a significant number of IL-10-containing cells were examined by ISH with IL-10-digoxigenin probe on paraffin sections, to better identify the IL-10-positive cells. Probe was transcribed in vitro in the presence of digoxigenin-UTP according to the manufacturer's procedure (Boehringer Mannheim, Mannheim, Germany) and sheared by alkaline hydrolysis to yield RNA of about 200 nucleotides in length. Sections were dewaxed and hybridized as previously described,24 with some modifications. Tissue sections were treated with 15 µg/ml protease IV (Sigma Chemical Co., St. Louis, MO) for 15 minutes at 37°C and acetylated. Hybridization was performed overnight at 52°C in a solution containing 50% formamide, 4x SSC, 1x Denhardt's solution, 10% dextran sulfate, 250 µg/ml yeast RNA, and 5 ng/µl of digoxigenin-labeled probe. Unbound labeled RNA probe was removed by an RNase treatment for 30 minutes at 37°C (20 µg/ml) and by washing in 2x SSC and 1x SSC for 30 minutes each at 52°C. Bound probe was detected with antidigoxigenin antibody Fab fragments conjugated with alkaline phosphatase (Boehringer Mannheim), and color reaction was performed with nitroblue tetrazolium and 5-bromo-4-chloro-3-indolyl phosphate (Sigma).
RNA Extraction and Reverse Transcription-Polymerase Chain Reaction (RT-PCR) for Human and Viral IL-10
Total RNAs were extracted from frozen tissues using Trizol reagent (Life Technologies, Inc., Gaithersburg, MD). RNAs were extracted in chloroform, precipitated in isopropanol, and resuspended in diethylpyrocarbonate-treated water. To avoid contamination with genomic DNA, RNA samples were treated with 1 U RNase-free RQI-DNase (Promega) for 10 minutes at 37°C and ethanol precipitated. One µg of DNase-treated RNAs was reverse transcribed using 300 ng of random hexanucleotides (Life Technologies), 200 U of SuperScript II reverse transcriptase (Life Technologies), 1 µl of 10 mmol/L deoxynucleotide triphosphate mixture, 2 µl of 0.1 mol/L DTT, 10 U of RNAsin (Life Technologies), and 4 µl of 5x first-strand buffer (250 mmol/L Tris-HCl, pH 8.3, 375 mmol/L KCl, 15 mmol/L MgCl2, and 0.1 mol/L DTT) in a final volume of 20 µl for 50 minutes at 42°C. Thirty µl of water was added at the end of the reaction.
PCR amplification of S14 ribosomal protein cDNA was performed on each sample as a control for efficient cDNA synthesis. Negative controls, which were performed without cDNA adjunction in the reagent mix, were included for every PCR analysis. Positive controls for IL-10 and BCRF1 were the cDNA of the SU-DHL-1 cell line and the B95-8 cell line, respectively. Specific primers were custom synthesized (Genomic, Collonges-sous-Salève, France). They were: IL-10 sense, 5'-ACCAAGACCCAGACATCAAG-3'; IL-10 antisense, 5'-GAGGTACAATAAGGTTTCTCAAG-3'; BCRF1 sense, 5'ATGGAGCGAAGGTTAGTGGT-3'; BCRF1 antisense, 5'-CACCCAAAGAATTGACATGGT-3'; S14 sense, 5'-GGCAGACCGAGATGAATCCTCA-3'; and S14 antisense, 5'- CAGGTCCAGGGGTCTTGGTCC-3'. One µl of the cDNA was amplified in 1x PCR buffer (10 mmol/L Tris-HCl, pH 8.3, and 50 mmol/L KCl) containing 0.4 µl of 10 mmol/L deoxynucleotide triphosphate mixture, 0.4 µl of each specific primer (10 pmol/µl), 0.5 U of Taq Gold polymerase (Perkin-Elmer Corp., Norwalk, CT), and 1.5 mmol/L MgCl2 for S14 or 2 mmol/L MgCl2 for IL-10 and BCRF1, in a total volume of 20 µl. The reaction mixture was amplified in a 2400 Perkin-Elmer thermal cycler, as follows: 10 minutes at 95°C followed by 28 (S14) or 33 (IL-10 and BCRF1) cycles of 30 seconds each at 94°C, 30 seconds at 58°C, and 30 seconds at 72°C. An autoextension of 2 seconds was added to each 72°C extension cycle. The amplified products were electrophoresed in ethidium bromide-stained 2% agarose gel.
EBV ISH
The procedure for the detection of EBER transcripts by ISH has been previously described.25 Probes used were fluorescein-conjugated oligonucletides complementary to the nuclear RNA portions of the EBER 1 and 2 genes (Dako, Glostrup, Denmark). The hybridization was detected using an immunohistological detection system, with a mouse anti-fluorescein antibody, rabbit anti-mouse immunoglobulins, and the alkaline phosphatase-anti-alkaline phosphatase complexes (Dako). The visualization of the reaction was carried out using nitroblue tetrazolium and bromochloroindolyl phosphate.
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In all of the 39 cases of T-cell lymphoma and in the 7 cases of
NK-cell lymphoma, cells containing IL-10 transcripts could be
demonstrated, with a heterogenous pattern of expression from case to
case. Moreover, a strong association with morphological subtypes was
shown. Results are summarized in Tables 1 to 3
and Figure 1
. In 3 of the 7 cases of nasal NK-cell
lymphoma, IL-10 transcripts were detected in a substantial proportion
of cells. In one of these cases, the positive cells were scattered
throughout the tissue section, thus preventing identification of the
cells. In the other two cases of NK-cell lymphoma, the IL-10-positive
cells were restricted to some areas, in which immunohistological
studies performed on serial sections demonstrated the presence of
CD30+/LMP1+ tumor cells (Figure 2, A and B)
. Eight of the 11 (73%)
anaplastic null-cell or T-cell lymphomas displayed a high number of
IL-10-expressing cells (>35 cells/mm2). In all cases, the
positivity, usually strong, seemed to be localized in the large
atypical cells. In eight cases, positive cells were predominantly found
in sinusal and perifollicular areas (Figure 3A)
. In two other cases with partial
involvement (cases 32 and 36), the localization of the positive cells
was restricted to the neoplastic areas. Among the three cases with a
low number of IL-10-expressing cells, a case of lymphohistiocytic
variant (case 30), with only a few scattered neoplastic cells,
displayed a similar pattern of IL-10-positive cells. Histological and
immunohistochemical analysis performed on serial sections demonstrated
an overlapping between CD30+ tumor areas and IL-10-positive
cells (Figure 3B)
, whereas no clear overlapping with CD68 could be
observed. ISH with a digoxigenin-labeled probe, performed on paraffin
sections of three ALCL IL-10 mRNA-expressing cases, confirmed the
presence of IL-10 in the cytoplasm of large cells with characteristic
cytological features of anaplastic cells (Figure 3C)
. Five of the seven
IL-10-positive ALCLs (one case was not available) expressed the
cytotoxic protein granzyme B in a large proportion of tumor cells,
whereas the last three cases, with only a few IL-10-expressing cells,
showed granzyme B expression in less than 20% of the tumor cells. In
all cases of AILD (11 of 11), only a few scattered IL-10-positive cells
were observed (always less than 25 cells/mm2), but their
nature could not be determined. Only 2 of 11 pleomorphic medium and
large cell lymphomas (PMLs; cases 18 and 19) showed an important
number of IL-10-positive cells. Hepatosplenic and nonhepatosplenic
T-cell lymphomas with monomorphic medium-sized or PML histology
displayed IL-10 expression in only rare scattered cells.
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. Lipopolysaccharide-stimulated peripheral blood mononuclear
cells, used as positive control, showed a higher frequency of labeling
of individual cells than unstimulated peripheral blood mononuclear
cells (10% versus 1%). ISH for EBV-encoded EBER 1 and 2 Transcripts
The presence of the EBV-encoded EBER 1 and 2 transcripts was
determined by ISH on paraffin sections. Results are reported in Tables 1 to 3
. All NK-cell lymphomas gave a signal in most, if not all, tumor
cells. Almost all cases of AILD were EBER 1 and 2 positive in some
scattered cells (9 of 10 tested). EBV could be detected in some tumor
cells in 3 of 11 PMLs but not in ALCLs. EBV was found in tumor cells of
three nonhepatosplenic T-cell lymphomas.
RT-PCR Analysis for Human and Viral IL-10
Total RNAs were extracted from frozen tissues of 12 cases of T- or
NK-cell non-Hodgkin's lymphoma (including 2 ALCLs, 2 AILDs, 3 PMLs,
and 5 EBV-associated nasal NK-cell lymphomas). These cases were
analyzed by RT-PCR to determine human or viral origin of the IL-10
detected by ISH (Figures 4 and 5)
. In all lymphoma samples, a 141-bp
S14-specific band of quite similar intensity was detected and used as a
control of cDNA synthesis. The intensity of the 351-bp hIL-10 band was
variable from case to case. Overall, there was a good correlation
between RT-PCR results and the amount of IL-10 mRNA found by ISH
despite some differences in band intensity from case to case (Figures 4 and 5
; Tables 1 to 3
). In addition, all analyzed samples, including the
five nasal NK-cell non-Hodgkin's lymphomas, which were strongly EBV
positive, were negative for BCRF1/vIL-10 mRNA expression.
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-PTCLs. We have also found a
correlation between IL-10 mRNA expression and NK-cell lymphomas,
because 3 of 7 (43%) of these tumors contained many IL-10-positive
cells. The finding that most systemic ALCLs expressed IL-10 mRNA is consistent with a recent report of IL-10 mRNA in cutaneous CD30+ lymphoproliferations.26 Despite differences in their clinical and biological aspects,3 these findings suggest a role for this cytokine in the pathogenesis of both cutaneous and systemic CD30+ ALCLs. Its possible implication in an autocrine pathway might be suggested because 1) the overlapping pattern between CD30 staining and IL-10 ISH results, neoplastic appearance of the IL-10-positive cells in the three cases studied on paraffin sections, and IL-10 production by the anaplastic lymphoma cell line SU-DHL-1 gave strong evidence that anaplastic cells were the major source of IL-10 production, and 2) human T cells have been shown to constitutively express the IL-10 receptor, although activation of T cells was associated with some decrease of the level of IL-10 receptor mRNA.27 Results concerning the role of IL-10 in the T-cell growth depend on the studied model. Indeed, IL-10 was first described as a mouse T-cell growth factor in the presence of IL-2.12 However, in human models, most in vitro studies have shown that IL-10 down-regulates mitogen or anti-CD3-induced T-cell proliferation in the presence or absence of accessory cells, via inhibition of endogenously produced IL-2.28,29 The autocrine role of IL-10 might be supported by preliminary experiments showing a moderate but reproducible decrease of proliferation of SU-DHL-1 cell line in the presence of anti-IL-10 antibody (20%) using in vitro [3H]thymidine proliferation assays (data not shown). Besides, IL-10 has been implicated in inhibition of apoptosis of human T cells.30 It could be hypothesized that IL-10 may rescue CD30+ ALCL cells from spontaneous apoptosis, thus allowing survival of tumor cells. Further support for an implication of IL-10 in the pathogenesis of CD30+ ALCLs can be provided by in vitro data concerning its involvement in the differentiation of mouse cytotoxic T cells.14 This could be of particular interest because, in keeping with previous reports,21,31-33 most cases of ALCL of this series expressed the cytotoxic proteins TIA-1 and/or granzyme B. It is noteworthy that a parallel was found between IL-10 expression and activated cytotoxic antigen profile.
IL-10 has also been shown to have pleiotropic immunosuppressive effects on T cells and macrophages, including inhibition of antigen presentation function and cytokine synthesis.15,34 Tumor cells, melanoma, or B cell lines pretreated with IL-10 or transfected with IL-10 gene are protected from lysis by tumor-specific cytotoxic T cells.35 These data suggest a role of IL-10 on the microenvironment resulting in the diminution of the immune surveillance and its contribution to lymphoma progression.
Taken together, our findings and those of the literature may suggest a
role of IL-10 in the survival of tumor cells in CD30+ ALCL.
In addition to the production of IL-6 and IL-9, as already reported,
this indicates a T-helper-2 profile for anaplastic
lymphomas.6,7
Besides ALCL, only two cases of PML showed
substantial levels of IL-10 mRNA. These two cases expressed the CD30
antigen in a proportion of cells (data not shown), but the relationship
between IL-10 and CD30 expression needs further investigation. None of
the cases of AILD showed significant levels of IL-10 mRNA. These
lymphomas are characterized by tumor necrosis factor-/lymphotoxin
association5
without IL-10 involvement. This finding in
combination with the association between IL-6/IL-9/IL-10 and
CD30+ ALCL1,6,7
suggests histotype-dependent
differences in the cytokine profile of PTCL. Furthermore, this
particular cytokine profile reinforces the individualization of ALCL
and AILD as distinct entities. In the present study, we have also
investigated six cases of PTCL, but IL-10 mRNA expression was
found in only very rare scattered cells. Previous studies did not
demonstrate IL-10 in normal T cells,36,37
and only
in vitro intraepithelial lymphocytes could be
stimulated to express IL-10.37
In our study, whatever the
site, tumor T cells were found to keep their basal IL-10 level.
In this series, three of seven NK-cell lymphomas were found to express IL-10 mRNA in a substantial proportion of tumor cells. By RT-PCR, we have demonstrated the human origin of IL-10, although all nasal NK-cell lymphomas were EBV positive. To the best of our knowledge, IL-10 production by NK cells was analyzed in only one study by enzyme-linked immunosorbent assay, and no hIL-10 was detected in resting or activated NK cells in vitro.38 Although the direct effect of IL-10 on human NK cells has not yet been fully investigated, these cells are known to express abundant IL-10 receptor, suggesting responsiveness to IL-10.38 Indeed, there is circumstantial evidence that IL-10 directly stimulates or potentiates NK-cell functions: hIL-10 can directly induce NK cytotoxic activity and increase IL-2-induced proliferation, cytotoxicity, and cytokine production.16 Thus, it might be suggested that IL-10 synthesized by tumor NK cells could act in an autocrine manner on the proliferation of the tumor cells and/or on the increase of cytotoxic activities in view of the expression of cytotoxic proteins by NK-cell lymphomas.21,33
In this study, no striking correlation was found between IL-10 expression and EBV detection irrespective of the histotype, the TCR expression, or the site of origin of the tumors. Only 4 of 22 EBV-positive T/NK-cell lymphomas, including 3 of 7 EBV-associated nasal NK-cell lymphomas, displayed significant hIL-10 expression in the absence of vIL-10/BCRF1, whereas IL-10-expressing ALCLs were EBV negative. This absence of clear correlation between IL-10 expression and presence of EBV differs from studies reported on acquired immunodeficiency syndrome-related B-cell lymphomas and Hodgkin's disease, in which presence of EBV was associated with increased hIL-10 levels.19,39
In summary, our findings show a frequent association between CD30+ ALCLs and hIL-10 mRNA expression by neoplastic cells of these tumors. IL-10 may rescue tumor cells from apoptosis and may be inhibitory to the generation of antitumor cytotoxic T-cell activities. In parallel with CD30+ ALCLs, a proportion of NK-cell lymphomas shows expression of cellular IL-10, suggesting an involvement of this cytokine in the pathogenesis of some NK-cell tumors. It is interesting that the level of IL-10 expression, ie, the number of IL-10-expressing cells, differs from case to case. In the present series, no clear association could be established between IL-10 expression and clinical features and outcome. However, clinical trials on larger series are needed to investigate the clinical and/or the prognostic significance of IL-10 expression, especially in ALCLs. In this respect, whatever the mechanism by which IL-10 could be involved in the pathogenesis of a proportion of CD30+ ALCLs and NK-cell lymphomas, the identification of IL-10 as a cytokine potentially involved in some T/NK-cell lymphomas could be useful for the development of new therapeutic strategies, as recently developed in B-cell lymphomas.
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Acknowledgements |
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Footnotes |
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Supported by grants from Association pour la Recherche sur le Cancer and Comité des Deux-Sèvres de la Ligue contre le Cancer.
Accepted for publication July 18, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/ß and / T-cell receptors in 57 cases of peripheral T-cell lymphomas: identification of a subset of T-cell lymphomas. Am J Pathol 1990, 137:617-628[Abstract]
ß and peripheral T-cell lymphomas. J Pathol 1997, 183:432-439[Medline]
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/ and /ß T cells. Scand J Immunol 1994, 39:209-215[Medline]
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