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CORRESPONDENCE The malignant Hodgkin and Reed-Sternberg (H/RS) cells of Hodgkin
disease (HD) and the surrounding infiltrating cells are known to
secrete several types of cytokines and chemokines, many of which have
been implicated in the different clinical and histological presentations of HD.1-4 Most recently, interleukin-13
(IL-13) and IL-13 receptors have been shown to be expressed by cultured HD-derived cell lines and primary H/RS cells.5,6
Furthermore, IL-13 has been detected in the supernatants of cultured
HD-derived cell lines, and neutralizing antibody to IL-13 has been
shown to inhibit the growth of these cell lines in vitro,5
suggesting that H/RS cells may enhance their own survival by an IL-13
autocrine and paracrine cytokine loop.5 Because of the
potential implication of these observations for treatment of HD, we
examined IL-13 levels in serum samples from patients with newly
diagnosed and relapsed HD and compared these levels with serum IL-13
levels in healthy volunteers. IL-13 levels were determined using an enzyme-linked immunosorbent assay
(ELISA) kit from Biosource International (Camarillo, CA) and were
measured in duplicate using a µ-Quant plate reader equipped with KC4
software (Biotech Instruments, Winooski, VT). The sensitivity of this
ELISA is less than 12 pg/mL. All experiments included a set of standard
wells containing known quantities of recombinant human IL-13. Results
are reported as the average value of duplicate measurements.
Supernatants from 3 HD-derived cell lines that are known to secrete
IL-13 (HD-LM-2, L-428, and KMH2) were used as positive
controls.5 Supernatants from one additional HD-derived
cell line (HD-MYZ) were used for comparison. The cell lines were
obtained from the German Collection of Microorganisms and Cell Cultures
(Department of Human and Animal Cell Cultures, Braunschweig,
Germany).7 Cell lines were cultured (5 x
105/mL) in RPMI medium supplemented with penicillin (5%),
streptomycin (5%), and heat-inactivated fetal calf serum (10%).
Supernatants were collected after 24 hours in culture and immediately
assayed for IL-13 levels by ELISA. Serum from 108 consecutive patients with newly diagnosed HD and from 31 patients with relapsed HD was
studied. Serum from 40 healthy donors was used for comparison. All
serum samples were obtained after proper consent was granted and were
stored in a freezer at Consistent with a previously published report, the 3 IL-13-producing
cell lines that we examined expressed a range of IL-13 levels, from 85 to 300 pg/mL5 (Figure 1). The
HD-MYZ cells did not secrete IL-13. None of the 40 serum samples that
were obtained from healthy donors contained detectable levels of IL-13 (Figure 1). Subsequently, sera from 108 patients with newly diagnosed HD were examined. Of these patients, 70% had nodular sclerosis histology, and 36% had stage III or IV disease (Table
1). Thirty-one patients (28%) had B
symptoms. Eleven (10%) of the 108 serum samples contained detectable
levels of IL-13 (Figure 1). In all 11 cases, IL-13 levels were at least
30 pg/mL (range, 34 to 82 pg/mL). The 3 patients with the highest IL-13
levels had nodular sclerosis histology; 2 had stage IIA disease, and
one had stage IIB disease. IL-13 levels did not correlate with gender,
disease stage, histological subtype, disease bulk, or presence of
extranodal involvement. This lack of correlation may simply be due to
the small number of patients who were found to have elevated serum
IL-13 levels. There was a trend for a higher percentage of patients
with B symptoms to have elevated IL-13 levels (45.8% vs 26.8%), but
this difference was not statistically significant (
We also studied IL-13 levels in serum samples from 31 patients with relapsed HD. All samples were collected at the time of active disease and before therapy was started. In this group, 28 patients had nodular sclerosis histology, and 3 had unclassified histologies. Five (16%) of 31 patients had elevated IL-13 levels; 3 had stage II disease, and 2 had stage III disease. Only one had B symptoms. The median serum IL-13 level was 46 pg/mL (range, 42 to 48 pg/mL). Although the number of patients with elevated IL-13 levels was small, this does not rule out the possibility that the majority of the patients may have had clinically significant IL-13 levels at the site of disease. Our data confirm the potential clinical relevance of IL-13 in patients with HD and warrant further exploration of novel therapeutic strategies to examine the clinical significance of the IL-13 survival loop in patients with HD.
Paolo Fiumara, Fernando Cabanillas, and Anas Younes
References 1. Kadin ME. Pathology of Hodgkin's disease. Curr Opin Oncol. 1994;6:456-463[Medline] [Order article via Infotrieve]. 2. Gruss HJ, Pinto A, Duyster J, Poppema S, Herrmann F. Hodgkins disease: a tumor with disturbed immunological pathways. Immunol Today. 1997;18:156-163[CrossRef][Medline] [Order article via Infotrieve].
3.
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 4. Teruya-Feldstein J, Tosato G, Jaffe ES. The role of chemokines in Hodgkin's disease. Leuk Lymphoma. 2000;38:363-371[Medline] [Order article via Infotrieve].
5.
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
6.
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 7. 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].   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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70°C until used.
2
test). Of the 11 newly diagnosed patients who had elevated levels of
IL-13, only one patient experienced disease progression, 4 months after
completing therapy for stage IIB bulky mixed-cellularity disease.
Interestingly, 2 of 12 patients with lymphocyte-predominant HD had
elevated serum IL-13 levels. These data are in contrast with a
previously published report that showed that IL-13 mRNA expression was
limited to primary H/RS cells of the classic type.
