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Blood, 15 January 2002, Vol. 99, No. 2, pp. 722-723
CORRESPONDENCE
To the editor:
Interleukin-15 as a potential costimulatory cytokine in CD154
gene therapy of chronic lymphocytic leukemia
In their work recently published in Blood, Wierda and
coworkers1 demonstrated that adenovirus-mediated gene
transfer of CD154 into chronic lymphocytic leukemia (CLL) B cells and
the retransfer of these cells into the bloodstream of CLL patients resulted in increased or de novo expression of immune accessory molecules, such as CD54, CD95, CD80, and CD86, on CLL bystander cells
and restored the capacity of CLL cells to stimulate autologous T cells.
As a result, rising plasma levels of Thl-type cytokines and increased
absolute numbers of blood T cells were observed, as well as a T-cell
subset reactive against autologous CLL cells. These findings
correlated with a clinical response manifested as a reduction in
absolute lymphocyte count and lymph node size. The idea behind a CD154 gene therapy protocol was based on an earlier
study in which an impaired intrinsic CD40 activation of CLL cells was
observed and contributed to a suppression of CD154 expression on T
cells by B-CLL cells.2 In the present study, we found
significantly lower basal CD40 expression levels in CLL compared to B
cells from age- and sex-matched healthy donors (mean specific
fluorescence intensity [MFI] CLL (n = 41): mean ± SEM
2.7 ± .22 vs healthy controls (n = 41): 4.6 ± .26,
P < .000l). Besides lower expression levels, the
CD40-mediated signal transduction was impaired, as an up-regulation of
CD95 expression following CD40 activation could be observed only in
normal but not in CLL B-cells (Figure 1).
From our results, we conclude that not only aberrant regulation of
CD154, but also deficiencies in CD40 expression and/or signal
transduction might contribute to the impaired T-cell activation in CLL.
In an attempt to increase CD40 expression and signaling in CLL cells,
we tested the effect of interleukin-15 (IL-15), a known T- and natural
killer (NK)-cell activator. Although in vitro experiments suggested an
increase in [3H]-thymidine uptake in CLL cells
triggered by IL-15,3 such a tumor-promoting effect might
be counteracted by the induction of a successful T-cell response. In
fact, this cytokine has been shown to up-regulate costimulatory
molecules in hematopoietic cell lines.4 Our results
demonstrated that stimulation of B-CLL cells by IL-15 enhances CD40
expression significantly (MFI untreated: 3.9 ± .19 vs IL-15-treated:
5.4 ± .38, P < .002, n = 14), accompanied by a
reconstitution of CD40 signaling capacity, as shown by the up-regulation of CD95 following costimulation of CLL cells with IL-l5
and also by CD40 cross-linking (IL-I5/CD40XL) (Figure 1). Wierda et al
demonstrated that CD154-mediated CD40 activation led to the stimulation
of T cells reactive against CLL cells.1 We observed that
IL-15 was a prerequisite for the induction of apoptosis in CLL cells
via the CD40 pathway (Figure 2). It has been shown that the killing of target cells by cytotoxic T cells is
mediated, at least in part, via the activation of CD95.5 Since we observed the up-regulation of CD9S on CLL cells activated by
IL-l5 and CD40, we tested whether this increases the sensitivity of CLL
cells toward CD95 ligation following the addition of an agonistic
anti-CD95 antibody (CHll, 250 ng/mL for 3 days). As also observed for
spontaneous apoptosis, CD40 activation following IL-15 prestimulation
resulted in an increased number of apoptotic CLL cells (Figure 2). From
these data it can be concluded that the combination of IL-15 and CD40
stimulation renders B-CLL cells more sensitive to FasL+
cells, which are either cytotoxic T cells or themselves B-CLL cells.6
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| Figure 1.
PBMC of 20 CLL patients (gray squares) and of 24 healthy
donors (white squares) were left untreated or stimulated with IL-15 (50 ng/mL, 7 days) or activated via CD40 cross-linking (CD40XL, ie,
treated with 1 µg/mL anti-human CD40 mab followed by a 5-day
incubation with an antimouse mab).
The expression of CD95 was determined by staining of cells with a
specific FITC-labeled antihuman CD95 mab or a relevant
isotype-specific control.
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| Figure 2.
PBMCs of 18 CLL patients were left untreated or
stimulated with IL-15 (7 days), activated via CD40XL (5 days), or stimulated with an anti-CD95 mab (CH11, 250 ng/mL, 3 days).
Apoptosis was measured by using an annexin V/PI assay. All statistics
were done using ANOVA tests.
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In conclusion, we wonder whether autologous IL-l5 contributes to some
of the immunological effects observed during treatment with adenovirus
CD154-modified B-CLL cells and suggest that the cytokine might qualify
as an adjuvant augmenting the therapeutic efficacy by rendering B-CLL
cells more susceptible to killing by tumor-specific T cells.
Gabriele Anether, Ingrid Marschitz, Inge Tinhofer, and Richard Greil
Correspondence: Richard Greil, Laboratory of Molecular Cytology,
Internal Medicine, and Tyrolean Cancer Research Institute, University
of Innsbruck, Austria.
Acknowledgments
Supported by Oesterreichische Nationalbank, grant no. 8222 (R.G.,
G.A.); Austrian Science Foundation, grant no. T95-Pat (I.T.); and
Tyrolean Cancer Aid (R.G., I.M.).
References
1.
Wierda WG, Cantwell MJ, Woods SJ, Rassenti LZ, Prussak CE, Kipps TJ.
CD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia.
Blood.
2000;96:2917-2924[Abstract/Free Full Text].
2.
Cantwell M, Hua T, Pappas I, Kipps TJ.
Acquired CD40-ligand deficiency in chronic lymphocytic leukemia.
Nat Med.
1997;3:984-989[CrossRef][Medline]
[Order article via Infotrieve].
3.
Trentin L, Cerutti A, Zambello R, et al.
Interleukin-15 promotes the growth of leukemic cells of patients with B-cell chronic lymphoproliferative disorders.
Blood.
1996;87:3327-3335[Abstract/Free Full Text].
4.
Zheng Z, Takahashi M, Aoki S, et al.
Expression patterns of costimulatory molecules on cells derived from human hematological malignancies.
J Exp Clin Cancer Res.
1998;17:251-258[Medline]
[Order article via Infotrieve].
5.
Hahn S, Gehri R, Erb P.
Mechanism and biological significance of CD4-mediated cytotoxicity.
Immunol Rev.
1995;146:57-79[CrossRef][Medline]
[Order article via Infotrieve].
6.
Tinhofer I, Marschitz I, Kos M, et al.
Differential sensitivity of CD4+ and CD8+ T lymphocytes to the killing efficacy of Fas (Apo-l/CD95) ligand+ tumor cells in B chronic lymphocytic leukemia.
Blood.
1998;91:4273-4281[Abstract/Free Full Text].
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