Abstract
We previously reported the TLR9 ligand CpG ODN can induce apoptosis of CLL cells. Interleukin 21 (IL-21), a recently discovered cytokine with structural homology to IL-2, IL-4 and IL-15, has pleiotropic effects on lymphocyte populations including NK, T and B cells. IL-21 is known to co-stimulate normal human B cell proliferation induced by CD40 ligation, and to inhibit B cell proliferation induced by anti-IgM antibodies and IL-4. We explored the impact of these two agents on CLL because of the overlapping nature of their signaling pathways. Gene chip array studies demonstrated CLL cells express the receptor for IL-21, and expression of this receptor is upregulated by CpG ODN. IL-21 as a single agent induced apoptosis of CLL cells in most samples studied. The combination of IL-21 and CpG ODN induced a greater degree of apoptosis than either agent alone.
Figure
Dosing studies demonstrated synergy between these two agents in their ability to induce apoptosis of CLL cells.
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The effect of IL-21 and CpG ODN was also evaluated in peripheral blood from normal donors, and in umbilical cord blood. In both types of samples, therapy preferentially eliminated CD5(+) B-cells. Monoclonal antibody against CD5, but not control antibody, was able to inhibit the pro-apoptotic effect of IL-21. Our results suggest treatment with IL-21 and CpG ODN preferentially eliminates CD5(+) B cells in both malignant and benign samples, and may be a useful combination for the treatment of CLL or autoimmune disorders dependent elevated B1 cell levels. Ongoing studies are exploring the underlying signaling pathways which might be responsible for these effects.
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