Elevated levels of biologically active soluble CD40 ligand in the serum of patients with chronic lymphocytic leukaemia

Abstract

Summary. Chronic lymphocytic leukaemia (CLL) is an indolent lymphoproliferative disorder manifested by low growth fraction and prolonged survival of the malignant cells. The mechanisms that enable CLL cells to live longer and to resist apoptosis remain unclear. Because the malignant CLL cells express CD40 and Fas receptors, which can transduce cell-survival and cell-death signals, we examined the role of CD40 in the growth regulation of CLL cells and its interaction with Fas-mediated and fludarabine-induced apoptosis in vitro. Primary CLL cells underwent spontaneous apoptosis in culture, which was enhanced by exogenous human Fas ligand (FasL) or fludarabine. Exogenous CD40L rescued CLL cells from spontaneous apoptosis in a dose-dependent manner, and caused CLL cells to resist apoptosis induced by FasL or fludarabine. Patients' autologous plasma rescued CLL cells from spontaneous apoptosis, an effect that could be reversed with anti-CD40 ligand (CD40L) antibodies. The levels of soluble CD40 ligand in the sera of 51 CLL patients and 55 healthy donors were determined by enzyme-linked immunosorbent assay. The mean soluble CD40L level in normal donors was 0·29 ng/ml compared to a mean value of 0·80 ng/ml in CLL patients (P < 0·001). CD40L up-regulated bcl-X L mRNA but not bcl-2 in CLL cells within 3-6 h in culture. Our results demonstrated that serum of patients with CLL contained elevated levels of biologically active soluble CD40L, and that CD40L can prolong survival of CLL cells and mediate their resistance to FasL and fludarabine in vitro.

Role of CD40-CD40L in Mouse Severe Malaria

“…39 In humans, lymphoproliferative diseases have been reported to be associated with an increase of the amount of CD40L in plasma. 40,41 We were unable to measure the CD40L plasma levels in infected mice, but the evaluation of the mRNA levels in tissue showed an increased level in the lung, and an increased level per spleen if the spleen size (Figure 4) is taken into account. Expression of the cell receptor CD40, judged from its mRNA was increased in the brain and lung, observations that argue for an increase of CD40L-CD40 signaling during PbA infection.…”

Expression of CD154 on renal cell carcinomas and effect on cell proliferation, motility and platelet‐activating factor synthesis

“…24 The release of sCD154 has been also shown in the clinical setting as high levels of circulating CD154 were found in hematologic malignancies. 25 It is therefore possible that CD154 released by tumor cells may act as an autocrine/paracrine mediator.…”

Mechanisms involved in the pro- and anti-apoptotic role of NO in human leukemia

“…Serum of patients with B-CLL contained elevated levels of biologically active soluble CD40L that can prolong survival of the tumoral cells and mediate their resistance to FasL and fludarabine in vitro. 71 Thus, it would be worth testing the possibility that engagement of CD40 on B-CLL B cells leads to iNOS up-regulation. The constitutive expression of iNOS associated with NO-dependent protection of apoptosis in B-CLL has also been reported by Levesque et al,72 who found in addition that iNOS expression was increased by IFN-␥ and IL-4.…”