Deficient production of tumor necrosis factor by peripheral‐blood monocytes in chronic lymphocytic leukemia

Abstract

The production of tumor necrosis factor (TNF) by lipopolysaccharide (LPS)-triggered peripheral-blood mononuclear cells (PBM) was investigated in 23 patients with untreated B-cell chronic lymphocytic leukemia (B-CLL) and 14 control donors. Cells were stimulated at concentrations that reflect cell density in peripheral blood. Under these conditions, PBM from 11/23 of the CLL patients produced at least 10-fold less TNF as compared with controls. Monocyte numbers were decreased in percentage, while absolute numbers (normal range 233 +/- 120 X 10(3)/mm3) were decreased only in 2, normal in 17 and increased in 4 patients indicating that the deficiency is not a result of monocytopenia in most patients. Cell separation experiments indicate that after removal of leukemic B cells, percentages of monocytes return to control range and TNF production is improved (7/7). In mixing experiments, we found a suppression of TNF production in control mononuclear cells by CLL cell samples (75 X 10(6) cells/ml) in 5/19 cases, while control cells from thymus exhibited no or little suppression in these conditions. In 2-chamber experiments, leukemic samples suppress TNF production by normal monocytes across a 0.45 micron membrane indicating that a soluble factor is responsible for suppression. The factor exhibits higher stability in serum-free conditions and its molecular weight is below 20 kDa. Prostaglandins are not involved, since indomethacin did not abrogate suppression.

Interferon‐alpha 2b (IFNα) for Early‐Phase Chronic Lymphocytic Leukaemia with High Risk for Disease Progression: Results of a Randomized Multicentre Study

“…However, the role of TNF remains controversial as it may, itself, have antiproliferative effects (Foa et al, 1990). Furthermore, a deficiency of TNF production in CLL cells has been shown (Flieger et al, 1990;Dahlke et al, 1995). Fundamental questions concerning the antiproliferative effect of IFN arose when a proliferative effect of IFN on CLL cells was demonstrated (Robert et al, 1986;Ö stlund et al, 1989).…”

Decreased production of TNF and IL‐6 in whole blood of CLL patients

“…Furthermore, we could recently demonstrate that monocytes are abnormal in that they show an upregulation of cell surface receptors in some patients [18]. In addition, cytokine production by monocytes in CLL was found defective when analyzing isolated blood mononuclear cells stimulated with LPS [5].…”

“…[5]. The molecular nature of this factor is still elusive, although a role for PGE, or TGFP could be excluded [5]. B cells do, however, express a specific pattern of gangliosides [28-301, and these glycolipids may effectively suppress production of IL-1 and TNF [3 1,321.…”

“…The degree of suppression did not always correlate with the level of cytokines produced, since it depended on the level of cytokines produced in the given experiment by the control donor. The degree of suppression appeared to be high in patients with high leukemic count (patients 1 and 2, Table I), but some patients with moderate counts of around 30,000 cells/mm3 also had a substantial decrease [5,12,13], while other patients with such moderate counts had levels of TNF similar to the control donors [22-24, Table I). There was no apparent correlation of TNF deficiency to clinical stage in that, for instance, stage C patients were found to have a pronounced, moderate, or no defect in cytokine production ( Table I).…”

“…We recently could demonstrate a deficient TNF production in monocytes of CLL patients [5]. These studies were performed with isolated peripheral blood mononuclear cells (PBMC), and one might argue that the deficiency is an artefact brought about by the breakdown of the fragile CLL B cells during the separation procedure 0 1995 Wiley-Liss, Inc.…”