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

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.