Interleukin-4 enhances the survival of severe combined immunodeficient mice engrafted with human B-cell precursor leukemia

Human interleukin-4 (huIL-4) has been shown to inhibit the growth in vitro of cells from patients with acute lymphoblastic leukemia (ALL). With the aim of determining whether this cytokine might be useful in the treatment of patients with ALL, the effects of huIL-4 on human B- cell precursor ALL engrafted in severe combined immunodeficient (SCID) mice were examined. The inhibition of [3H] thymidine uptake of primary ALL cells by huIL-4 was maintained following engraftment and passage of leukemia in SCID mice. Five of seven xenograft leukemias showed significant inhibition in vitro by huIL-4 at concentrations as low as 0.5 ng/mL; furthermore, huIL-4 counteracted the proliferative effects of IL-7. When used to treat two human leukemias engrafted in SCID mice, huIL-4 200 microgram/kg/d, as a continuous 14-day subcutaneous infusion, suppressed the appearance of circulating lymphoblasts and extended survival of mice by 39% and 108%, respectively, the first demonstration of IL-4 activity against human leukemia in vivo. The mean steady-state huIL-4 level in mouse plasma during the infusion was 1.46 ng/mL (SEM +/- 0.14 ng/mL), which was similar to concentrations found to be effective in vitro. ALL cells obtained from mice relapsing after huIL-4 treatment continued to show inhibition by the cytokine in vitro. These data suggest that IL-4 may be useful in the treatment of patients with ALL.     

Down-modulation of neutrophil production by erythropoietin in human hematopoietic clones

In clonogenic assays of hematopoietic progenitors, high concentrations (4 U/mL) of erythropoietin (epo) reduced the formation of granulocyte- macrophage (GM) colonies and diminished the number of granulocytes formed per culture plate. Fetal progenitors were more sensitive to these effects of epo than were progenitors from adults, displaying these reductions at greater than or equal to 1 U epo/mL. The mechanism was investigated by growing fetal progenitors stimulated by recombinant GM-CSF, in the absence of epo, and when eight-cell clones first appeared, mapping their location, then adding epo, and assessing its effect on the subsequent differentiation of the clones. In the absence of epo, the clones developed exclusively into GM colonies. However, if developing clones were presented with epo, 85% matured into GM colonies, but 15% became multilineage or normoblast colonies. In addition, developing clones that were presented with epo produced colonies that contained fewer neutrophils. These effects of epo on neutrophil generation were observed with each of three varieties of recombinant epo, and also with purified human epo, but were not observed using epo that had been neutralized with rabbit anti-epo antiserum.     

Effect of high-dose methylprednisolone infusion on polymorphonuclear leukocyte function in patients with systemic lupus erythematosus

We have studied the effect of high-dose (1 gm) methylprednisolone infusion on polymorphonuclear leukocyte (PMN) function in 11 patients with active systemic lupus erythematosus (SLE). The only alteration of polymorphonuclear leukocyte function produced consistently by methylprednisolone was decreased adherence to plastic surfaces when tested 2 hours after infusion. This steroid-induced abnormality, however, was transient. Cells obtained from patients 24 hours after a single dose of drug exhibited normal adhesiveness. These results indicate that single, large doses of methylprednisolone do not produce long-lasting abnormalities of PMN function in patients with lupus.     

Kinetic evaluation of the pool sizes and proliferative response of neutrophils in bacterially challenged aging mice

Clinical observations during infection suggest that in aged patients, the kinetic or proliferative responses of neutrophils to infection may be deranged. To test this hypothesis, the neutrophil responses of 6- month-old and 30-month-old mice were compared. After intrapulmonary injection of Escherichia coli, young mice exhibited neutrophilia and diminution of the neutrophil storage pool (NSP) by a mean of 6.4 x 10(6) neutrophils/two femurs. This was accompanied by an increase in the pool of CFU-GM from a control value of 1.1 x 10(5) cells/two femurs (range 0.7 to 1.4) to 1.5 x 10(5) (1.1 to 1.9) (P less than .05) and the thymidine suicide (relative proliferative rate) of CFU-GM rose from 27% (19 to 42) to 51% (31 to 61) (P less than .05). Furthermore, the CFU-GM of infected young mice displayed enhanced differentiation to the neutrophil series. In contrast, old mice exhibited a greater mean diminution of the NSP: 12.8 x 10(6) neutrophils. Also, old mice experienced a reduction in CFU-GM from 2.3 x 10(5) (1.0 to 3.9) (controls) to 1.3 x 10(5) (1.2 to 1.5)/two femurs (P less than .05), a reduction in the proliferation of CFU-GM and reduced differentiation of CFU-GM to neutrophils. These experiments establish that the neutrophil response of infected old mice is disordered, with exaggerated depletion of the NSP and lack of stimulus-driven granulocytopoiesis as reflected by a paradoxical reduction in the number and proliferative rate of precursors. This defect may be compounded by decreased differentiation of precursors to neutrophils.