Inhibition of lymphocyte blastogenic response in healthy donors treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF): possible role of lactoferrin and interleukin-1 receptor antagonist

Abstract

The effects of rhG-CSF on lymphocyte blastogenesis were evaluated in six healthy donors, submitted to progenitor cell mobilization for allogeneic transplantation. Neutrophil, monocyte and lymphocyte count increased 6.7-fold, 5.3-fold and 2.0-fold on day +4 of rhG-CSF as compared with baseline. The DNA stimulation index (DNA SI) of 72 h phytohemagglutinin (PHA)-treated cultures decreased from 20% (15–35.5) prior to rhG-CSF to 6.7% (1.5–11.9; P = 0.0026), 8% (4–12; P = 0.0091) and 15% (9–22; P = 0.0091) on days +2, +4 and +6; similarily, reactivity to concanavalin A decreased from 18% (12–20) to 1.8% (0.5–7; P < 0.01), 3% (2–8; P < 0.01) and 5% (2–11; P = 0.009). No changes of lymphocyte response to pokeweed mitogen were observed. DNA SI of PHA-treated cultures inversely correlated with neutrophil and monocyte count. IL-1 receptor antagonist (IL-1ra) and lactoferrin (Lf) plasma levels sharply increased and correlated with neutrophil and monocyte count. IL-10 increased five-fold on day +2, returned to pretreatment values thereafter and did not show any correlation with DNA SI, suggesting that it was not responsible for the observed phenomena. Interestingly, DNA SI of PHA-treated cultures inversely correlated with IL-1ra and Lf levels. CD3⁺ and CD19⁺ lymphocyte activation status, ie CD23, CD25, CD30 and HLA-DR coexpression, was not affected by rhG-CSF administration. Pharmacological doses of rhG-CSF in healthy donors inhibit lymphocyte blastogenesis via an increased production and/or release of immunoregulatory soluble mediators, ie IL-1ra and Lf, by primed neutrophils and monocytes.