In Vitro and In Vivo Effects of Granulocyte Colony-Stimulating Factor on Neutrophils in Glycogen Storage Disease Type IB: Granulocyte Colony-Stimulating Factor Therapy Corrects the Neutropenia and the Defects in Respiratory Burst Activity and Ca²⁺ Mobilization

Abstract

ABSTRACT: Children with glycogen storage disease (GSD) type 1b are susceptible to recurrent bacterial infections and have chronic neutropenia accompanied by phagocytic cell dysfunction including decreased superoxide anion (O₂⁻) generation, calcium (Ca²⁺) mobilization, and chemotactic activity. Granulocyte colony-stimulating factor (G-CSF), a cytokine that corrects neutropenia in other diseases, in vitro enhances f-Met-Leu-Phe-triggered neutrophil O₂⁻ generation. Short-term pretreatment (15 min) of GSD 1b neutrophils with G-CSF increased the rate of O₂⁻ production (p < 0.01); however, this rate was still significantly below the rate of O₂⁻ production in control neutrophils. Recombinant human G-CSF (5 μg/kg/d) was administered s.c. to a GSD 1b patient. Before treatment, absolute neutrophil counts were < 500/mm³. Two d after G-CSF administration, the absolute neutrophil counts increased to 1333 and remained in the normal range during a 12-mo follow-up period. In vivo, G-CSF therapy increased f-Met-Leu-Phe-stimulated O₂⁻ production to 52% of control after 1 mo, and by mo 4, O₂⁻ production reached control levels. Our previous studies (J Clin Invest 56:196–202, 1990) demonstrated that decreased O₂⁻ production in neutrophils was associated with impaired Ca²⁺ mobilization. In vivo administration of G-CSF increased f-Met-Leu-Phe-triggered Ca²⁺ mobilization by neutrophils to 43% of control by mo 1 of G-CSF therapy and to 93% of control by mo 4, thus paralleling the improvements in O₂⁻ generation. In contrast, G-CSF therapy had no effect on the defective neutrophil chemotaxis. In summary, G-CSF therapy produced a rapid increase in circulating neutrophils and a gradual correction of O₂⁻ production. Long-term exposure to G-CSF may be required for correction of both neutropenia and O₂⁻ production in GSD 1b patients.