title: Restoration of phagocyte function by interferon-gamma in X-linked chronic granulomatous disease occurs at the level of a progenitor cell.
abstract: Phagocytes from X-linked chronic granulomatous disease (X-CGD) patients are deficient in their ability to generate superoxide because of a defective gene that encodes a heavy chain of cytochrome b, a critical component in the superoxide-generating pathway. Previously we have shown that a single in vivo treatment of selected X-CGD patients with interferon-gamma (INF-gamma) resulted 14 days later in near-normal levels of superoxide generation by phagocytes. The effect persisted for 28 days. This prolonged effect suggested that the lymphokine affected progenitor cells. In this study, we examined progenitor-derived colonies from the peripheral blood from this unusual X-CGD kindred. Progenitor-derived colonies examined before treatment were unable to generate superoxide as visualized by lack of nitro blue tetrazolium (NBT) reduction compared with normal controls. By contrast, colonies derived 7 days after a single INF-gamma injection were able to generate superoxide as shown by increased NBT reduction. Colonies harvested 21 days after treatment contained only rare cells capable of NBT reduction. Our results indicate that INF-gamma can reprogram the myeloid progenitor cells to express a partially corrected phenotype. This corrected phenotype is later expressed in daughter cells.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital, Boston, MA 02115.
authors.forename: R A
authors.initials: RA
authors.lastname: Ezekowitz
authors.forename: C A
authors.initials: CA
authors.lastname: Sieff
authors.forename: M C
authors.initials: MC
authors.lastname: Dinauer
authors.forename: D G
authors.initials: DG
authors.lastname: Nathan
authors.forename: S H
authors.initials: SH
authors.lastname: Orkin
authors.forename: P E
authors.initials: PE
authors.lastname: Newburger
mesh_terms: D002454:Cell Differentiation; D008040:Genetic Linkage; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D006651:Histocytochemistry; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D009580:Nitroblue Tetrazolium; D010586:Phagocytes / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D010641:Phenotype; D013481:Superoxides / Q000378:metabolism; D014960:X Chromosome
chemical_list: D013481:Superoxides; D009580:Nitroblue Tetrazolium; D007371:Interferon-gamma