Cellular and molecular effects of recombinant interferon gamma in chronic granulomatous disease.
We have examined the potential of IFN-gamma to ameliorate the physiologic defect of CGD by studying its effects on CGD phagocyte superoxide generation, NADPH-oxidase kinetics, and expression of the gene for the phagocyte cytochrome b heavy chain. In vitro treatment with IFN-gamma increased the respiratory burst activity of PMN and macrophages from three patients in two kindreds with type IA (variant, X-linked). Phagocytes from type I (classic, X-linked) and types IIA and III (autosomal recessive) CGD did not respond to IFN-gamma in vitro. Preliminary studies of in vivo treatment of several of the same patients with subcutaneous IFN-gamma demonstrated similar responses. All subjects whose phagocytes had responded in vitro showed complete or partial correction of the CGD defect in superoxide generation for up to 1 month after IFN-gamma administration. One patient with type I CGD with no detectable in vitro response also showed improved phagocyte respiratory burst activity after in vivo IFN-gamma treatment. These studies establish the potential efficacy of IFN-gamma in the treatment of patients with X-linked CGD and provide an example of pharmacologic modulation of gene expression in human disease. The ease of administration and absence of toxicity suggest a place for IFN-gamma as an adjunct to more conventional antimicrobial therapy during acute infections in CGD and perhaps even other congenital and acquired immunodeficiency states.
Newburger
P E
PE
University of Massachusetts Medical School, Worcester.
Ezekowitz
R A
RA
D003573:Cytochrome b Group / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006105:Granulomatous Disease, Chronic / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D019255:NADPH Oxidases; D010101:Oxygen Consumption; D010586:Phagocytes / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013481:Superoxides / Q000378:metabolism
D003573:Cytochrome b Group; D011994:Recombinant Proteins; D013481:Superoxides; D007371:Interferon-gamma; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases