Dose-dependent enhancements by interferon-gamma on functional responses of neutrophils from chronic granulomatous disease patients.
Interferon-gamma (IFN-gamma) is recommended as prophylaxis against infections in patients with chronic granulomatous disease (CGD). However, since the optimal dose, the dosing interval, and the mechanisms of action are not well-defined, we studied the effects on CGD neutrophil (PMN) functions ex vivo of interferon-gamma (IFN-gamma). Evaluations were made on oxidative capacity, measured by superoxide anion production and chemiluminescence after stimulation with f-met-leu-phe (f-MLP) or phorbol-myristate-acetate, the killing of Aspergillus fumigatus hyphae (assessed as conversion of the tetrazolium salt MTT to formazan), and on the expression of Fc gammaRI receptor (CD64). After randomization, 9 CGD patients (4 with gp91phox, 3 with p47phox, 1 with p67phox deficiency and 1 with unspecified CGD) were given IFN-gamma, either 50 or 100 microg/m2 subcutaneously on 2 consecutive days after double blinded randomization. Furthermore, one female hyperlyonized X-linked carrier with a CGD phenotype was also studied separately after IFN-gamma treatment. Evaluations were made the day before and on days 1, 3, 8, and 18 after IFN-gamma administration. The killing of A fumigatus hyphae, being close to zero before IFN-gamma, was enhanced on day 3, being 36% higher than pretreatment values in the high-dose CGD group and 17% in the low-dose group. The expression of Fc gammaRI on PMN increased 3.7-fold in the high-dose and 2.3-fold in the low-dose CGD group, being maximal on day 1. Oxidative functions were raised in only selected patients represented by different subtypes of CGD. The hyperlyonized carrier of X-linked CGD responded to IFN-gamma with more enhanced oxidative responses and Aspergillus killing of her PMNs than the other patients. This study suggests that a higher dose of IFN-gamma than currently recommended confers transient enhancements of certain PMN functions in CGD patients.
Ahlin
A
A
Department of Pediatrics, The Karolinska Institute at Sachs' Children's Hospital, Stockholm, Sweden.
Elinder
G
G
Palmblad
J
J
D000293:Adolescent; D000328:Adult; D001230:Aspergillus; D002648:Child; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000097:blood / Q000235:genetics / Q000628:therapy*; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology / Q000627:therapeutic use*; D007700:Kinetics; D008163:Luminescent Measurements; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009245:NADH Dehydrogenase / Q000172:deficiency; D009252:NADPH Dehydrogenase / Q000172:deficiency; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010587:Phagocytosis / Q000187:drug effects; D010750:Phosphoproteins / Q000172:deficiency; D011994:Recombinant Proteins; D013481:Superoxides / Q000097:blood; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D011994:Recombinant Proteins; C079789:neutrophil cytosol factor 67K; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D007371:Interferon-gamma; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D009252:NADPH Dehydrogenase; D009245:NADH Dehydrogenase; D013755:Tetradecanoylphorbol Acetate