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Recombinant human interferon-gamma reconstitutes defective phagocyte function in patients with chronic granulomatous
J M Sechler1, H L Malech, C J White
1Bacterial Diseases Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892.
Insights
Recombinant human interferon-gamma (rHuIFN-gamma) partially corrects the phagocyte defect in chronic granulomatous disease (CGD) patients. This treatment improved bacterial killing and superoxide production in patients with CGD.
Area of Science:
- Immunology
- Genetics
Background:
- Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by impaired phagocyte function.
- Patients with CGD are susceptible to recurrent, life-threatening infections due to defective microbicidal activity.
Purpose of the Study:
- To evaluate the in vitro and in vivo efficacy of recombinant human interferon-gamma (rHuIFN-gamma) in patients with chronic granulomatous disease (CGD).
- To assess the impact of rHuIFN-gamma on phagocyte function, including superoxide production and bactericidal activity.
Main Methods:
- Monocytes from CGD patients were treated with rHuIFN-gamma in vitro and stimulated to assess superoxide production.
- A subset of patients received subcutaneous rHuIFN-gamma therapy.
- Phagocyte bactericidal activity against Staphylococcus aureus and superoxide production were measured before, during, and after treatment.
Main Results:
- In vitro, rHuIFN-gamma induced superoxide production in monocytes from 19 of 30 CGD patients, particularly those with cytochrome b-positive CGD.
- In vivo, rHuIFN-gamma treatment led to significant improvements in phagocyte bactericidal activity and superoxide production.
- The therapeutic effects persisted for over a week after cessation of treatment.
Conclusions:
- Recombinant human interferon-gamma (rHuIFN-gamma) demonstrates partial correction of the phagocyte defect in CGD patients.
- A significant proportion of CGD patients may benefit from rHuIFN-gamma therapy, enhancing their phagocyte microbicidal function.
- The study suggests a potential therapeutic role for rHuIFN-gamma in managing CGD.
Abstract:
Monocytes from 19 of 30 patients with the classic phenotype of chronic granulomatous disease of childhood (CGD) responded to 3 days of treatment in culture with recombinant human interferon-gamma (rHuIFN-gamma) at 100 units/ml by producing superoxide after stimulation with phorbol 12-myristate 13-acetate. Cells from 15 of 16 patients with cytochrome b-positive CGD (15 with autosomal and 1 with X chromosome-linked inheritance) and cells from 4 of 14 patients with cytochrome b-negative CGD (13 with X chromosome-linked and 1 with autosomal recessive inheritance) responded. Subcutaneous rHuIFN-gamma (0.01-0.05 mg/m2) administered as a single dose, daily or every other day, for five or six doses to 3 patients whose phagocytes responded to rHuIFN-gamma in vitro resulted in significant improvement in phagocyte bactericidal activity against Staphylococcus aureus and increases in superoxide production. Studies on 1 patient's cells indicated the increases in superoxide production correlated with increased membrane cytochrome b. The effects of rHuIFN-gamma persisted for more than a week following cessation of therapy. Thus, we have demonstrated a partial correction in vivo of these CGD patients' phagocyte defect with rHuIFN-gamma. Moreover, the data suggest that a significant proportion of patients with CGD will respond to rHuIFN-gamma with augmentation of phagocyte microbicidal function.