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Cellular and molecular effects of recombinant interferon gamma in chronic granulomatous disease
1University of Massachusetts Medical School, Worcester.
Insights
Interferon-gamma (IFN-gamma) shows potential in treating X-linked chronic granulomatous disease (CGD). This therapy can improve phagocyte function, offering a new adjunct treatment for infections.
Area of Science:
- Immunology
- Genetics
- Pharmacology
Background:
- Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by defective phagocyte superoxide generation.
- The underlying defect involves mutations in the NADPH oxidase complex, crucial for pathogen killing.
Purpose of the Study:
- To investigate the therapeutic potential of interferon-gamma (IFN-gamma) in ameliorating the physiologic defect in CGD.
- To assess the effects of IFN-gamma on phagocyte superoxide generation, NADPH-oxidase kinetics, and gene expression in CGD patients.
Main Methods:
- In vitro and in vivo studies involving IFN-gamma treatment of phagocytes from CGD patients.
- Assays for superoxide generation and NADPH-oxidase activity.
- Analysis of phagocyte cytochrome b heavy chain gene expression.
Main Results:
- In vitro IFN-gamma treatment enhanced respiratory burst activity in PMNs and macrophages from patients with type IA (variant, X-linked) CGD.
- Phagocytes from other CGD types (I, IIA, III) showed no in vitro response.
- In vivo IFN-gamma administration led to partial or complete correction of superoxide generation defects in responsive patients for up to one month.
- One patient with type I CGD, unresponsive in vitro, showed improved respiratory burst activity after in vivo IFN-gamma treatment.
Conclusions:
- IFN-gamma demonstrates potential efficacy in treating X-linked CGD by pharmacologically modulating gene expression.
- Its ease of administration and lack of toxicity suggest IFN-gamma as an adjunct therapy for CGD infections and potentially other immunodeficiencies.
Abstract:
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.