title: Gene correction reduces cutaneous inflammation and granuloma formation in murine X-linked chronic granulomatous disease.
abstract: Our laboratory previously demonstrated that X-linked chronic granulomatous disease (X-CGD) mice develop exaggerated inflammatory responses and form granulomas following intradermal challenge with sterile Aspergillus fumigatus (AF) hyphae. In this study, we examined the efficacy of retroviral-mediated gene transfer (RMGT) into X-CGD bone marrow stem cells in preventing this abnormal inflammatory response. Sterile AF or saline was injected subcutaneously into the ears of wild-type, female X-CGD carrier, X-CGD, or X-CGD mice chimeric for varying numbers of either wild-type or RMGT-corrected neutrophils. Intradermal AF induced marked inflammation at both 3 and 30 d in the X-CGD mice, but not in the carriers or the wild-type mice. Similar to wild-type mice, chimeric X-CGD mice with >20% oxidase-positive neutrophils displayed a minimal and self-limited inflammatory response. Inflammation in chimeric (both wild-type and RMGT-corrected) mice with <15% oxidase-positive neutrophils was also improved compared to X-CGD mice, although still abnormal. This is the first evidence that partial correction of NADPH oxidase activity by gene therapy is likely to be beneficial in reducing or preventing the chronic inflammatory complications of CGD patients if sufficient numbers of RMGT-corrected neutrophils are obtained.
authors.affiliation: Department of Pediatrics (Hematology/Oncology), Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: W Scott
authors.initials: WS
authors.lastname: Goebel
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Mark
authors.forename: Steven D
authors.initials: SD
authors.lastname: Billings
authors.forename: Justin L
authors.initials: JL
authors.lastname: Meyers
authors.forename: Nancy
authors.initials: N
authors.lastname: Pech
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Travers
authors.forename: Mary C
authors.initials: MC
authors.lastname: Dinauer
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus; D003872:Dermatitis / Q000517:prevention & control*; D005260:Female; D008040:Genetic Linkage; D015316:Genetic Therapy; D006099:Granuloma / Q000517:prevention & control*; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D014960:X Chromosome
chemical_list: D008562:Membrane Glycoproteins; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases