title: Variable correction of host defense following gene transfer and bone marrow transplantation in murine X-linked chronic granulomatous disease.
abstract: Chronic granulomatous disease (CGD) is an inherited immunodeficiency in which the absence of the phagocyte superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase results in recurrent bacterial and fungal infections. A murine model of X-linked CGD (X-CGD) was used to explore variables influencing reconstitution of host defense following bone marrow transplantation and retroviral-mediated gene transfer. The outcomes of experimental infection with Aspergillus fumigatus, Staphylococcus aureus, or Burkholderia cepacia were compared in wild-type, X-CGD mice, and transplanted X-CGD mice that were chimeric for either wild-type neutrophils or neutrophils with partial correction of NADPH oxidase activity after retroviral-mediated gene transfer. Host defense to these pathogens was improved in X-CGD mice even with correction of a limited number of neutrophils. However, intact protection against bacterial pathogens required relatively greater numbers of oxidant-generating phagocytes compared to protection against A fumigatus. The host response also appeared to be influenced by the relative level of cellular NADPH oxidase activity, particularly for A fumigatus. These results may have implications for developing effective approaches for gene therapy of CGD. (Blood. 2001;97:3738-3745)
authors.affiliation: Herman B Wells Center for Pediatric Research, Department of Pediatrics (Hematology/Oncology, James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202, USA. mdinauer@iupui.edu
authors.forename: M C
authors.initials: MC
authors.lastname: Dinauer
authors.forename: M A
authors.initials: MA
authors.lastname: Gifford
authors.forename: N
authors.initials: N
authors.lastname: Pech
authors.forename: L L
authors.initials: LL
authors.lastname: Li
authors.forename: P
authors.initials: P
authors.lastname: Emshwiller
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000517:prevention & control / Q000628:therapy; D016026:Bone Marrow Transplantation / Q000379:methods*; D019121:Burkholderia Infections / Q000517:prevention & control / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D008040:Genetic Linkage; D006105:Granulomatous Disease, Chronic / Q000150:complications / Q000201:enzymology / Q000628:therapy*; D016867:Immunocompromised Host / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology / Q000637:transplantation; D013203:Staphylococcal Infections / Q000517:prevention & control / Q000628:therapy; D018183:Transplantation Chimera; D014960:X Chromosome
chemical_list: D019255:NADPH Oxidases