1. ^*Department of Pediatrics (Hematology/Oncology), Indiana University School of Medicine, Indianapolis, Indiana, USA
2. ^†Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
3. ^‡Department of Pathology, and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA

Correspondence: Mary C. Dinauer, MD, PhD, Cancer Research Institute R4, 402A, Indiana University School of Medicine, 1044 W. Walnut Street, Indianapolis, IN 46202, USA. Email: mdinauer@iupui.edu

Received 18 March 2005; Revised 2 June 2005; Accepted 24 June 2005.

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.