Variable correction of host defense following gene transfer and bone marrow transplantation in murine X-linked chronic granulomatous disease

Chronic granulomatous disease (CGD) is an inherited immunodeficiency in whi ch the absence of the phagocyte superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase results in recurrent bacterial and f ungal infections. A murine model of X-linked CGD (X-CGD) was used to explor e variables influencing reconstitution of host defense following bone marro w transplantation and retroviral-mediated gene transfer. The outcomes of ex perimental infection with Aspergillus fumigatus, Staphylococcus aureus, or Borkholderia cepacia were compared in wild-type, X-CGD mice, and transplant ed X-CGD mice that were chimeric for either wild-type neutrophils or neutro phils with partial correction of NADPH oxidase activity after retroviral-me diated gene transfer, Host defense to these pathogens was improved in X-CGD mice even with correction of a limited number of neutrophils. However, int act protection against bacterial pathogens required relatively greater numb ers of oxidant-generating phagocytes compared to protection against A fumig atus, The host response also appeared to be influenced by the relative leve l of cellular NADPH oxidase activity, particularly for A fumigatus. These r esults may have implications for developing effective approaches for gene t herapy of CGD. (C) 2001 by The American Society of Hematology.